Medical Policy: 07.03.11 

Original Effective Date: April 2018 

Reviewed: April 2019 

Revised: July 2019 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Traditionally, high-dose chemotherapy, also known as myeloablative therapy, and extensive radiation therapy have been used to treat certain drug-resistant cancers or relapsed diseases. High-dose chemotherapy and radiation generally affect cells that divide rapidly, and cancer cells divide more often than most healthy cells. High-dose chemotherapy involves the administration of cytotoxic agents at doses several times greater than the standard therapeutic dose.

 

The rationale for high-dose chemotherapy is that many chemotherapeutic agents act according to a steep dose-response curve. Small increments in drug dosage result in relatively large increases in tumor cell destruction. The limiting dynamic of high-dose chemotherapy and radiation therapy is the toxic effect that these treatments have on bone marrow cells. Although high-dose chemotherapy kills the tumor cells, it also increases the incidence and severity of adverse effects associated with chemotherapy, such as bone marrow destruction (myeloablation), opportunistic infection, hemorrhage, and organ failure.

 

Bone marrow is a soft, spongelike material found inside bones. Bone marrow contains cells known as hematopoietic, or blood-forming, cells. Hematopoietic stem cells either divide to form additional blood-forming stem cells, or they mature to form one of three types of cells: white cells (leukocytes), red blood cells (erythrocytes), or platelets. Most hematopoietic stem cells are found in bone marrow, but some are also found in the bloodstream and are known as peripheral blood stem cells. Blood in the umbilical cord also contains hematopoietic stem cells. In individuals who have undergone high-dose chemotherapy and radiation, hematopoietic stem cell transplantation can be used to regenerate bone marrow and aid in the development of mature blood cell products, thereby decreasing the incidence of life-threatening conditions and aiding in the individual's recovery.

 

Hematopoietic stem cell transplantation (also referred to as bone marrow transplantation) are used to restore stem cells destroyed by high-dose chemotherapy and radiation therapy. Transplantation is accomplished in the same manner as a blood transfusion.

 

The transplantation of hematopoietic stem cells is an adjunctive therapy and follows the administration of high-dose chemotherapy and/or whole-body or localized radiotherapy prior to the transplant. The transplantation of hematopoietic stem cells has been found to increase the efficacy of high-dose chemotherapy and/or radiotherapy in the treatment of certain conditions including but not limited to the following: leukemias, lymphomas (e.g, Hodgkin's lymphoma, Non-Hodkin’s lymphoma), central nervous system tumors (embryonal), multiple myeloma, solid tumors of childhood, amyloidosis, some genetic diseases and acquired anemias.

 

Transplants are classified as one of three types:

  • Autologous: an individual receives his or her own stem cells
  • Allogeneic: an individual receives stem cells from another individual. They can be from a matched related or unrelated donor or donor without a complete match

 

Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplant)

In autologous hematopoietic stem cell transplantation, the individual receives his or her own stem cells, which were harvested prior to myeloablative therapy and are relatively cancer-free. Myeloablative chemotherapy is performed to eradicate cancerous cells from the blood and bone marrow, thereby permitting subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic progenitor cells or cells that allow themselves to differentiate from other cells. As a result, autologous stem cell transplantation is typically performed as consolidation therapy when the individual's disease is in complete remission. Individuals who receive autologous stem cell transplantation are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not graft-versus-host disease.

 

High-dose chemotherapy, in conjunction with autologous hematopoietic stem cell transplantation, is the established standard of therapy for various malignancies including but not limited to acute myelogenous leukemia, multiple myeloma, and non-Hodgkin's lymphoma. Autologous hematopoietic stem cell transplantation is also preferred for the elderly or for individuals who lack a donor with suitable HLA typing. Advantages of autologous transplants include the reduced toxicity that is associated with treatment and an extended, disease-free survival time, most often without the need for additional treatment.

 

Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplant)

Allogeneic hematopoietic stem cell transplantation involves using hematopoietic stem cells harvested from another individual. They can be from a matched related or unrelated donor or a donor without a complete match. The success of the transplant depends in part on how well the HLAs of the donor’s stem cells match those of the recipient’s stem cells. HLAs are a set of proteins that are found on the surface of cells and are identifiable by a special blood test, the higher the number of matching HLAs between the individuals, the greater the chance that the recipient will accept the donor’s stem cells. Close relatives, especially siblings, are more likely than unrelated individuals to be HLA-matched (6/6 HLA match); however, only 25 to 35 percent of transplant candidates have a sibling who is an HLA match.

 

A syngeneic allogeneic stem cell transplant is when the patient receives donor stem cells from his or her healthy identical twin.

 

For patients who lack an HLA-matched sibling (6/6 HLA match), alternative sources of donors include suitably HLA-matched unrelated donors, umbilical cord blood stem cells, and partially HLA-mismatched, or HLA-haploidentical related donors.

 

Umbilical Cord Stem Cells

Blood harvested from the umbilical cord shortly after delivery of neonates contains stem and progenitor cells capable of restoring hematopoietic function after myeloablation. This cord blood has been used as an alternative source of allogeneic stem cells. Cord blood is readily and is thought to be antigenically naïve, thus potentially minimizing the incidence of graft-versus-host disease and permitting the broader use of unrelated cord blood transplants. Unrelated donors are typically typed at low resolution for human leukocyte antigen (HLA) A and B and a high resolution only for HLA-DR; HLA matching at 4 of 6 loci is considered acceptable. Under this matching protocol, an acceptable donor can be identified for almost any patients. Cord blood requires no mobilization, once collected it is mixed in a preservation solution and stored at a very low temperature until needed.

 

Haploidentical Donor

An HLA-haploidentical donor is one who shares, by common inheritance, exactly one HLA haplotype with the recipient and is mismatched for a variable number of HLA genes, ranging from zero to six, on the unshared haplotype. Potential HLA-hapoidentical donors include biological parents, biological children, full or half siblings.

 

Only a related donor can be deemed to be HLA-haploidentical to a recipient because the Sanger-based sequencing methods widely used for high resolution HLA typing cannot determine whether nucleotides at polymorphic sites are located on the same (cis-position) or on different (trans-position) chromosome, and so alleles are assigned to haplotypes only with an assumption of relatedness.

 

When available a matched sibling is preferred over other donor sources due to clinical outcomes following transplant (e.g. less graft versus-host disease [GVHD] and the speed and cost-effectiveness of the search). When a matched sibling donor is not available, the transplant center usually proceeds with an unrelated donor search. Alternative donor sources i.e. HLA-haploidentical may be considered if there is an urgent need to proceed to transplantation or if the preliminary search indicates a low likelihood of finding an eight of eight allele-matched unrelated donor.

 

Hapolidentical allogeneic stem cell transplant is a treatment option that is not offered in all transplant centers.

 

Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) consists of the following conditioning regimens:

  • Myeloablative is a severe form of myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is a side effect of some cancer treatments prior to receiving the donor’s marrow or stem cells.
  • Non-myeloablative (also knowns as reduced intensity conditioning) is a bone marrow transplant in which the individual’s marrow is not completely destroyed prior to receiving the donor’s marrow or stem cells

 

Reduced intensity conditioning regimens (non-myeloablative) would be considered for individuals who would otherwise qualify for a myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), but would not tolerate standard myeloablative conditioning regimen. This may include the following: age typically > 60 years or comorbidities (e.g. liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score).

 

Tandem Transplantation

Tandem transplantation is a type of stem cell transplantation in which the individual receives two sequential courses of high-dose chemotherapy and stem cell therapy that are typically given within six months of each other.

 

Stages of Transplantation

Hematopoietic stem cell transplantation (bone marrow transplantation) involves the mobilization, harvesting, and transplantation of hematopoietic stem cells that have been collected from bone marrow or peripheral blood.

 

Mobilization

Preparing for a hematopoietic stem cell transplantation first requires stem cell mobilization. Mobilization makes harvesting more efficient and occurs when the accumulation of stem cells has reached its highest level.

 

Prior to harvesting, autologous blood stem cell donors are occasionally given a course of chemotherapy to destroy some of the malignant tumors in their body. This low-dose chemotherapy reduces the risk for tumor contamination and facilitates the filtering of stem cells for collection. Autologous donors may also receive injections of a colony-stimulating factor. Colony-stimulating factors are groups of proteins that cause blood cells to grow and mature, which facilitates mobilization. In some cases, a combination of chemotherapy and colony-stimulating factor is used.

 

In allogeneic donors, mobilization is accomplished through a series of subcutaneous injections of colony-stimulating factors (i.e., granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]). Typically, the colony-stimulating factor is administered for 4 to 5 days, followed by apheresis, which generally occurs over the next day or two. Apheresis, also called pheresis, is a procedure in which blood is collected, the stem cells are removed, and the remaining blood is given back to the donor. The stem cells are frozen until they are given to the recipient.

 

Harvesting

After mobilization, hematopoietic stem cells can be harvested from bone marrow and/or peripheral blood. Harvesting from bone marrow involves inserting a hollow needle into the pelvic (hip) bone or, in rare cases, the sternum (breastbone), under general or regional anesthesia. The procedure takes about 1 hour. The cells are harvested prior to myeloablative therapy. The harvested cells can sometimes be treated before transplantation in a process known as purging. This process reduces the number of cancer cells, thereby minimizing the likelihood that cancer will recur. Because purging may damage healthy stem cells, an excess of cells is removed from the individual prior to transplantation so that an adequate supply of healthy stem cells will remain after purging.

 

In most instances, the harvested marrow is filtered and given to the recipient on the same or next day. If the transplantation cannot occur within that timeframe, the marrow can be combined with a preservative solution and frozen until needed. Known as cryoablation, this technique can preserve the harvested marrow for years. When the recipient is ready to receive the marrow, it is thawed and transfused in a procedure that is similar to a blood transfusion. The hematopoietic stem cells are then drawn to the bone marrow, where they start to grow and produce new blood cells.

 

In individuals undergoing peripheral blood stem cell transplantation, stem cells are removed from the bloodstream via apheresis. The purpose of therapeutic apheresis is to remove a component of the blood that contributes to an illness. In apheresis, blood is removed through a large vein in the arm or a central venous catheter (a flexible tube that is placed in a large vein in the neck, chest, or groin area) and sent to sterile equipment, where it is separated into various components, such as red cells, white cells, and plasma. Healthy parts of the blood are then returned to the individual. Apheresis typically takes 4 to 6 hours. For 4 or 5 days before apheresis, the donor may be given a medication to increase the number of stem cells released into the bloodstream.

 

Transplantation

Upon entering the bloodstream, the stem cells travel to the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets in a process known as engraftment. Engraftment typically occurs within 2 to 4 weeks after transplantation, and is monitored by blood counts. Following the transplant, full recovery of the immune system may take several months for autologous transplantation recipients and as much as 1 to 2 years for individuals receiving allogeneic transplantation. A bone marrow aspiration may also be performed to determine the progress of the new marrow.

 

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

Acute Lymphoblastic Leukemia (Adult and AYA) Version 2.2019
NCCN Recommendations for Ph-Positive ALL

AYA Patients with Ph-Positive ALL

For AYA patients experiencing a CR after initial induction therapy, an MRD assessment should be performed prior to consolidation with allogeneic HCT if a matched donor is available. The optimal time for a patient to receive an allogeneic HCR is unclear; however, for fit patients, additional therapy may be considered to eliminate MRD before transplant. In younger AYA patients (age ≤ 21 years) emerging data suggest that allogeneic HCT may not confer an advantage over chemotherapy combined with TKIs.

 

For patients without a donor, consolidation therapy after a CR should comprise a continuation of multiagent chemotherapy combined with a TKI. These patients should continue to receive post-consolidation maintenance therapy with a regimen that includes a TKI.

 

Adult Patients with Ph-Positive ALL

Although the age cutoff indicated in the guidelines has been set at 65 years, it should be noted that chronologic age alone is not a sufficient surrogate for defining fitness; patients should be evaluated on an individual basis to determine fitness for therapy based on factors such as performance status, end organ function and end organ reserve.

 

For relatively fit adult patients (age < 65 years without substantial comorbidities), the recommended treatment approach is similar to that for AYA patients. Induction therapy would comprise multiagent chemotherapy combined with a TKI. For patients experiencing a CR after induction, an MRD assessment should be performed prior to consolidation with allogeneic HCT if a matched donor is available. Similar to treatment strategy for AYA patients, the optimal time for a patient to receive allogeneic HCT is unclear; however, for fit patients, additional therapy may be considered to eliminate MRD before transplant.

 

For patients without a donor, consolidation therapy after a CR should comprise a continuation of multiagent chemotherapy combined with TKI. These patients should continue to receive post consolidation maintenance therapy with a regimen that includes a TKI.

 

For adult patients who are less fit (age ≥ 65 years or with substantial comorbidities), the recommended induction therapy includes a TKI with corticosteroids or with low-intensity chemotherapy regimens.

 

Patients with Relapsed/Refractory Ph-Positive ALL

For all patients with relapsed for refractory Ph-positive ALL, participation in a clinical trial is preferred. In the absence of an appropriate trial, patients may be considered for second line therapy with an alternative TKI (i.e. different from the TKI used as part of induction therapy) alone, TKI comibined with multiagent chemotherapy, or TKI combined with corticosteroids (especially for elderly patients who may not tolerate multiagent combination therapy). These options should be combined with allogeneic HCT in the eligible patient if a donor is available.

 

Acute Lymphoblastic Leukemia (Pediatric) Version 1.2020
Principles of Hematopoietic Stem Cell Transplant
  • Indications for HSCT (B-cell) in First Remission
    • Unfavorable cytogenetics
      • Consider HSCT if MLL/KMT2A mutation (<6 months in age) with high risk features
    • MRD
      • Consider HSCT if MRD ≥ 0.01% post consolidation (week 9-12 from diagnosis)
    • Other considerations
      • The role of HSCT for patients with hypodiploid ALL in CR1 has not yet been established even in patients who are MRD-positive at end-induction
        • HSCT for hypodiploid ALL may be considered in the setting of a clinical trial
      • HSCT is not indicated for Ph+ ALL in CR1 (while on TKI plus systemic chemotherapy)
      • For patients who are MRD positive (≥ 0.01%) at end-induction, there is insufficient evidence to suggest a survival advantage for HSCT, even in patients with kinase activating mutations (i.e. IKZF1, CDKN2A/B, PDGFRB, ABL1, ABL2, CSF1R, JAK2, CRLF, EPOR) or iAMP21
  • Indications for HSCT (B-cell) in Non-First Remission Settings
    • Induction failure (M3 marrow): recommend HSCT after achieving MRD negative status
    • CR2: consider HSCT based upon timing of relapse (or refractory disease) and leukemic phenotype
    • CR3: recommend HSCT
    • For a patient with CNS involvement at the time of relapse (or refractory disease), consider CNS boost at the time of administration of TBI. For those without CNS involvement at the time of relapse (or refractory disease), there is no clear evidence that CNS boost will prevent subsequent CNS relapse.
    • For relapsed for refractory disease
      • B-ALL first relapse – Medullary (isolated or combined)
        • <36 months from initial diagnosis, subsequent therapy
        • Consider HSCT – consideration for HSCT depends upon donor availablility and patients’s clinical status at the time of potential HSCT
      • B-ALL first relapse – Extramedullary (isolated)
        • <18 months from initial diagnosis, subsequent therapy
        • Consider HSCT – consideration for HSCT depends upon donor availablility and patient’s clinical status depends upon donor availability and patient’s clinical status at the time of potential HSCT
  • Indications for HSCT (T-cell)
    • HSCT should be considered for:
      • Patients with MRD positivity (>0.1%) at completion of consolidation. Additional therapy should be given prior to HSCT to achieve MRD negativity
      • Induction failure (M3 marrow)
      • Patients with medullary or extramedullary relapse (any time point) (see below)
    • For relapsed/refractory disease
      • T-ALL first relapse - Medullary (isolated or combined)
        • Any time point, subsequent therapy
        • Consider HSCT - consideration for HSCT depends upon donor availablility and patients’s clinical status at the time of potential HSCT
      • T-ALL first relapse – Extramedullary (isolated)
        • Any time point, subsequent thrapy
        • Consider HSCT - consideration for HSCT depends upon donor availablility and patients’s clinical status at the time of potential HSCT

 

Discussion section is under development.

 

Acute Myeloid Leukemia Version 3.2019
Management of Relapsed APL

Following completion of the first cycle of consolidation, if the patient does not enter molecular remission, a matched sibling or alternative donor (haploidentical, unrelated donor or cord blood) HCT or clinical trial is recommended.

 

The NCCN AMP Panel recommends enrollment in a clinical trial for treatment induction of younger patients (< 60 years) with AML (preferred).

 

Patients with antecedent hematologic disease or treatment related AML are considered poor-risk, unless they have favorable cytogenetics such as t(8;21), inv(16), t(16;16) or t(15;17). In addition, patients with unfavorable karyotypes, such as 11q23 abnormalities, monosomy -5 or -7, complex-cytogenetic abnormalities, are also considered to have poor risk. Although all patients with AML are best managed within the context of an appropriate clinical trial, it is particularly important that this poor-risk group of patients should be entered into a clinical trial (incorporating either chemotherapy or novel agents), if available, given that only 40% to 50% of these patients experience a CR with standard induction therapy, In addition, HLA testing should be performed promptly in those who may be candidates for either fully ablative or reduced intensity conditioning (RIC) allogeneic HCT from a matched sibling or an alternative donor, which constitutes the best option for long-term disease control.

 

Post Induction Therapy

If an HLA matched sibling or alternative donor has been identified, an allogeneic HCT may be effective in 25% to 30% of patients with induction failure.

 

Postremission or Consolidation Therapy

The panel has provided the following options for consolidation therapy for patients with favorable risk cytogenetics (those with CBF leukemia, without KIT mutations, or favorable-risk molecular abnormalities):

  1. Participation in a clinical trial; or
  2. 3 to 4 cycles of HiDAC (category 1)

 

There are not sufficient data to evaluate the use of allogeneic HCT in first remission for patients with AML and favorable risk cytogenetics outside of a clinical trial. However, outcomes in favorable risk patients who have KIT mutations are more similar to those of patients with intermediate risk karyotype, and these patients should be considered for either clinical trials targeted toward the molecular abnormality or consolidation strategies similar to those used in the intermediate risk group. A well designed plan for relapse therapy with either a matched sibling or alternate donor HCT should be an important part of the treatment decision for these patients.

 

The panel strongly recommends clinical trials as standard therapy for patients with poor prognostic features, which includes FLT3 abnormalities in the setting of otherwise NK-AML, high WBC (>50,000/mcl) at diagnosis, or 2 cycles of induction therapy needed to achieve CR. If cytogenic remission is observed, consolidation therapy is recommended. Allogeneic HCT with matched sibling or matched alternative donor (including umbilical cord blood products) as consolidation therapy for patients with poor risk cytogenetics or molecular abnormalities is a treatment option. HiDAC based consolidation may be required to maintain remission while searching for a potential matched donor.

 

Postremission Therapy

The role of myeloablative allogeneic HCT is limited in older patients because of significant comorbidities; however, ongoing interest has been shown in RIC (reduced intensity chemotherapy) allogeneic HCT as consolidation therapy.

 

Anal Carcinoma Version 1.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Bladder Cancer Version 4.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Bone Cancer Version 2.2019
Ewing Sarcoma

High Dose Therapy Followed by Stem Cell Transplant

High dose therapy followed by stem cell transplant (HDT/SCT) has been evaluated in patients with localized as well as metastatic disease. HDT/SCT has been associated with potential survival benefit in patients with non-metastatic disease. However, studies that have evaluated HDT/SCT in patients with primary metastatic disease have shown conflicting results.

 

All patients with Ewing Sarcoma should be treated with the following protocol: primary treatment followed by local control therapy and adjuvant treatment. Primary treatment consists of multiagent chemotherapy along with appropriate growth factor support for at least 9 weeks (category 1).

 

Relapsed or Refractory Disease

HDT/SCT has been associated with improved long-term survival in patients with relapsed or progressive Ewing Sarcoma in small, single institution studies. The role of this approach is yet to be determined in prospective randomized studies.

 

Breast Cancer Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Central Nervous System Cancers Version 1.2019
Medulloblastoma and Supratentorial PNET

Recurrence and Progression

Maximal safe resection should be attempted on recurrent brain tumors. High dose chemotherapy with autologous stem cell rescue may be considered for patients showing no evidence of disease following resection or conventional reinduction chemotherapy.

 

Primary CNS Lymphoma

Systemic Therapy

Several groups have tested high dose chemotherapy with autologous stem cell transplantation with some success, although evidence of its advantage over conventional treatment is lacking. The panel includes this as a category 2B option to consider for progressive or recurrent disease.

 

Progressive Disease

For patients who were initially treated with high dose methotrexate based chemotherapy but did not receive WBRT, the decision about whether to use more chemotherapy or proceed to RT at the time of relapse depends on the duration of response to initial chemotherapy. If a patient had experienced a relatively long-term response of one year or more, then treating either with the same or another regimen is reasonable. However, for patients who either have no response or relapsed within a very short time after systemic therapy, recommendations include WBRT or involved field RT, with or without chemotherapy. In either case, palliative/best supportive care remains an option, or high dose chemotherapy with stem cell transplantation may be considered (category 2B).

 

Cervical Cancer Version 4.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Version 4.2019

Current National Comprehensive Cancer Network Guidelines for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) state that allogeneic HCT may be considered for patients:

  • With relapsed/refractory CLL/SLL and without del(17p) or TP53 mutation
  • With CLL/SLL a response to treatment and with a complex karyotype (≥ 3 abnormalities)
  • With CLL progression, histological transformation to diffuse large B-cell lymphoma

 

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Version 5.2019

Indications for Allogeneic HCT

Allogeneic HCT can be considered for CLL/SLL refractory to small molecular inhibitor therapy in patients without significant comorbidities.

 

For patients with CLL/SLL with del(17p) or TP53 mutation, a discussion of allogeneic HCT could be considered for patients in remission with or without ibrutinib therapy, if complex karyotype (≥ 3 abnormalities) is present. However, available data suggest that complex karyotype (≥ 5 abnormalities) is associated with inferior OS and EFS following allogeneic HCT with reduced intensity conditioning in patients with high risk interphase cytogenetics.

 

Chronic Myeloid Leukemia Version 1.2019
Allogeneic Hematopoietic Cell Transplantation (HCT)

Allogeneic HCT is potentially curative treatment for patients with chronic myeloid leukemia (CML). Ongoing advances in alternative donor sources (such as unrelated donors and cord blood), more accurate HLA testing for a stringent selection of unrelated matched donors, and the use of reduced intensity conditioning regimens have improved outcomes following allogeneic HCT.

 

Allogeneic HCT is an appropriate treatment option for the very rare patients presenting with BP-CML at diagnosis, patients with disease that is resistant to TKIs, patients with progression to AP-CML or BP-CML while on TKI therapy, and for the rare patients intolerant to all TKIs.

 

Definition of Accelerated Phase

  • Peripheral blood blasts ≥ 15% and < 30%
  • Peripheral blood blasts and promyelocytes combined ≥ 30%
  • Peripheral blood basophils ≥ 20%
  • Platelet count < 100 x 109/L unrelated to therapy
  • Additional clonal cytogenetic abnormalities in Ph+ cells

 

Definition of Blast Phase

International Bone Marrow Transplant Registry

  • ≥ 30% blasts in the blood, marrow or both
  • Extramedullary infiltrates of leukemic cells

 

Colon Cancer Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Rectal Cancer Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Esophageal and Esophagogastric Junction Cancers Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Gastric Cancer Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Head and Neck Cancers Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Hepatobiliary Cancers Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Hodgkin Lymphoma (>18 years) Version 2.2019
NCCN Recommendations for Relapsed Disease

Suspected relapse should be confirmed with biopsy. Observation (with short-interval follow-up with PET/CT) is appropriate if biopsy is negative. Restaging is recommended for patients with positive biopsy. Second-line systemic therapy with or without ISRT or HDT/ASCR is the preferred treatment option for patients with stage IA or IIA disease who were initially treated with chemotherapy alone and experienced failure at the initial sites. RT alone (conventional or extended field treatment) may be appropriate for selected patients. All other patients experiencing disease relapse after initial treatment with chemotherapy or combined modality therapy should be treated with second-line systemic therapy.

 

Summary

HDTR/ASCR is the best treatment option for patients with refractory or relapsed CHL, although it does not improve OS. Second-line therapy (RT or second-line systemic therapy with or without RT) may be given prior to HDT/ASCR. Maintenance therapy with brentuximab vedotin (for one year) following HDT/ASCR is included as an option for patients with primary refractory disease.

 

Allogeneic HSCT with myeloablative conditioning has been associated with lower relapse rate in patients with relapsed or refractory disease; however, TRM was 50%. Allogeneic HSCT with reduced intensity conditioning has been reported to have decreased rates of TRM. However, this approach remains investigational. The panel has included allogeneic HSCT with a category 3 recommendations for select patients with refractory or relapsed disease.

 

Kidney Cancer Version 1.2020

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Malignant Pleural Mesothelioma Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Melanoma
  • Cutaneous Melanoma 2.2019
    • The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.
  • Uveal Melanoma 1.2019
    • The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Multiple Myeloma Version 3.2019
Stem Cell Transplantation

High dose therapy with stem cell support is a critical component in the treatment plan of eligible patients newly diagnosed with MM. The types of SCT may be single autologous SCT, a tandem SCT (a planned second course of high dose therapy and SCT within 6 months of the first course), or allogeneic SCT. An allogeneic SCT can be performed after prior myeloablative therapy or after nonmeyloablative therapy. Nonmyeloablative therapy, also referred to as “mini transplant,” has been investigated as a technique to decrease toxicity of the allotransplant while preserving the alloimmune graft-versus-myeloma effect. It is important to note that nonmyeloablative allogeneic transplant by itself is not adequate therapy and is usually done following maximal tumor control through adequate induction therapy or an autologous SCT. An allogeneic SCT may also follow an autologous SCT.

 

The NCCN Guidelines for Multiple Myeloma indicate that all types of SCT are appropriate in different clinical settings; these indications are discussed further below. In general, all candidates for high-dose chemotherapy must have sufficient liver, renal, pulmonary, and cardiac function. However, renal dysfunction is not an absolute contraindication to transplant.

  • Autologous Stem Cell Transplants:
    • According to the NCCN guidelines for transplant eligible patients autologous stem cell transplant (SCT) is an option after primary induction therapy (category 1) and for treatment of progressive/refractory disease after primary treatment.

Stem cell transplant for the treatment of progressive or relapsed myeloma for eligible patients who did not receive a stem cell transplant as part of their initial treatment.

  • Tandem Stem Cell Transplants:
    • Tandem SCT refers to a planned second course of high dose therapy and SCT (stem cell transplant) within 6 months of the first course. Planned tandem transplants have been studied in several randomized trials.

According to the NCCN Multiple Myeloma Panel, a tandem transplant with or without Maintenance therapy can be considered for all patients who are candidates for STC (stem cell transplant), and is an option for patients who do not achieve at least a VGPR (very good partial response) after the first autologous SCT.

 

A second autologous SCT (stem cell transplant) can be considered at the time of disease relapse. According to the NCCN Multiple Myeloma Panel, repeat autologous SCT for relapsed disease may be considered on or off clinical trial depending on the time interval between the proceeding SCT an documented progression. Data from retrospective studies suggest 2 to 3 years as the minimum length of remission for consideration of second autologous SCT for relapsed disease.

  • Allogeneic Stem Cell Transplant:

Allogeneic SCT includes either myeloablative or nonmyeloablative (i.e. mini transplant) transplants.

 

The NCCN guidelines consider myeloablative allogeneic SCT an accepted option, preferably in a clinical trial in; 1) patients whose disease responds to primary therapy; 2) patients with primary PD; or 3) patients with PD after an initial autologous SCT.

 

Footnote for relapse and progressive disease states: Allogeneic stem cell transplant may include nonmyeloablative (mini) following autologous stem cell transplant or fully myeolablative on a clinical trial. Current data do not support mini-allografting alone.

 

POEMS Syndrome

NCCN guidelines do not address the treatment of POEMS syndrome.

 

Systemic Light Chain Amyloidosis Version 1.2019
Primary Treatment

High dose melphalan followed by stem cell transplant (SCT) is one of the therapeutic options listed by the NCCN panel. However, patients have to be carefully selected as this treatment modality is associated with significant treatment related mortality. The extent of organ involvement is considered a predictor of outcome.

 

Definition of Organ Involvement Based on Amyloidosis Consensus Criteria
OrganDefinition of Organ Involvement
Kidney 24-h urine protein > 0.5 g/d, predominately albumin
Heart Echo: mean wall thickness > 12 mm, no other cardiac cause or an elevated NT-proBNP (>332 ng/L) in the absence of renal failure or atrial fibrillation
Liver Total liver span > 15 cm in the absence of heart failure or alkaline phosphatase > 1.5 times institutional upper limit or normal
Nerve Peripheral: Clinical; symmetric lower extremity sensorimotor peripheral neuropathy
Autonomic: gastric emptying disorder, pseudo-obstruction, voiding dysfunction not related to direct organ infiltration
Gastrointestinal tract Direct biopsy verification with symptoms
Lung Direct biopsy verification with symptoms
Interstitial radiographic pattern
Soft Tissue
  • Tongue enlargement
  • Clinical
  • Arthropathy
  • Claudication, presumed vascular amyloid
  • Skin
  • Myopathy by biopsy or psuedohypertrophy
  • Lymph node (may be localized)
  • Carpal tunnel syndrome

 

Waldenstrom’s MacroGlobulinemia/Lymphoplasmacytic Lymphoma Version 2.2019

SCT (stem cell therapy) is also an option for relapsed WM in selected patients. SCT options listed in the NCCN guidelines for WW/LPL are for high dose therapy with autologous stem cell rescue. According to the NCCN panel meyloablative or non-myeloablative allogeneic STC may be considered but preferably in the context of a clinical trial.

 

Myelodysplastic Syndromes Version 1.2018

Myelodysplastic syndromes (MDS) represent myeloid clonal hemopathies with a relative heterogenous spectrum of presentation. The major clinical problems in these disorders are morbidities caused by cytopenias and the potential of MDS to evolve into acute myeloid leukemia (AML).

 

The category of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) was added to the 2008 update of the WHO classification of myeloid neoplasm. This category includes chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative, and juvenile myleomonocytic leukemia (JMML) as disorders having overlapping dysplastic and proliferative features. The MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) and the MDS/MPN unclassified groups are also included in this category.

 

Recommended Treatment Approaches:

Therapy for lower risk patients (IPSS low, Intermediate-1; IPSS-R very low, low, intermediate; or WPSS very low, low, intermediate

Regarding the therapeutic options for lower risk patients with clinically significant cytopenias or increased bone marrow blasts, the NCCN Guidelines Panel recommends stratifying these patients into several groups. Patients with no response to hypomethylating agents or lenalidomide in this setting should be considered for participation in a clinical trial with other relevant agents, or for allogeneic HCT (see therapy for higher risk patients)

 

Therapy for higher risk patients (IPSS intermediate-2, high: IPSS-R intermediate, high, very high; or WPSS high, very high)

Treatment for higher risk patients is dependent on whether they are possible candidates for intensive therapy (e.g. allogeneic HCT, intensive chemotherapy). Clinical features relevant for this determination include patient age, performance status, absence of major comorbid conditions, psychosocial status, patient preference and availability of a suitable donor and caregiver. Patients may be taken immediately to transplant or bridging therapy can be used to decrease marrow blasts to an acceptable level prior to transplant. The patient’s personal preference for type of therapy needs particular consideration. Regardless supportive care should be provided for all patients.

 

Intensive Therapy – Allogeneic Hematopoietic Cell Transplantation

For patients who are transplant candidates, an HLA matched sibling or HLA-matched unrelated donor can be considered. Results with HLA-matched unrelated donor consideredhave improved to levels of comparable to .those obtained with HLA-matched siblings. With the increasing use of cord blood or HLA-haploididentical ralted donors, HCT has become a viable option for many patients. High dose conditioning is typically used for younger patients, whereas RIC for HCT is generally the strategy in older individuals.

 

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) WHO Classification
SubtypeBloodBone MarrowFrequent Mutations
Chronic myelomonocytic leukemia (CMML) - 0 gt;1 x 109/L monocytes, <2% blasts, monocytes Dysplasia in > 1 hematopoietic line, < 5% blasts TET2, SRSF2, ASKL1, RUNX1, NRAS, CBL
CMML-1 >1 x 109/L monocytes, 2%-4% blasts, > 10% monocytes Dysplasia in > 1 hematopoietic line, 5%-9% blasts TET2, SRSF2, ASXL1, RUNX1, NRAS, CBL
CMML-2 >1 x 109/L monocytes, 5%-19% blasts or Auer rods, > 10% monocytes Dysplasia in > 1 hematopoietic line, 10%-19% blasts or Auer rods TET2, SRSF2, ASKL1, RUNX1, NRAS, CBL
Atypical chronic myeloid leukemia (aCML), BCR-ABL negative WBC > 13 x 109/L, neutrophil precursors > 10%, < 20% blasts, dysgranulopoiesis Hypercellular < 20% blasts SETBP1, ETNK1
Juvenile myelomonocytic leukemia (JMML) >1 x 109/L monocytes, < 20% blasts, > 10% monocytes, increased HbF >1 x 109 monocytes < 20% blasts Ph negative GM-CSF hypersensitive PTPN11, NF1, N/KRAS, CBL, SETBP, JAK3
MDS/MPN unclassified (“Overlap syndrome”) Dysplasia + myeloproliferative features, no prior MDS or MPN Dysplasia + myeloproliferative features TET2, NRAS, RUNX1, CBL, SETBP1, ASKL1
MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) Dysplasia + myeloproliferative features, platelets > 450 x 109/L, > 15% ring sideroblasts Dysplasia + myeloproliferative features SF3B1, JAK2, MPL, CALR
Chronic neutrophilic leukemia (CNL) (BCR-ABL negative) WBC > 25,000 with PMN/bands > 80%, myeloid precursors < 10%, no dysplasia Mature myeloid hyperplasia, < 5% blasts, no dysplasia CSF3R (G-CSF receptor

 

Myeloproliferative Neoplasms Version 2.2019

Myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET) are a group of heterogenous disorders of the hematopoietic system collectively known as Philadelphia-chromosome-negative myeloproliferative neoplasm (MPN).

 

Treatment Recommendations Based on Symptom Assessment and Risk Stratification

The selection of appropriate treatment should be based on the risk score and the presence of symptoms. Enrollment in clinical trial is recommended for all patients with the aim of reducing bone marrow fibrosis, improving cytopenias and symptom burden, restoring transfusion independence, and preventing/delaying progression to AML.

 

Low Risk or Intermediate 1-Risk (Int-1 Risk) Myelofibrosis (MF)

Allogeneic HCT is included as an option for patients with INT-1-risk MF. Although the outcome following allogeneic HCT are better for patients with low-risk or INT-1-risk MF, due to the high transplant-related morbidity and mortality, treatment decisions regarding allogeneic HCT should be individualized for patients with INT-1-risk MF. Allogeneic HCT should be considered for low-risk or INT-1-risk MF in patients with either refractory, transfusion-dependent anemia; circulating blast cells > 2% in peripheral blood; or adverse cytogenetics. Evaluation for allogeneic HCT is recommended for patients with low platelet counts or complex cytogenetics.

 

Treatment for Intermediate Risk 2 (INT-2-Risk) or High-Risk Myelofibrosis (MF)

Evaluation for allogeneic HCT is recommended for all patients with INT-2-risk and high-risk MF. The selection of patients for allogeneic HCT should be based on age, performance status, major comorbid conditions, psychosocial status, patient preference, and availability of caregiver. Allogeneic HCT is recommended for patients with INT-2-risk or high-risk MF if they are candidates for transplant. Patients may be taken immediately to allogeneic HCT or bridging therapy can be used to decrease marrow blasts to an acceptable level prior to allogeneic HCT.

 

Disease progression to advanced phase or Transformation to Acute Myeloid Leukemia

Treatment options

Allogeneic HCT remains the only curative option resulting in long-term disease control in selected transplant-eligible patients who achieve a CR to induction chemotherapy.

 

Treatment Recommendations Based on Eligibility for Transplant

The selection of patients for allogeneic HCT should be based on age, performance status, major comorbid conditions, psychosocial status, patient preference, and the availability of caregiver. Patients may be taken immediately to transplant or bridging therapy can be used to decrease marrow blasts to an acceptable level prior to transplant.

 

Disease control/reduction in blast counts with hypomethylating agents (azacytidine or decitabine) or intensive AML-type induction chemotherapy followed by allogeneic HCT is recommended for patients who are candidates for transplant.

 

2017 WHO Diagnostic Criteria for Primary Myelofibrosis

WHO prePMF Criteria

(Diagnosis of prePMF requires all 3 major criteria, and at least 1 minor criterion)

  • Major criteria
    • Megakaryocytic proliferation and atypia, without reticulin fibrosis > grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased erythropoiesis
    • No meeting WHO criteria for BCR-ABL1 + CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms.
    • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of minor reactive BM reticulin fibrosis
  • Minor criteria
    • Presence of at least one of the following, confirmed in 2 consecutive determinations:
      • Anemia not attributed to a comorbid condition
      • Leukocytosis ≥ 11 x 109/L
      • Palpable splenomegaly
      • LDH increased to above upper normal limit of institutional reference range

 

WHO Overt PMF criteria

(Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criteria)

  • Major criteria
    • Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3
    • Not meeting WHO criteria for ET, PV, BCR-ABL + CML, myelodysplastic syndromes, or other myeloid neoplasms
    • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clona markers, or absence of reactive myelofibrosis
  • Minor criteria
    • Presence of at least one of the following, confirmed in 2 consecutive determinations:
      • Anemia not attributed to a comorbid condition
      • Leukocytosis ≥ 11 x 109/L
      • Palpable splenomegaly
      • LDH increased to above upper normal limit of institutional reference range
      • Leukerythroblastosis

 

Myelofibrosis Grading

  • MF-0

    • Scattered linear reticulin with no intersections (crossovers) corresponding to normal BM

  • MF-1

    • Loose network or reticulin with many intersections, especially in perivascular areas

  • MF-2

    • Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick fibers mostly consistent with collagen, and/or focal osterosclerosis

  • MF-3

    • Diffused and dense increase in reticulin

 

2017 WHO Diagnostic Criteria for Polycythermia Vera and Essential Thrombocythemia

Polycythemia Vera (PV)

(Diagnosis requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion)

  • Major criteria
    • Hemoglobin > 16.5 g/dL in men, >16.0 g/dL in women; OR
      Hematocrit > 49% in men, > 48 men in women; OR
      Increased cell mass (RCM)
    • Bone marrow biopsy showing hypercellularity for age with trilineage growth (pathmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature magakaryocytes (differences in size)
    • Presence of JAK2V617F or JAK2 exon 12 mutation
  • Minor criteria
    • Subnormal serum EPO level

 

Essential Thrombocythemia (ET)

(Diagnosis requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion)

  • Major criteria
    • Platelet count ≥ 450 x 109/L
    • Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase of left shift in neutrophil granulopoiese or erythopoises and very rarely minor (grade 1) increase in reticulin fibers
    • Note meeting WHO criteria for CML, PV, PMF, myelodysplastic syndromes or other myeloid neoplasms
    • Presence of JAK2, CALR, or MPL mutation
  • Minor criterion
    • Presence of a clonal marker or absence of evidence for reactive thrombocytosis

 

IWG-MRT Diagnostic Criteria for Post-Polycythemia Vera (PV) and Post-Essential (ET) Myelofribrosis

Criteria for Post-PV Myelofibrosis

  • Required criteria
    • Documentation of a previous diagnosis of PV as defined by the WHO criteria
    • Bone marrow fibrosis grade 2-3 (on 0-3 scale) or grade 3-4 (on 0-4 scale)
  • Additional criteria (two are required)
    • Anemia or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytes
    • A leukoerythrobalstic peripheral blood picture
    • Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥ 5 cm (distance of the tipe of the spleen from the left costal margin) or the appearance of a newly palapable splenomegaly
    • Development of ≥ 1% of three constitutional symptomas: > 10% weight loss in 6 months, night sweats, unexplained fever (> 37.5 degrees Celsius)

Criteria for Post-ET Myelofibrosis

  • Required criteria
    • Documentation of a previous diagnosis of ET as defined by WHO criteria
    • Bone marrow fibrosis grade 2-3 (on 0-3 scale) or grade 3-4 (on 0-4 scale)
  • Additional criteria (two are required)
    • Anemia and ≥ 2g/dl decrease from baseline hemoglobin level
    • A leukoerythoblastic peripheral blood picture
    • Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥ 5cm (distance of the tip of the spleen from the lest cost margin) or the appearance of a newly palpable splenomegaly
    • Increased LDH (above reference level)
    • Development of ≥ 1 of 3 constitutional symptoms: > 10% weight loss in 6 months, night sweats, unexplained fever (37.5 degrees Celsius)

 

Neuroendocrine and Adrenal Tumors Version 1.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

B-Cell Lymphomas Version 4.2019
Histological Transformation to Diffuse Large B-Cell Lymphoma

Multiple prior therapies → responsive disease → Consider high dose therapy with autologous stem cell rescue or allogeneic stem cell transplant.

 

Minimal or no prior chemotherapy

CR: observation; clinical trial; consider high dose therapy with autologous stem cell rescue or allogeneic stem cell transplant (Footnote: strongly recommended this treatment be given in the context of a clinical trial).

 

PR: consider high dose therapy with autologous stem cell rescue or allogeneic stem cell transplant (Footnote: strongly recommended this treatment be given in the context of a clinical trial); clinical trial; consider radioimmunotherapy; consider ISRT.

 

Diffuse Large B-Cell Lymphoma

Stage I, II: Pre-RT evaluation repeat all positive studies (end of first line chemoimmunotherapy)

Partial response (PET positive) → complete planned course of therapy with higher RT dose; if PET + after 6 cycles of RCHOP, high dose therapy with autologous stem cell rescue +/- RT pre or post-transplant; clinical trial (may include allogeneic stem cell transplant +/- RT pre or post-transplant).

 

Stage III, IV after 2-4 cycles restage to confirm response

Complete response PET negative → observation; consider RT to initially bulky disease or isolated skeletal sites; consider high dose therapy with autologous stem cell rescue in high risk patients (category 2B).

 

Relapse refractory disease

For patients with intention to proceed to high dose therapy.

 

Second line therapy see suggested regimens→ complete or partial response → high dose therapy with autologous stem cell rescue (category 1 for CR, category 2A for all others) +/- ISRT; clinical trial; allogeneic stem cell transplant in selected cases (Footnote: selected cases include mobilization failures and persistent bone marrow involvement).

 

Burkitt Lymphoma

Low risk: induction therapy→ complete response→ relapse

 

Clinical trial; second line chemotherapy followed by HDT/ASCR or allogeneic stem cell transplant in selected patients; best supportive care.

 

High risk: induction therapy → complete response → relapse

 

Clinical trial; second line chemotherapy followed by HDT/ASCR or allogeneic stem cell transplant in selected patients; best supportive care.

 

Castleman’s Disease

Relapsed/Refractory Disease: Consider alternative single-agent or combination therapy; autologous hematopoietic stem cell transplant.

 

Mantle Cell Lymphoma

Stage II bulky, III, IV: Aggressive

Candidate for HDT/ASCR→ induction therapy; CR→ consolidation → high dose therapy with autologous stem cell rescue

 

Indolent: symptomatic or other induction for treatment → evaluate for clinical concern or transformation→ rebiopsy and evaluate for TP53/del(17p); Negative → optimal treatment is unknown; chemoimmunotherapy; induction therapy followed by HDT/ASCR may be appropriate

 

Primary Cutaneous B-Cell Lymphomas Version 2.2019
Mycosis Fungoides (MF) and Sezary Syndrome (SS)

Cutaneous T-cell lymphoma (CTCLs) are a group of non-Hodgkin’s lymphomas (NHL) of mature T-cells that primarily present in the skin, and at times progress to involve lymph nodes, blood and visceral organs. Mycosis fungoides (MF) is the most common subtype with primary cutaneous involvement and sezary syndrome (SS) is an erythrodermic, leukemic variant of CTCL that is characterized by significant blood involvement and lymphadenopathy.

 

Autologous hematopoietic stem cell transplantation (HCT)has been used infrequently for patients with CTCL. In general, the duration of response have been short, thus limiting its utility and uptake. Allogeneic HCT for patients with advanced MF and SS has been reported in small prospective series or in retrospective studies.

 

Allogeneic HCT appears to be promising therapeutic strategy in patients with advanced CTCL. Further data from prospective studies are needed to establish the role of allogeneic HCT in these patients.

 

Treatment Recommendations Based on Clinical Stage

Indications for Allogeneic HCT

Allogeneic HCT may be considered for patients with stage IIB-IV disease that is progressive or refractory to primary treatment options. Appropriate patients (with stage IIB or stage III MF who have failed multiple systemic therapies/combination therapies and adequate trial of skin directed therapy; high risk stage IV patients with relapse or inadequate response following primary treatment with systemic therapies; combination therapies and/or multiagent chemotherapy) may be referred for a transplant consultation. In general, patients should have failed biologic options and single-agent chemotherapy prior to allogeneic HCT.

 

The ideal timing for allogeneic HCT is when the disease is well controlled with induction therapy and before disease has progressed to state where the chance of response or survival with allogeneic HCT is low. This is particularly true for patients with high-risk stage IV disease that has relapsed (or has persistent disease) after primary treatment. For these patients, consideration of allogeneic HCT should be made earlier in the treatment phase to optimize response to induction therapy prior to transplant. Thus, for high-risk stage IV disease, allogeneic HCT should be a “last resort” option.

 

T-Cell Lymphomas Version 2.2019
Treatment for Relapsed or Refractory

Second-Line Systemic Therapy

Participation in a clinical trial is strongly preferred for patients with relapsed/refractory disease. In the absence of a suitable clinical trial, the initial treatment for relapse/refractory disease depends largely on patient’s eligibility for transplant. Second-line systemic therapy followed by consolidation with HDT/ASCR or allogeneic HCT for those with a CR or PR is recommended for patients who are candidates for transplant. Localized relapse (limited to one or two sites) may be treated with ISRT before or after HDT/ASCR. Allogeneic HCT, when feasible, should be considered as a more reliably curative therapy for the majority of patients with relapsed/refractory disease. HDT/ASCR may be an appropriate option for patients, particularly those with ALCL and for selected patients with other subtypes with chemosensitive relapsed disease.

 

Basal Cell Skin Cancer Version 1.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Dermatofibrosarcoma Protuberans Version 1.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Merkel Cell Carcinoma Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Squamous Cell Skin Cancer Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Non-Small Cell Lung Cancer Version 5.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Occult Primary (Cancer of Unknown Primary) Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Ovarian Cancer Version 1.2019
Malignant Germ Cell Tumors

Any stage embryonal tumor; or any stage endodermal sinus tumor (yolk sac tumor); or Stage II-IV dysgerminoma; or Stage I, grade 2 or 3 or Stage II-IV immature teratoma – Chemotherapy

 

Adjuvant treatment → complete clinical response → abnormal markers definitive recurrent disease → consider additional chemotherapy (category 2B); or high dose chemotherapy (category 2B) (Footnote: high dose chemotherapy regimens vary among institutions. Some patients are potentially curable with stem cell transplantation. Patients with potentially curable recurrent germ cell disease should be referred to tertiary care institution for stem cell transplant consultation and potentially curative therapy)

 

Adjuvant treatment → persistently elevated markers with definitive residual disease → TIP (paclitaxel/ifosfamide/cisplatin); high dose chemotherapy (strongly recommend referral to tertiary care center for potentially curative regimen) (Footnote: high dose chemotherapy regimens vary among institutions. Some patients are potentially curable with stem cell transplantation. Patients with potentially curable recurrent germ cell disease should be referred to tertiary care institution for stem cell transplant consultation and potentially curative therapy)

 

Pancreatic Adenocarcinoma Version 3.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Penile Cancer Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Prostate Cancer Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Small Cell Lung Cancer 1.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Soft Tissue Sarcoma Version 2.2019

The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

 

Systemic Mastocytosis Version 2.2019
Allogeneic HCT

The role of allogeneic HCT needs to be determined in a prospective trial. However, given the rarity of SM (systemic mastocytosis), no larger prospective trials of HCT have been initiated to confirm the role of allogeneic HCT.

 

In 2016, a consensus opinion was published on indication for allogeneic HCT in patients with advanced SM (systemic mastocytosis). Alllogeneic HCT can be considered as an initial treatment option for patients with advanced SM and acute MCL (mast cell leukemia). Among patients SM-AHN (systematic mastocytosis with an associated hematologic neoplasm) allogeneic HCT should be considered as part of initial treatment when the AHN (associated hematologic neoplasm) component requires HCT and it should also be considered if the SM component presents as advanced SM during treatment.

 

Treatment for Aggressive Systemic Mastocytosis (ASM)
  • ASM – 1 or more “C findings” per WHO criteria or eligible organ damage findings per IWG-MRT-ECNM criteria
    • Clinical trial; or
    • Midostaurin; or
    • Cladribine; or
    • Imatinib (only if KIT D816V mutation negative or unknown or if eosinophilia is present with FIP1L1-PDGFRA fusion gene); or
    • Interferons (interferon alfa-2b, peginterferon alfa-2a, or peginterferon alfa-2b) +/- prednisone; or
    • Allogeneic HCT
      • Adequate response to treatment
        • Continue treatment; and/or
        • Consider evaluation for allogeneic HCT

 

Treatment for Systemic Mastocytosis with an Associated Hematologic Neoplasm (SM-AHN)
  • SM-AHN
    • Does AHN component require more immediate treatment? → Yes
      • AHN-directed therapy (including consideration of allogeneic HCT with concurrent management of SM); or
      • Monitor for progression of AHN component
  • SM-AHN and SM component requiring more immediate treatment (e.g. 1 or more C findings)
    • Clinical trial; or
    • Midostaurin; or
    • Cladribine; or
    • Interferons (Interferon alfa-2b, peginterferon alfa-2a, or peginterferon alfa-2b) +/- prednisone; or
    • Allogeneic HCT
      • Progression of AHN requiring treatment
        • AHN directed therapy (including consideration of allogeneic HCT with concurrent management of SM)
      • Adequate response
        • Continue treatment; and/or
        • Consider evaluation for allogeneic HCT

 

Treatment for Mast Cell Leukemia
  • MCL +/- AHN
    • Clinical trial; or
    • Midostaurin; or
    • Cladribine
      • Adequate response
        • Continue treatment and/or
        • Consider evaluation for allogeneic HCT
      • Progression of AHN or transformation to AM
        • AHN directed therapy (including multiagent chemotherapy; and/or
        • Consideration evaluation for allogeneic HCT with concurrent management of MCL

 

2017 World Health Organization (WHO) Classification of Mastocytosis
  • Cutaneous mastocytosis (CM)
  • Systemic mastocytosis (SM)
    • Indolent systemic mastocytosis (ISM)
    • Smoldering systemic mastocytosis (SSM)
    • Systemic mastocytosis with an associated hematological neoplasms (SM-AHN)
    • Aggressive systemic mastocytosis (ASM)
    • Mast cell leukemia (MCL)
  • Mast cell sarcoma (MCS)

 

2017 WHO Diagnostic Criteria for Cutaneous and Systemic Mastocytosis
Systemic Mastocytosis (SM)

The diagnosis of SM can be made when the major criterion and at least one minor criterion are present, or when three or more minor criteria are present.

 

Major Criterion:

Multifocal, dense infiltrates of mast cells (≥ 15 mast cells in aggregates) detected in sections of bone marrow and/or other extracutaneous organ(s).

 

Minor Criteria:

  • In biopsy sections of bone marrow or other extracutaneous organs, > 25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology of > 25% of all mast cells in bone marrow aspirate smears, are immature or atypical.
  • Detection of an activating point mutation at codon 816 of KIT in the bone marrow, blood, or another extracutaneous organ.
  • Mast cells in bone marrow, blood or other extracutaneous organs express CD25, with or without CD2, in addition to normal mast cell markers.
  • Serum total tryptase persistently > 20 ng/ml (unless there is an associated myeloid neoplasm, in which case this parameter is not valid).

 

Systemic Mastocytosis with an Associated Hematological Neoplasm

  • Meets the general criteria for systemic mastocytosis
  • Meets the criteria for an associated hematologic neoplasm (i.e. a myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, lymphoma or another hematological neoplasm classified as a distinct entity in the WHO classification)

 

Aggressive Systemic Mastocytosis

  • Meets the general criteria for systemic mastocytosis
  • ≥ 1 C finding
  • Does not meet the criteria for mast cell leukemia
  • Skin lesions are usually absent

 

Mast Cell Leukemia

  • Meets the general criteria for systemic mastocytosis
  • Bone marrow biopsy shows diffuse infiltration (usually dense) by atypical, immature mast cells
  • Bone marrow aspirate smears show ≥ 20% mast cells
  • In classic cases, mast cells account for ≥ 10% of the peripheral blood white blood cells, but the aleukaemic variant (in which mast cells account for < 10% is more common)
  • Skin lesions are usually absent

 

World Health Organization (WHO) Criteria for B-Findings and C-Findings in Patients with Systemic Mastocytosis (SM)

B-Findings:

Indicate a high burden of mast cells (MCs) and expansion of the neoplastic process into multiple hematopoietic lineages, without evidence of organ damage

  • High mast cells burden (shown on bone marrow biopsy): > 30% infiltration of cellularity by mast cells and (focal dense aggregates) AND serum total tryptase > 200 ng/ml
  • Signs of dysplasia or myeloproliferation in non-mast cell lineage(s), but criteria are not met for definitive diagnosis of an associated hematological neoplasm, with a normal or only slightly abnormal blood counts
  • Hepatomegaly without impairment of liver function, palpable splenomegaly without hyperslenism, and/or lymphadenopathy on palpation or imaging.

 

C-Findings:

Are indicative of organ damage produced by MC infiltration (should be confirmed by biopsy if possible)

  • Bone marrow dysfunction caused by neoplastic mast cell infiltration, manifested by ≥ 1 cytopenia; absolute neutrophil count < 1.0 x109/L, hemoglobin level <10 g/dl, and/or platelet count < 100 x 109/L
  • Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension
  • Skeletal involvement, with large osteolytic lesions with or without pathologic fractures (pathologic fractures caused by osteoporosis do not qualify as a C finding)
  • Palpable splenomegaly with hypersplenism
  • Malabsorption with weight loss due to gastrointestinal mast cell infiltrates

 

IWG-MRT-SCNM Criteria for Eligible Organ Damage to Assess Clinical Improvement (CI) and Treatment Response
Nonhematologic
Organ DamageOrgan Damage Eligible for CI ResponseCI Response Criteria
Ascites or pleural effusions
  1. Symptomatic ascites or pleural effusion requiring medical intervention such as use of diuretics (grade 2), OR
  2. > 2 therapeutic paracenteses or thoracenteses at least 28 days apart over 12 weeks prior to study entry (grade 3), and one of the procedures is performed during the 6 weeks prior drug start
  1. Complete resolution of symptomatic ascites or pleural effusion AND no longer in need of diuretic(s) for > 12 weeks, OR
  2. No therapeutic paracentesis or thoracentesis for > 12 weeks
Liver function abnormalities > Grade 2 abnormalities in direct bilirubin, AST, ALT, AP in the presence of ascites, and/or clinically relevant portal hypertension, and/or liver MC infiltration that is a biopsy-proven or other causes for abnormal liver function are not identified Reversion of 1 or more liver function tests to normal range for > 12 weeks
Hypoalbuminemia > Grade 2 hypoalbuminemia (,3.0 g/dL) Reversion of albumin to normal range for > 12 weeks
Symptomatic marked splenomegaly Symptomatic marked splenomegaly: a spleen that is palpable > 5 cm below that left costal margin and the patient endorses symptoms of discomfort and/or early satiety > 50% reduction in palpable splenomegaly and no endorsement of discomfort and/or early satiety for > 12 weeks (3D computed tomography/magnetic resonance imaging evaluation may also be undertaken)

 

IWG-MRT-ECNM Criteria for Eligible Organ Damage to Assess Clinical Improvement (CI) and Treatment Response
Hematologic
Organ Damage Organ Damage Eligible for CI Response CI Response Criteria
ANC Baseline grade > ANC (<1 x109/L) A minimum 100% increase in the ANC and an ANC of at least 0.5 x 109/L for > 12 weeks
Anemia (transfusion-independent) Grade > 2 anemia (Hb < 10 g/dL) An increase in Hb level of at lest 2 g/dL that is maintained for > 12 weeks
Anemia (transfusion dependent) Transfusion of a minimum of 6 units of PRBC in the 12 weeks before the start of treatment with the most recent transfusion occurring in the previous 4 weeks. RBC transfusions are only considered as part of the baseline criteria if they are administered for an Hb level
< 8.5 g/dL and not associated with bleeding, hemolysis, or therapy
Transfusion independence for > 12 weeks and maintenance of a minimum Hb level of 8.5 g/dL at the end of the 12 week period of response duration
Thromobocytopenia (transfusion-independent) Grade > 2 thrombocytopenia (<75 x 109/L) A minimum of 100% increase in the platelet count and an absolute platelet count increase of at least 50 x 109/L and no need for platelet transfusions for > 12 weeks
Thrombocvtopenia (transfusion-dependent)
  1. Transfusion of a minimum of 6 units of apheresed platelets during the 12 weeks preceding treatment; and
  2. at least 2 units transfused in the previous 4 weeks; and
  3. transfusions are administered only for a platelet count < 20 x 109/L
Transfusion independence for a minimal period of 12 weeks and maintenance of a platelet count of > 20 x 109/L

     

    IWG-MRT-ECNM Consensus Response Criteria for Patients with ASM, MCL, and SM Associated with a Myeloid Neoplasm

    • Complete remission (CR): Requires all 4 criteria and response duration must be ≥ 12 weeks
      • No presence of compact neoplastic mast cell aggregates in the BM or other biopsied extracutaneous organ
      • Serum tryptase level < 20 ng/mL
      • Peripheral blood count remission defined as ANC ≥ 1 x 109/L with normal differential, Hb level ≥ 11 g/dL, and platelet count ≥ 100 x 109/L
      • Complete resolution of palpable hepatosplenomegaly and all biopsy proven or suspected SM related organ damage (CI findings)
    • Partial remission (PR): Requires all 3 criteria and response duration must be ≥ 12 weeks, in the absence of both CR and progressive disease (PD)
      • Reduction by ≥ 50% in neoplastic MCs in the marrow and/or or other extracutaneous organ at biopsy demonstrating eligible SM0-related organ damage
      • Reduction of serum tryptase level by >50%
      • Resolution of 1 or more biopsy proven or suspected SM-related organ damage (CI findings)
    • Clinical Improvement (CI): Response duration must be ≥ 12 weeks
      • Requires 1 or more of the nonhematologic and/or hematologic response criteria to be fulfilled (see above tables) in the absence of both CR/PR assignement or progressive diseae (PD)
    • Stable Disease:
      • Not meeting criteria for CR, PR, CI or PD
    • Progressive Disease(PD): Requires at least 1 element of either criteria 1 or 2 and duration must be ≥ 8 weeks
      1. For patients with baseline grade 2 nonhematologic organ damage:
      • Worsening by 1 grade; and
      • Minimum 100% increase (doubling) of laboratory abnormality
      • For patients with baseline ≥ 2 albumin:
        • Worsening by 1 grade; and
        • Decrease by ≥ 0.5 g/dL
      • For patients with baseline ≥ 3 nonhematologic organ damage: minimum 100% increase (doubling) of laboratory abnormality
      • For patients with baseline ≥ 2 transfusion – independent anemia or thrombocytopenia: New transfusion dependence of ≥ 4 units of RBCs or platelets at 8 weeks
      • For patients with baseline transfusion-dependent anemia or thrombocytopenia: ≥ 100%
      • Increase in the average transfusion frequency for an 8 weeks period compared with the 12 week pretreatment period
      • For patients with baseline grade ≥ 3 neutropenia:
        • >50% decrease in neutrophil count, and
        • Absolute decrease of neutrophil count of ≥ 250/mm3, and
        • Grade 4
      1. Development of at least 10-cm palpable symptomatic splenomegaly for a baseline spleen size of not palpable or ≤ 5cm, OR if baseline symptomatic splenomegaly is >5cm, a >50% worsening and development of at least 10cm of palpable symptomatic splenomegaly compared with the baseline value.
      • Loss of Response (LOR):
        • Loss of a documented CR, PR, or CI that must be for ≥ 8 weeks. Downgrading of CR to PR or PR to CI is considered as such but is not considered as loss of response unless CI is also lost for a minimum of 8 weeks. The baseline value for LOR is the pretreatment measurement(s) and not the nadir values during response.

     

    Testicular Cancer Version 1.2019
    Second Line and Subsequent Therapy for Metastatic Germ Cell Tumors

    Second Line Therapy

    Patients with disease relapse following first-line therapy, or those who do not experience a durable complete response to first-line therapy are divided into those with a favorable or unfavorable prognostic groups based on prognostic factors. Favorable prognostic factors include low levels of post orchiectomy serum tumor markers and low volume disease, complete response to first-line therapy, and the presence of a testicular primary tumors. Unfavorable prognostic f.eatures include an incomplete response to first-line therapy, high levels of serum tumor markers, high volume disease, and the presence of an extratesticular primary tumor. Second line therapy options for those with favorable and unfavorable prognosis include enrollment in a clinical trial (preferred), or conventional dose or high dose chemotherapy. If chemotherapy is given both conventional dose and high dose regimens are preferred in this setting. The conventional dose regimens are TIP or VelP. The high dose regimen include high dose carboplatin plus etoposide followed by autologous stem cell transplant, or paclitaxel plus ifosfamide followed by high dose carboplatin plus etoposide with stem cell support.

     

    It is not known whether high dose chemotherapy is better than standard doses as second line chemotherapy for patients with relapsed disease. The NCCN Panel recommends clinical trial enrollment as the preferred option for these patients. There is ongoing, prospective randomized, international phase III trial (TIGER trial) comparing standard dose chemotherapy with high dose chemotherapy in patients with relapsed germ cell tumors patients. Participation in this trial is highly encouraged (Clinical Trial ID NCT02375204).

     

    Late relapses (>2 years after completion of primary therapy) occur in 2% to 3% of testicular cancer survivors. The NCCN Panel refers surgical salvage for patients with late relapse, if technically feasible. Conventional dose and high dose chemotherapy are also options for patients with late relapse.

     

    Third-Line Therapy

    Participation in clinical trial is preferred treatment option for patients who experience relapse following first and second line therapy. Patients previously treated with conventional dose chemotherapy should be considered for high-dose regimens. Alternative options for patients previously treated with high dose regimens include conventional dose salvage chemotherapy, surgical salvage (if solitary site of relapse), and microsatellite instability/mismatch repair (MSI/MMR) testing (if disease progresses after high dose chemotherapy or third line therapy).

     

    The preferred treatment option for patients who experience a late relapse (>2 years after completion of second-line therapy) is surgical salvage, if the recurrent mass is resectable. Conventional dose or high dose chemotherapy (if not previously given), are also options for patients with late relapse.

     

    Thymomas and Thymic Carcinomas Version 2.2019

    The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

     

    Thyroid Carcinoma Version 1.2019

    The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

     

    Uterine Neoplasms Version 3.2019

    The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

     

    Vulvar Cancer (Squamous Cell Carcinoma) Version 2.2019

    The evidence review does not discuss hematopoietic stem cell transplantation as a treatment option.

     

    Adolescent and Young Adult Oncology Version 1.2020
    Treatment Options

    Selected AYA patients usually tolerate more intensive therapies than older patients, since they have fewer comorbid conditions that limit the intensity of treatment in older adults. Dose-intensive and dose-dense treatment is associated with improved outcomes in some malignancies. Therefore, more intensive therapy may be considered for every AYA patient if such regimen exists for that particular disease and there are no contraindications.

     

    Surgery, RT, chemotherapy, and hematopoietic stem cell transplant (HSCT) are the main treatment options for patients who are able to tolerate curative treatment. All of these options are associate with both acute and late side effects.

     

    Hematopoietic Stem Cell Transplant

    HSCT is a potentially curative treatment option for an increasing number of AYA patients with leukemias and lymphomas. Graft versus host disease (GVHD), chronic immunosuppression, and gonadal dysfunction in males and females related to high dose conditioning chemotherapy and RT are the major post-transplant complications associated with HSCT.

     

    Summary

    AYA patients with cancer should be recognized as a distinct age group that has unique medical and psychosocial needs. It is important for physicians to identify issues specific to the AYA population and recommend appropriate interventions with the aim of improving clinical outcomes. Most importantly all AYA patients should have access to age appropriate supportive care as well as medically subspecialty services appropriate for their cancer diagnosis.

     

    American Society of Blood and Marrow Transplantation

    In 2015, the American Society of Blood and Marrow Transplantation issued a guideline indications for autologous and allogeneic hematopoietic stem cell transplantation. This guideline was developled in a response to a need identified by patients, providers, payers and policymakers, established a Task Force to provide guidance on indications for HCT, that is, which indications may be considered as routine care versus indications where evidence is emerging or insufficient.

     

    Definitions for Classifying Indications
    Standard of Care (S):
    This category includes indications that are well defined and generally supported by evidence in the form of high quality clinical trials and/or observational studies.
    Standard of Care, Clinical Evidence Available (C):
    This category includes indications for which large clinical trials and observational studies are not available. However, HCT has been shown to be an effective therapy with acceptable risk or morbidity or mortality in sufficiently large single or multicenter cohort studies. HCT can be considered as a treatment option for individual patients after careful evaluation of risk and benefits. As more evidence becomes available, some indications may be reclassified as “S”.
    Standard of Care, Rare Indication (R):
    Indications included in this category are rare disease for which clinical trials and observational studies with sufficient number of patients are not currently feasible because of their very low incidence. However, single or multicenter or registry studies in relatively small cohorts of patients have shown HCT to be effective treatment with acceptable risks of morbidity and mortality. For patients with diseases in this category, HCT can be considered as a treatment option for individual patients after careful evaluation of risks and benefits.
    Developmental (D):
    Developmental indications include diseases where preclinical and/or early phase clinical studies show HCT to be a promising treatment option. HCT is best pursued for these indications as part of a clinical trial. As more evidence becomes available, some indications may be reclassified as “C” or “S”.
    Not Generally Recommended (N):
    Transplantation is not currently recommended for these indications where evidence and clinical practice do not support the routine use of HCT. This recommendations does not preclude investigation of HCT as a potential treatment, and transplantation may be pursued for these indications within the context of a clinical trial.

     

    Indications for HCT in Pediatric Patients (Generally Age < 18 years)
    Indication and Disease StatusAllogeneic HCTAutologous HCT
    Acute myeloid leukemia
    CR1 low risk Not Generally Recommended Not Generally Recommended
    CR1 intermediate risk Standard of Care, Clinical Evidence Available Not Generally Recommended
    CR1 high risk Standard of Care Not Generally Recommended
    CR2+ Standard of Care Not Generally Recommended
    Not in remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    Acute promyelocytic leukemia, relapse Standard of Care, Rare Indication Standard of Care, Rare Indication
    Acute lymphoblastic leukemia
    CR1 standard risk Not Generally Recommended Not Generally Recommended
    CR1 high risk Standard of Care Not Generally Recommended
    CR2 Standard of Care Not Generally Recommended
    CR3+ Standard of Care, Clinical Evidence Available Not Generally Recommended
    Not in remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    Chronic myeloid leukemia
    Chronic phase Standard of Care, Clinical Evidence Available Not Generally Recommended
    Accelerated phase Standard of Care, Clinical Evidence Available Not Generally Recommended
    Blast phase Standard of Care, Clinical Evidence Available Not Generally Recommended
    Myelodysplastic syndromes
    Low risk Standard of Care, Clinical Evidence Available Not Generally Recommended
    High risk Standard of Care Not Generally Recommended
    Juvenile myelomonocytic leukemia Standard of Care Not Generally Recommended
    Therapy related Standard of Care Not Generally Recommended
    T-cell non-Hodgkin's Lymphoma
    CR1 standard risk Not Generally Recommended Not Generally Recommended
    CR1 high risk S Not Generally Recommended
    CR2 Standard of Care Not Generally Recommended
    CR3+ Standard of Care, Clinical Evidence Available Not Generally Recommended
    Not in remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    Lymphoblastic B cell non-Hodgkin lymphoma (non-Burkitt)
    CR1 standard risk Not Generally Recommended Not Generally Recommended
    CR1 high risk Standard of Care Not Generally Recommended
    CR2 Standard of Care Not Generally Recommended
    CR3+ Standard of Care, Clinical Evidence Available Not Generally Recommended
    Not in remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    Burkitt's lymphoma
    First remission Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    First or greater relapse, sensitive Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    First or greater relapse resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Hodgkin lymphoma
    CR1 Not Generally Recommended Not Generally Recommended
    Primary refractory, sensitive Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Primary refractory, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    First relapse, sensitive Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    First relapse, resistant Standard of Care, Clinical Evidence Available N
    Second or greater relapse Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Anaplastic large cell lymphoma
    CR1 Not Generally Recommended Not Generally Recommended
    Primary refractory, sensitive Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Primary refractory, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    First relapse, sensitive Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    First relapse, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Second or greater relapse Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Solid tumors
    Germ cell tumor, relapse Developmental Standard of Care, Clinical Evidence Available
    Germ cell tumor, refractory Developmental Standard of Care, Clinical Evidence Available
    Ewing's sarcoma, high risk or relapse Developmental Standard of Care
    Soft tissue sarcoma, high risk or relapse Developmental Developmental
    Neuroblastoma, high risk or relapse Developmental Standard of Care
    Wilm's tumor, relapse Not Generally Recommended Standard of Care, Clinical Evidence Available
    Osteosarcoma, high risk Not Generally Recommended Standard of Care, Clinical Evidence Available
    Medulloblastoma, high risk Not Generally Recommended Standard of Care, Clinical Evidence Available
    Other malignant brain tumors Not Generally Recommended Standard of Care, Clinical Evidence Available
    Nonmalignant diseases
    Severe aplastic anemia, new diagnosis Standard of Care Not Generally Recommended
    Severe aplastic anemia, relapse/refractory Standard of Care Not Generally Recommended
    Fanconi's anemia Standard of Care, Rare Indication Not Generally Recommended
    Dyskeratosis congenital Standard of Care, Rare Indication Not Generally Recommended
    Blackfan-Diamond anemia Standard of Care, Rare Indication Not Generally Recommended
    Sickel cell disease Standard of Care, Clinical Evidence Available Not Generally Recommended
    Thalassemia Standard of Care Not Generally Recommended
    Congenital amegakaryocytic thromobocytopenia Standard of Care, Rare Indication Not Generally Recommended
    Severe combined immunodeficiency Standard of Care, Rare Indication Not Generally Recommended
    T-cell immunodeficiency, SCID variants Standard of Care, Rare Indication Not Generally Recommended
    Wiskott-Aldrich syndrome Standard of Care, Rare Indication Not Generally Recommended
    Hemophagocytic disorders Standard of Care, Rare Indication Not Generally Recommended
    Lymphoproliferative disorders Standard of Care, Rare Indication Not Generally Recommended
    Severe congenital neutropenia Standard of Care, Rare Indication Not Generally Recommended
    Chronic granulomatous disease Standard of Care, Rare Indication Not Generally Recommended
    Other phagocytic cell disorders Standard of Care, Rare Indication Not Generally Recommended
    IPEX syndrome Standard of Care, Rare Indication Not Generally Recommended
    Juvenile rheumatoid arthritis Developmental Standard of Care, Rare Indication
    Systemic sclerosis Developmental Standard of Care, Rare Indication
    Other autoimmune and immune dysregulation disorders Standard of Care, Rare Indication Not Generally Recommended
    Mucopolysaccharoidoses (MPS-I and MPS-VI) Standard of Care, Rare Indication Not Generally Recommended
    Other metabolic disorders Standard of Care, Rare Indication Not Generally Recommended
    Osteoporosis Standard of Care, Rare Indication Not Generally Recommended
    Globoid cell leukodystrophy (Krabbe) Standard of Care, Rare Indication Not Generally Recommended
    Metachromatic leukodystrophy Standard of Care, Rare Indication Not Generally Recommended
    Cerebal X-linked adrenoleukodystrophy Standard of Care, Rare Indication Not Generally Recommended

     

    Indications for HCT in Adults (Generally Age ≥ 18 years)
    Indication and Disease StatusAllogeneic HCTAutologous HCT
    Acute myeloid leukemia
    CR1 low risk Not Generally Recommended Standard of Care, Clinical Evidence Available
    CR1 intermediate risk Standard of Care Standard of Care, Clinical Evidence Available
    CR1 high risk Standard of Care Standard of Care, Clinical Evidence Available
    CR2 Standard of Care Standard of Care, Clinical Evidence Available
    CR3+ Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Not in remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    Acute promyelocytic leukemia
    CR1 Standard of Care, Clinical Evidence Available Standard of Care
    CR2, molecular remission Standard of Care Not Generally Recommended
    CR2, not in molecular remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    CR3+ Standard of Care, Clinical Evidence Available Not Generally Recommended
    Not in remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Acute lymphoblastic leukemia
    CR1 standard risk Standard of Care Standard of Care, Clinical Evidence Available
    CR1 high risk Standard of Care Not Generally Recommended
    CR2 Standard of Care Standard of Care, Clinical Evidence Available
    CR3+ Standard of Care, Clinical Evidence Available Not Generally Recommended
    Not in remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    Chronic myeloid leukemia
    Chronic phase I, TKI intolerant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Chronic phase I, TKI refractory Standard of Care, Clinical Evidence Available Not Generally Recommended
    Chronic phase 2+ Standard of Care Not Generally Recommended
    Accelerated phase Standard of Care Not Generally Recommended
    Blast phase Standard of Care Not Generally Recommended
    Myelodysplastic syndromes
    Low/intermediate Standard of Care, Clinical Evidence Available Not Generally Recommended
    Intermediate -2/high risk Standard of Care Not Generally Recommended
    Therapy related AML/MDS CR1 Standard of Care Not Generally Recommended
    Myelofibrosis and myeloproliferative diseases
    Primary low risk Standard of Care, Clinical Evidence Available Not Generally Recommended
    Primary intermediate/high risk Standard of Care, Clinical Evidence Available Not Generally Recommended
    Secondary Standard of Care, Clinical Evidence Available Not Generally Recommended
    Hypereosinophilic syndromes, refractory Standard of Care, Rare Indication Not Generally Recommended
    Plasma cell disorders
    Myeloma, initial response Developmental Standard of Care
    Myeloma, sensitive relapse Standard of Care, Clinical Evidence Available Standard of Care
    Myeloma, refractory Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Plasma cell leukemia Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Primary amyloidosis Not Generally Recommended Standard of Care, Clinical Evidence Available
    POEMS syndrome Not Generally Recommended Standard of Care, Rare Indication
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Hodgkin lymphoma
    CR1 (PET negative) Not Generally Recommended Not Generally Recommended
    CR1 (PET positive) Not Generally Recommended Standard of Care, Clinical Evidence Available
    Primary refractory, sensitive Standard of Care, Clinical Evidence Available Standard of Care
    Primary refractory, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    First relapse, sensitive Standard of Care Standard of Care
    First relapse, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Second or greater relapse Standard of Care, Clinical Evidence Available Standard of Care
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Diffuse large B cell lymphoma
    CR1 (PET negative) Not Generally Recommended Not Generally Recommended
    CR1 (PET positive) Not Generally Recommended Standard of Care, Clinical Evidence Available
    Primary refractory, sensitive Standard of Care, Clinical Evidence Available Standard of Care
    Primary refractory, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    First relapse, sensitive Standard of Care Standard of Care
    First relapse, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Second or greater relapse Standard of Care, Clinical Evidence Available Standard of Care
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Follicular lymphoma
    CR1 Not Generally Recommended Standard of Care, Clinical Evidence Available
    Primary refractory, sensitive Standard of Care Standard of Care
    Primary refractory, resistant Standard of Care Not Generally Recommended
    First relapse, sensitive Standard of Care Standard of Care
    First relapse, resistant Standard of Care Not Generally Recommended
    Second or greater relapse Standard of Care Standard of Care
    Transformation to high grade lymphoma Standard of Care, Clinical Evidence Available Standard of Care
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Mantle cell lymphoma
    CR1/PR1 Standard of Care, Clinical Evidence Available Standard of Care
    Primary refractory, sensitive Standard of Care Standard of Care
    Primary refractory, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    First relapse, sensitive Standard of Care Standard of Care
    First relapse, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Second or greater relapse Standard of Care, Clinical Evidence Available Standard of Care
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Not Generally Recommended
    T-cell lymphoma
    CR1 Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Primary refractory, sensitive Standard of Care, Clinical Evidence Available Standard of Care
    Primary refractory, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    First relapse, sensitive Standard of Care, Clinical Evidence Available Standard of Care
    First relapse, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Second or greater relapse Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Lymphoplasmacytic lymphoma
    CR1 Not Generally Recommended Not Generally Recommended
    Primary refractory, sensitive Not Generally Recommended Standard of Care, Clinical Evidence Available
    Primary refractory, resistant Standard of Care, Rare Indication Not Generally Recommended
    First relapse, sensitive Standard of Care, Rare Indication Standard of Care, Clinical Evidence Available
    First relapse, resistant Standard of Care, Rare Indication Not Generally Recommended
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Burkitt's lymphoma
    First remission Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    First or greater relapse Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    First or greater relapse, resistant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Not Generally Recommended
    Cutaneous T-cell lymphoma
    Relapse Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Relapse after autologous transplant Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Plasmablastic lymphoma
    CR1 Standard of Care, Rare Indication Standard of Care, Rare Indication
    Relapse Standard of Care, Rare Indication Standard of Care, Rare Indication
    Chronic lymphocytic leukemia
    High risk, first or greater remission Standard of Care, Clinical Evidence Available Not Generally Recommended
    T-cell prolymphocytic leukemia Standard of Care, Rare Indication Standard of Care, Rare Indication
    B cell, prolymphocytic leukemia Standard of Care, Rare Indication Standard of Care, Rare Indication
    Transformation to high grade lymphoma Standard of Care, Clinical Evidence Available Standard of Care, Clinical Evidence Available
    Solid Tumors
    Germ cell tumor, relapse Not Generally Recommended Standard of Care, Clinical Evidence Available
    Germ cell tumor, refractory Not Generally Recommended Standard of Care, Clinical Evidence Available
    Ewing's sarcoma, high risk Not Generally Recommended Standard of Care, Clinical Evidence Available
    Breast cancer, adjuvant high risk Not Generally Recommended Developmental
    Breast cancer, metastatic Developmental Developmental
    Renal cancer, metastatic Developmental Not Generally Recommended
    Nonmalignant diseases
    Severe aplastic anemia, new diagnosis Standard of Care Not Generally Recommended
    Severe aplastic anemia, relapse/refractory Standard of Care Not Generally Recommended
    Fanconi's anemia Standard of Care, Rare Indication Not Generally Recommended
    Dyskeratosis congenital Standard of Care, Rare Indication Not Generally Recommended
    Sickel cell disease Standard of Care, Clinical Evidence Available Not Generally Recommended
    Thalassemia Developmental Not Generally Recommended
    Hemophagocytic syndromes, refractory Standard of Care, Rare Indication Not Generally Recommended
    Mast cell diseases Standard of Care, Rare Indication Not Generally Recommended
    Common variable immunodeficiency Standard of Care, Rare Indication Not Generally Recommended
    Wiskott-Aldrich syndrome Standard of Care, Rare Indication Not Generally Recommended
    Chronic granulomatous disease Standard of Care, Rare Indication Not Generally Recommended
    Multiple sclerosis Not Generally Recommended Developmental
    System sclerosis Not Generally Recommended Developmental
    Rheumatoid arthritis Not Generally Recommended Developmental
    Systemic lupus erythematosus Not Generally Recommended Developmental
    Chron's disease Not Generally Recommended Developmental
    Polymyositis-dermatomyositis Not Generally Recommended Developmental

     

    In 2008, the American Society for Blood and Marrow Transplantation issued a position statement regarding collection and preservation of cord blood for personal use. The recommendations include the following:

     

    • Expectant parents are encouraged to donate their newborn’s UCB (umbilical cord blood) for public banking when that option is available. Donation makes the CB (cord blood), which is rich in HSCs (hematopoietic stem cells), available for life-saving treatments when there is a suitable match with a patient.
    • Private storage of CB for future use by a newborn is not routinely recommended. The likelihood of the stored blood being used for HSCT (hematopoietic stem cell transplantation) is very small, probably as low as 0.04% to 0.001% in the first 20 years of life. If later in life a transplant is required, there likely will be superior sources of suitable stem cells than the child’s own CB.
    • Family member banking (collecting and storing CB for a family member) may be recommended for a newborn who has a sibling with a disease that can be successfully treated with HSCT. Family member banking on behalf of a parent with a disease that may be treated successfully with allogeneic transplant is only recommended when there are shared HLA-antigens between the parents.
    • Accurate and complete information about UCB collection and banking should be available to expectant parents so that they can make informed decisions. Parents who choose to store CB for personal use should carefully review their contract and financial responsibilities, and inquire about quality standards, median nucleated cell dose of stored units and accreditation of the CB bank.

     

    The committee acknowledges the potential for an expansion of indications for CB in the future, and these recommendations will be reviewed periodically so that they remain consistent with current medical knowledge.

     

    American Academy of Neurology

    In 2014, the American Academy of Neurology issued a summary of evidence based guideline on complementary and alternative medicine in multiple sclerosis, this guideline does not mention or discuss the use of hematopoietic stem cell transplantation as a therapeutic option in the treatment of multiple sclerosis.

     

    In 2016, the American Academy of Neurology issued international consensus guidance myasthenia gravis. The consensus guideline does not discuss hematopoietic stem cell transplantation as a therapeutic option.

     

    American College of Rheumatology

    In 2012, the American College of Rheumatology issued a guideline for screening, treatment and management of Lupus Nephritis which does not discuss hematopoietic stem cell transplantation as a therapeutic option.

     

    In 2013, the American College of Rheumatology updated the 2011 guideline recommendations for the treatment of juvenile idiopathic arthritis which does not discuss hematopoietic stem cell transplantation as a therapeutic option.

     

    In 2015, the American College of Rheumatology issued a guideline for the treatment of rheumatoid arthritis which does not discuss hematopoietic stem cell transplantation as a therapeutic option.

     

    The American College of Obstetricians and Gynecologists

    In 2015, the American College of Obstetricians and Gynecologists published a committee opinion (number 648) on umbilical cord blood banking. The recommendations regarding umbilical cord blood banking include the following:

    • Umbilical cord blood collection should not compromise obstetric or neonatal care or later routine practice for the timing of umbilical cord clamping.
    • In a patient requests information on umbilical cord blood banking, balanced and accurate information regarding the advantages and disadvantages of public and private umbilical cord blood banking should be provided.
    • The current indications for cord blood transplant are limited to select genetic, hematologic and malignant disorders.
    • Patient’s should be aware that in certain instances, use of one’s own stem cells is contraindicated. Most conditions potentially treated by a patient’s own umbilical cord blood already exist in his or her own cells and, therefore, the stored blood cannot be used to treat the same individual.
    • Counseling should include disclosure that the chance a child or family member develops a condition that could be treated with an autologous transfusion of umbilical blood is rare.
    • The routine storage of umbilical cord blood as “biologic insurance” against future disease is not recommended.
    • Directed cord blood banking is available through private and public umbilical cord blood banks for any pregnant patients who has a family member with a disease potentially treated by hematopoietic stem cell transplant.
    • Some states have passed legislation requiring physicians to inform their patients about umbilical cord blood banking options. Obstetricians-gynecologists and other obstetric care providers should consult their state medical associations for more information regarding state laws.
    • As a variety of circumstances may arise during the process of labor and delivery that may preclude collection, it is important to obtain well documented informed consent that various medical circumstances of the mother or the neonate may prevent umbilical cord blood collection.
    • Physicians or other professions who recruit pregnant women and their families for profit umbilical cord blood banking should disclose any financial interest or other potential conflicts of interest.

     

    Prior Approval:

    Prior approval is required.

     

    Policy:

    Coverage for hematopoietic stem cell transplantation (bone marrow transplantation) is provided when both the type of transplant and the individual’s condition meet the medical necessity criteria outlined below.

     

    For those indications in which the type of transplant and the individual’s condition does not meet the criteria outlined below the available evidence is insufficient and does not demonstrate improved net health outcomes and would be considered investigational.

     

    Autoimmune Diseases

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary as a treatment for systemic sclerosis/scleroderma if ALL of the following criteria are met:

    • Adult patients < 60 years of age; AND
    • Maximum duration of condition of 5 years; AND
    • Modified Rodnan Scale Score > 15; AND
    • Internal organ involvement indicated by the following measurements:
      • Cardiac: abnormal electrocardiogram; OR
      • Pulmonary: diffusing capacity of carbon monoxide (DLCo) < 80% of predicted value; decline of forced vital capacity (FVC) of > 10% in last 12 months; pulmonary fibrosis; ground glass appearance on high resolution chest CT; OR
      • Renal: scleroderma related renal disease; AND
    • The individual does not have the following internal organ involvement indicated by the following measurements:
      • Cardiac: left ventricular ejection fraction < 50%; tricuspid annual plane systolic excursion < 1.8 cm; pulmonary artery systolic pressure >40 mm Hg; mean pulmonary artery pressure > 25 mm Hg
      • Pulmonary: DLCo < 40% of predicted value; FVC < 45% of predicted value
      • Renal: creatinine clearance < 40 ml/minute; AND
    • History of < 6 months treatment with cyclophosphamide

     

    Notes

    • Autologous HCT should be considered for patients with systemic sclerosis (SSc) only if the condition is rapidly progressing and the prognosis for survival is poor. An important factor influencing the occurrence of treatment-related adverse effects and response to treatment is the level of internal organ involvement. If organ involvement is severe and irreversible, HCT is not recommended.
    • Modified Rodnan Scale Score: This score consists of an evaluation of patient’s skin thickness rated by clinical palpation using a 0–3 scale (0=normal skin; 1=mild thickness; 2=moderate thickness; 3=severe thickness with inability to pinch the skin into a fold) for each of 17 surface anatomic areas of the body: face, anterior chest, abdomen, (right and left separately), fingers, forearms, upper arms, thighs, lower legs, dorsum of hands and feet. These individual values are added and the sum is defined as the total skin score.

     

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) as a treatment of systemic sclerosis/scleroderma not meeting the above criteria is considered investigational.

     

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) as a treatment of systemic sclerosis/scleroderma is considered investigational.

     

    Autologous or allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational as a treatment of autoimmune diseases, including, but not limited to the following:

    • Multiple sclerosis
    • Systemic lupus erythematosus
    • Juvenile idiopathic or rheumatoid arthritis
    • Chronic inflammatory demyelinating polyneuropathy
    • Type 1 diabetes

     

    Most patients with autoimmune disorders respond to conventional drug therapies; however, conventional drug therapies are not curative and a proportion of patients suffer from autoimmune diseases that range from severe to the recalcitrant to the rapidly progressive. It is in this group of patients with severe autoimmune disease that alternative therapies have been sought, including hematopoietic stem cell transplantation. Based on review of the peer reviewed medical literature the literature for autoimmune diseases utilizing autologous or allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) includes randomized controlled trials (RCT), case series, case reports, observational studies, registry data, meta-analysis and small retrospective studies. Some studies may show promise in improving clinical parameters following hematopoietic stem cell transplantation (HSCT) compared with baseline, however, adverse events were high, and studies reported treatment related deaths. Additional controlled trials (with appropriate comparator therapies) that report on clinical outcomes are needed to demonstrate efficacy. The guideline from the American Society for Blood and Marrow Transplantation regarding indications for autologous and allogeneic hematopoietic stem cell transplantation (HSCT) state the following regarding multiple sclerosis, rheumatoid arthritis, systemic sclerosis and systemic lupus erythematous: allogeneic HSCT is not currently recommended for these indications and clinical practice does not support the routine use of HSCT, transplantation for these indications may be pursued within the context of a clinical trial; autologous HSCT developmental indications where pre-clinical and/or early phase clinical studies show HSCT to be a promising treatment option, but HSCT is best pursued for these indications as part of a clinical trial. The evidence is insufficient to determine the safety and/or efficacy of autologous or allogeneic hematopoietic stem cell transplantation for the treatment of autoimmune diseases.

     

    Solid Tumors in Adults

    Autologous or allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for the treatment for malignancies in adults, including, but not limited to the following:

    • Lung cancer (any histology)
    • Colon cancer
    • Rectal cancer
    • Pancreatic cancer
    • Stomach cancer
    • Esophageal cancer
    • Gallbladder cancer
    • Cancer of the bile duct
    • Renal cell cancer
    • Breast cancer
    • Cervical cancer
    • Uterine cancer
    • Cancer of the fallopian tubes
    • Epithelial ovarian cancer
    • Prostate cancer
    • Nasopharyngeal cancer
    • Paranasal sinus cancer
    • Neuroendocrine tumors
    • Soft tissue sarcomas
    • Thyroid cancer
    • Tumors of the thymus
    • Tumors of unknown primary origin
    • Malignant melanoma
    • Malignant astrocytomas and gliomas (e.g. gliobastoma multiforme, oligodendroglioma)

     

    Based upon the review of the peer reviewed medical literature treatment with autologous and allogeneic hematopoietic stem cell transplantation (blood marrow transplantation) for solid tumors in adults has not been medically proven outside the investigational setting for these patients. Current National Comprehensive Cancer Network (NCCN) guidelines do not discuss hematopoietic stem cell transplantation (bone marrow transplantation) as a treatment option. Available evidence is insufficient and does not demonstrate improved net health outcomes. Additional controlled trials (with appropriate comparator therapies) that report on clinical outcomes are needed to demonstrate efficacy. The evidence is insufficient to determine the safety and/or efficacy of autologous or allogeneic hematopoietic stem cell transplantation for the treatment of solid tumors in adults.

     

    Solid Tumors of Childhood

    Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the following:

    • Ewing’s sarcoma, for any of the following:
      • Initial treatment of high-risk Ewing’s sarcoma
      • Recurrent or refractory Ewing’s sarcoma
    • Neuroblastoma, for any of the following:
      • Initial treatment of high-risk neuroblastoma
      • Recurrent or refractory neuroblastoma
    • Metastatic retinoblastoma

     

    Tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for high-risk neuroblastoma.

     

    Tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for the treatment of all other types of solid tumors of childhood except high-risk neuroblastoma, as noted above.

     

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for the following:

    • Initial treatment of low or intermediate risk Ewing sarcoma
    • Initial treatment of low or intermediate risk neuroblastoma
    • For other solid tumors of childhood including, but not limited, to the following:
      • Rhabdomyosarcoma
      • Wilms tumor
      • Osteosarcoma
      • Retinoblastoma without metastases

     

    Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Allogeneic (myeloablative or non-myeloablative) hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for the treatment of solid tumors of childhood.

     

    Salvage allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) for solid tumors of childhood that relapse after autologous hematopoietic stem cell transplantation (bone marrow transplantation) or fail to respond is considered investigational.

     

    Definitions
    Refractory:
    Refractory is a cancer that does not respond to treatment. The cancer may be resistant at the beginning of treatment, or it may become resistant to treatment. Also called resistant cancer.
    Relapse:
    Relapse is a cancer that recurs after prior complete response
    Salvage therapy:
    Salvage therapy is treatment that is given after the cancer has not responded to other treatment.

     

    International Neuroblastoma Staging System
    StageDescription
    Stage I Localized tumor with complete gross excision, with or without microscopic residual disease; lymph nodes negative for tumor
    Stage 2A Localized tumor with incomplete gross excision; lymph nodes negative for tumor
    Stage 2B Localized tumor with or without complete gross excision, with ipsilateral lymph nodes positive for tumor
    Stage 3 Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration or by lymph node involvement
    Stage 4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S
    Stage 4S Localized primary tumor as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (marrow involvement less than 10%), limited to children younger than 1 year of age

     

    International Neuroblastoma Risk Group (INRG) Staging System
    StageDescription
    L1 Localized tumor not involving vital structures as defined by the list of image-defined risk factors and confined to one body compartment
    L2 Locoregional tumor with presence of one or more image defined risk factors
    M Distant metastatic disease (except stage MS)
    MS Metastatic disease in children younger than 18 months with metastasis confined to skin, liver, and/or bone marrow

     

    In the INRG classification system, a combination of clinical, pathologic and genetic markers are used to predict whether the tumor will grow and how it will respond to treatment. These markers are used to define risk. Using the following factors, neuroblastoma is classified into 1 of 4 categories: very low-risk, low-risk, intermediate-risk, or high risk.

    • The stage of the disease according to the INRG staging system
    • Age at the time of diagnosis
    • Histologic category such as maturing ganglioneuroma versus ganglioneuroblastoma, intermixed versus ganglioneuroblastoma or nodular versus neuroblastoma
    • Grade or how cells of the tumor are differentiated
    • MYCN gene status
    • Chromosome 11q status
    • Tumor cell ploidy, which is the DNA content of tumor cells

     

    High risk neuroblastoma is characterized by age older than 1 year, disseminated disease, MYCN oncogene amplification, and unfavorable histopathologic findings.

     

    Central Nervous System Embryonal Tumors and Ependymoma

    Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the following:

    • To treat recurrent embryonal tumors of the central nervous system (e.g. medulloblastoma, neuroblastoma of the central nervous system, ependymoblastoma, pineoblastoma)
    • As consolidation therapy for previously untreated embryonal tumors of the central nervous system that show partial or complete response to induction chemotherapy, or stable disease after induction therapy.

     

    Tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational and therefore, not covered for the following:

    • To treat embryonal tumors of the central nervous system
    • To treat ependymoma.

     

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational to treat ependymoma.

     

    Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Allogeneic hematopoietic stem cell transplantation (Bone Marrow Transplantation) is considered investigational for the following:

    • To treat embryonal tumors of the central nervous system
    • To treat ependymoma

     

    Notes:

    • Classification of brain tumors is based on both histopathologic characteristics of the tumor and location in the brain. Central nervous system (CNS) embryonal tumors are more common in children and are the most common brain tumor in childhood. CNS embryonal tumors are primarily composed of undifferentiated round cells, with divergent patterns of differentiation.
      • Embryonal tumors of central nervous system (CNS) include medulloblastoma, medulloepithelioma, supratentorial PNETs (sPNETs; pineoblastoma, cerebral neuroblastoma, ganglioneuroblastoma), ependymoblastoma, atypical teratoid/rhabdoid tumor.
      • Ependymoma is a neuroepithelial tumor that arises from the ependymal lining cell of the ventricles and is, therefore, usually continguous with the ventricular system. An ependymoma tumor typically arises intracranially in children, while in adults a spinal cord location is more common. Ependymomas have access to the cerebrospinal fluid and may spread throughout the neuroaxis.

     

    Genetic Diseases and Acquired Anemias

    Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for the treatment of genetic diseases and acquired anemias.

     

    Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the following:

     

    Hemoglobinopathies
    • Sickle cell anemia for children or young adults with either a history of prior stroke or at increased risk of stroke or end organ damage
    • Homozygous beta-thalassemia (i.e. thalassemia major)

     

    Note: Factors associated with increased risk of stroke or end organ damage include recurrent vaso-occlusive crisis, recurrent chest syndrome, red blood cells alloimmunization on chronic transfusion therapy.

     

    Bone Marrow Failure Syndromes
    • Aplastic anemia severe or very severe including hereditary forms (e.g. Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond, Diamond-Blackfan) or acquired forms (e.g. secondary to drug or toxin exposure)

     

    Note: Aplastic anemia is divided into three categories: non-severe aplastic anemia, severe aplastic anemia and very severe aplastic anemia. The presence of two of the following criteria defines aplastic anemia: hemoglobin < 10,000 mm3, platelet count < 50,000 mm3, or neutrophil count < 1,500 mm3. Severe aplastic anemia is defined by the presence of hypoplastic bone marrow two of the following: neutrophil count < 500 mm3, platelet count < 20,000 mm3, or reticulocyte count < 20,000 mm3. A neutrophil count < 200 mm3 classifies very severe aplastic anemia.

     

    Primary Immunodeficiencies
    • Absent or defective T-cell function (e.g. severe combined immunodeficiency (SCID), Wiscott-Aldrich syndrome, X-linked lymphoproliferative syndrome)
    • Absent or defective natural killer function (e.g. Chediak-Higashi syndrome)
    • Absent or defective neutrophil function (e.g. Kostmann syndrome, chronic granulomatous disease, leukocyte adhesion defect)

     

    Note: Also see Guideline 1

     

    Inherited Metabolic Disorders
    • Lysosomal and peroxisomal storage disorders except Hunter, Sanfilippo and Morquio syndromes
      • Allogeneic hematopoietic stem cell transplant has not been effective in Hunter, Sanfilippo or Morquio syndromes and would be considered investigational.

     

    Note: Also see Guideline 2

     

    Genetic Disorders Affecting Skeletal Tissue
    • Infantile malignant osteopetrosis (Albers-Schonberg disease or marble bone disease)

     

    Guideline 1

    The following guideline lists the immunodeficiencies that have been successfully treated by allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) (Gennery & Cant et. al. 2008)

     

    Lymphocyte Immunodeficiencies

    • Adenosine deaminase deficiency
    • Artemis deficiency
    • Calcium channel deficiency
    • CD 40 ligand deficiency
    • Cernunnos/X-linked lymphoproliferative disease deficiency
    • CHARGE syndrome with immune deficiency
    • Common gamma chain deficiency
    • Deficiencies in CD45, CD3, CD8
    • DiGeorge syndrome
    • DNA ligase IV deficiency syndrome
    • Interleukin-7 receptor alpha deficiency
    • Janus-associated kinase 2 (JAK3) deficiency
    • Major histocompatibility class II deficiency
    • Omenn syndrome
    • Purine nucleoside phosphorylase deficiency
    • Recombinase-activating gene (RAG) 1/2 deficiency
    • Reticular dysgenesis
    • Winged helix deficiency
    • Wiskott-Aldrich syndrome
    • X-linked lymphoproliferative disease
    • Zeta-chain-associated protein 70 (ZAP 70) deficiency

     

    Phagocytic Deficiencies

    • Chediak-Higashi syndrome
    • Chronic granulomatous disease
    • Griscelli syndrome type 2
    • Hemophagocytic lymphohistiocytosis
    • Interferon-gamma receptor deficiencies
    • Leukocyte adhesion deficiency
    • Severe congenital neutropenias
    • Shwachman-Diamond syndrome

     

    Other Immunodeficiencies

    • Autoimmune lymphoproliferative syndrome
    • Cartilage hair hypoplasia
    • CD25 deficiency
    • Hyper IgD and IgE syndromes
    • ICF syndrome (Immunodeficiency,centrmeric instability,and facial dysmorphism syndrome)
    • IPEX syndrome (Immunodysregulaton polyendocrinopathy enteropathy X-linked syndrome)
    • NEMO deficiency (Nuclear factor-k B (NF-kB) essential modulator deficiency)
    • NF-kB inhibitor, alpha (IkB-a) deficiency
    • Nijmegen breakage syndrome

     

    Guideline 2

    Metabolic diseases are a diverse group that includes mucopolysaccharidoses, leukodystrophies, and disorders of glycoprotein metabolism. Typically an enzyme deficiency results in failure to hydrolyze specific substrate. Due to substrate accumulation, organelle dysfunction occurs and call destruction ensues. While disease phenotypes vary widely, they can be identified by the presence of abnormal cellular metabolites due to the specific enzyme deficiency. Allogeneic hematopoietic cell transplantation (HCT) is either the only therapy or the most effective long term treatment for selected metabolic diseases.

     

    In the inherited metabolic disorders, allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) has been proven effective in some cases of the following (Mehta, 2004):

    • Hurler
    • Maroteaux-Lamy
    • Sly syndromes
    • Childhood onset cerebral X-linked adrenoleukodystrophy
    • Globoid cell leukodystrophy
    • Metachromatic leukodystrophy
    • Alpha-mannosidosis
    • Aspartylglucosaminuria

     

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is possibly effective for the following (Mehta, 2004):

    • Fucosidosis
    • Gaucher types 1 and 3
    • Farber lipogranulomatosis
    • Galactosialidosis
    • GM1 gangliosidosis
    • Mucolipidosis II (I-cell disease)
    • Multiple sulfatase deficiency
    • Niemann-Pick
    • Neuronal ceroid lipofuscinosis
    • Sialidosis
    • Wolman Disease

     

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation has not been effective in the following (Mehta, 2004):

    • Hunter
    • Sanfilippo
    • Morquio syndromes

     

    Germ Cell Tumors

    Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Single autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for germ cell tumors (testicular, ovarian, mediastinal or retroperitoneal) for any of the following:

    • In individuals with favorable prognostic factors that have failed a previous course of conventional dose salvage chemotherapy; or
    • In individuals with unfavorable prognostic factors as initial treatment of first relapse (i.e. without a course of conventional dose salvage chemotherapy) and in individuals with platinum-refractory disease

     

    Autologous hematopoietic stem cell transplant is considered investigational as a component of first-line treatment for germ cell tumors and for all other indications not indicated above.

     

    Tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation) or transplant with sequential high dose chemotherapy may be considered medically necessary for the treatment of testicular tumors either as salvage therapy or with platinum-refractory disease.

     

    All other uses of tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation is considered investigational except as indicated above.

     

    Allogeneic Hematopoietic Stem Cell Transplants (Bone Marrow Transplants)

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational to treat germ cell tumors, including but not limited to its use as therapy after a prior failed autologous hematopoietic stem cell transplant (bone marrow transplant).

     

    Notes:

    • Germ cell tumors are composed primarily of testicular neoplasms (seminomas or nonseminomatous tumors) as well as ovarian and extragonadal germ cell tumors (e.g. retroperitoneal or mediastinal tumors). Germ cell tumors are classified according to their histology, stage, prognosis and response to chemotherapy.
    • Germ cell tumor histologies include seminoma, embryonal carcinoma, teratoma, choriocarcinoma, yolk sac tumor, and mixed germ cell tumors. Seminomas are the most common; all other types are collectively referred to as nonseminomatous germ cell tumors.
    • Patients with favorable prognostic factors include those with a testis or retroperitoneal primary site, a complete response to initial chemotherapy, low levels of serum tumor markers, and low volume disease.
    • Patients with unfavorable prognostic factors are those with incomplete response to initial therapy, high levels of serum tumor markers and high volume disease.

     

    Definitions

    Salvage therapy
    Salvage therapy is treatment that is given after the cancer has not responded to other treatment.
    Sequential chemotherapy
    Sequential chemotherapy is a chemotherapy regimen consisting of several (2 to 4) sequential monochemotherapies with only one chemotherapeutic agent per course. The idea behind this approach is that when using single-agent chemotherapy, the physician can easily escalate the dose of the drug to the maximum tolerable dose by the patient, avoiding hematological toxicity from chemotherapeutic combinations.

     

    Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms

    Myelodysplastic syndromes (MDS)

    Myelodysplastic syndromes (MDS) represent myeloid clonal hemopathies with a relative heterogenous spectrum of presentation. The major clinical problems in these disorders are morbidities caused by cytopenias and the potential of MDS to evolve into acute myeloid leukemia (AML).

     

    The category of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) was added to the 2008 update of the WHO classification of myeloid neoplasm. This category includes chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative, and juvenile myleomonocytic leukemia (JMML) as disorders having overlapping dysplastic and proliferative features. The MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) and the MDS/MPN unclassified groups are also included in this category.

     

    Myelofibrosis (MF)

    Myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET) are a group of heterogenous disorders of the hematopoietic system collectively known as Philadelphia-chromosome-negative myeloproliferative neoplasm (MPN).

     

    Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for the treatment of myelodysplastic syndromes and myeloproliferative neoplasms (e.g. myelofibrosis).

     

    Allogenic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary as a treatment of:

    • Myelodysplastic syndromes
    • Myeloproliferative neoplasms (e.g. myelofibrosis (MF))

     

    Reduced-intensity (non-myeloablative) conditioning allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary as a treatment of:

    • Myelodysplastic syndromes
    • Myeloproliferative neoplasms (e.g. myelofibrosis (MF))

     

    Note: Reduced intensity conditioning regimens (non-myeloablative allogeneic transplantation) would be considered for individuals who would otherwise qualify for a myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), but would not tolerate standard myeloablative conditioning regimen. This may include the following age typically > 60 years or comorbidities (e.g. liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score).

     

    Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) WHO Classification
    SubtypeBloodBone MarrowFrequent Mutations
    Chronic myelomonocytic leukemia (CMML) - 0 gt;1 x 109/L monocytes, <2% blasts, monocytes Dysplasia in > 1 hematopoietic line, < 5% blasts TET2, SRSF2, ASKL1, RUNX1, NRAS, CBL
    CMML-1 >1 x 109/L monocytes, 2%-4% blasts, > 10% monocytes Dysplasia in > 1 hematopoietic line, 5%-9% blasts TET2, SRSF2, ASXL1, RUNX1, NRAS, CBL
    CMML-2 >1 x 109/L monocytes, 5%-19% blasts or Auer rods, > 10% monocytes Dysplasia in > 1 hematopoietic line, 10%-19% blasts or Auer rods TET2, SRSF2, ASKL1, RUNX1, NRAS, CBL
    Atypical chronic myeloid leukemia (aCML), BCR-ABL negative WBC > 13 x 109/L, neutrophil precursors > 10%, < 20% blasts, dysgranulopoiesis Hypercellular < 20% blasts SETBP1, ETNK1
    Juvenile myelomonocytic leukemia (JMML) >1 x 109/L monocytes, < 20% blasts, > 10% monocytes, increased HbF >1 x 109 monocytes < 20% blasts Ph negative GM-CSF hypersensitive PTPN11, NF1, N/KRAS, CBL, SETBP, JAK3
    MDS/MPN unclassified (“Overlap syndrome”) Dysplasia + myeloproliferative features, no prior MDS or MPN Dysplasia + myeloproliferative features TET2, NRAS, RUNX1, CBL, SETBP1, ASKL1
    MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) Dysplasia + myeloproliferative features, platelets > 450 x 109/L, > 15% ring sideroblasts Dysplasia + myeloproliferative features SF3B1, JAK2, MPL, CALR
    Chronic neutrophilic leukemia (CNL) (BCR-ABL negative) WBC > 25,000 with PMN/bands > 80%, myeloid precursors < 10%, no dysplasia Mature myeloid hyperplasia, < 5% blasts, no dysplasia CSF3R (G-CSF receptor

     

    2017 WHO Diagnostic Criteria for Primary Myelofibrosis
    WHO prePMF Criteria

    (Diagnosis of prePMF requires all 3 major criteria, and at least 1 minor criterion)

    • Major criteria
      • Megakaryocytic proliferation and atypia, without reticulin fibrosis > grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased erythropoiesis
      • No meeting WHO criteria for BCR-ABL1 + CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms.
      • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker, or absence of minor reactive BM reticulin fibrosis
    • Minor criteria
      • Presence of at least one of the following, confirmed in 2 consecutive determinations:
        • Anemia not attributed to a comorbid condition
        • Leukocytosis ≥ 11 x 109/L
        • Palpable splenomegaly
        • LDH increased to above upper normal limit of institutional reference range
    WHO Overt PMF criteria

    (Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criteria)

    • Major criteria
      • Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3
      • Not meeting WHO criteria for ET, PV, BCR-ABL + CML, myelodysplastic syndromes, or other myeloid neoplasms
      • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clona markers, or absence of reactive myelofibrosis
    • Minor criteria
      • Presence of at least one of the following, confirmed in 2 consecutive determinations:
        • Anemia not attributed to a comorbid condition
        • Leukocytosis ≥ 11 x 109/L
        • Palpable splenomegaly
        • LDH increased to above upper normal limit of institutional reference range
        • Leukerythroblastosis

    Myelofibrosis Grading

    • MF-0
      • Scattered linear reticulin with no intersections (crossovers) corresponding to normal BM
    • MF-1
      • Loose network or reticulin with many intersections, especially in perivascular areas
    • MF-2
      • Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick fibers mostly consistent with collagen, and/or focal osterosclerosis
    • MF-3
      • Diffused and dense increase in reticulin

     

    2017 WHO Diagnostic Criteria for Polycythermia Vera and Essential Thrombocythemia
    Polycythemia Vera (PV)

    (Diagnosis requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion)

    • Major criteria
      • Hemoglobin > 16.5 g/dL in men, >16.0 g/dL in women; OR
        Hematocrit > 49% in men, > 48 men in women; OR
        Increased cell mass (RCM)
      • Bone marrow biopsy showing hypercellularity for age with trilineage growth (pathmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature magakaryocytes (differences in size
      • Presence of JAK2V617F or JAK2 exon 12 mutation
    • Minor criteria
      • Subnormal serum EPO level

     

    Essential Thrombocythemia (ET)

    (Diagnosis requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion)

    • Major criteria
      • Platelet count ≥ 450 x 109/L
      • Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase of left shift in neutrophil granulopoiese or erythopoises and very rarely minor (grade 1) increase in reticulin fibers
      • Note meeting WHO criteria for CML, PV, PMF, myelodysplastic syndromes or other myeloid neoplasms
      • Presence of JAK2, CALR, or MPL mutation
    • Minor criterion
      • Presence of a clonal marker or absence of evidence for reactive thrombocytosis

     

    IWG-MRT Diagnostic Criteria for Post-Polycythemia Vera (PV) and Post-Essential (ET) Myelofribrosis
    Criteria for Post-PV Myelofibrosis
    • Required criteria
      • Documentation of a previous diagnosis of PV as defined by the WHO criteria
      • Bone marrow fibrosis grade 2-3 (on 0-3 scale) or grade 3-4 (on 0-4 scale)
    • Additional criteria (two are required)
      • Anemia or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytes
      • A leukoerythrobalstic peripheral blood picture
      • Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥ 5 cm (distance of the tipe of the spleen from the left costal margin) or the appearance of a newly palapable splenomegaly
      • Development of ≥ 1% of three constitutional symptomas: > 10% weight loss in 6 months, night sweats, unexplained fever (> 37.5 degrees Celsius)
    Criteria for Post-ET Myelofibrosis
    • Required criteria
      • Documentation of a previous diagnosis of ET as defined by WHO criteria
      • Bone marrow fibrosis grade 2-3 (on 0-3 scale) or grade 3-4 (on 0-4 scale)
    • Additional criteria (two are required)
      • Anemia and ≥ 2g/dl decrease from baseline hemoglobin level
      • A leukoerythoblastic peripheral blood picture
      • Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥ 5cm (distance of the tip of the spleen from the lest cost margin) or the appearance of a newly palpable splenomegaly
      • Increased LDH (above reference level)
      • Development of ≥ 1 of 3 constitutional symptoms: > 10% weight loss in 6 months, night sweats, unexplained fever (37.5 degrees Celsius)

     

    Definitions

    Karnofosky Performance Status
    Karnofosky Performance Status is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The scores on the scale range from 0 to 100. A higher score means the individual is better able to carry out daily activities. The Karnofsky Performance Status may be used to determine an individual’s prognosis, to measure changes in an individual’s ability to function, or to decide whether an individual could be included in a clinical trial.
    • 100 – normal no complaints
    • 90 – able to carry on normal activities. Minor signs or symptoms of disease
    • 80 – normal activity with effort
    • 70 – care for self, unable to carry on normal activity or do active work
    • 60 – requires occasional assistance, but able to care for most of his or her needs
    • 50 – requires considerable assistance and frequent medical care
    • 40 – disabled requires special care and assistance
    • 30 – severely disabled, hospitalization indicated though death not imminent
    • 20 – very sick, hospitalization necessary, active supportive treatment necessary
    • 10 - moribund (approaching death, deepening stupor and coma)
    Myeloablative
    Myeloablative is a severe form of myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is a side effect of some cancer treatments.
    Non-myeloablative
    Non-myeloablative (also knowns as reduced intensity conditioning) is a bone marrow transplant in which the individual’s marrow is not completely destroyed prior to receiving the donor’s marrow or stem cells

     

    Systemic Mastocytosis

    Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational to treat any subtype of systemic mastocytosis.

     

    Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the treatment for aggressive systemic mastocytosis (ASM) as a first line treatment when ALL of the following criteria are met:

    • Patient ≤ 60 years of age; and
    • The patient meets the diagnostic criteria for systemic mastocytosis below; and
    • The patient has one or more “C-finding” per WHO Criteria below; or
    • Eligible organ damage finding per IWG-MRT-ECNM criteria below; and
    • Does not meet the criteria for mast cell leukemia below.

     

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the treatment for systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) when ALL of the following criteria are met:

    • Patient ≤ 60 years of age; and
    • The patient meets the diagnostic criteria for systemic mastocytosis below; and
    • Systemic mastocytosis (SM) component is requiring more immediate treatment (e.g. 1 or more “C Findings” below); and
    • There is also progression of AHN (associated hematologic neoplasm) (i.e. myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, lymphoma) requiring treatment.

     

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the treatment for acute mast cell leukemia (MCL) when ALL of the following criteria are met:

    • Patient ≤ 60 years of age; and
    • The patient meets the diagnostic criteria for systemic mastocytosis below; and
    • Bone marrow biopsy shows diffuse infiltration (usually dense) by atypical immature mast cells; and
    • Bone marrow aspirate smears show > 20% mast cells; and
    • The patient has one or more “C-findings” per WHO Criteria below due to mast cell infiltration.

     

    Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation is considered investigational for all other indications except as indicated above.

     

    2017 WHO Diagnostic Criteria for Cutaneous and Systemic Mastocytosis
    Systemic Mastocytosis (SM)

    The diagnosis of SM can be made when the major criterion and at least one minor criterion are present, or when three or more minor criteria are present.

     

    Major Criterion:

    Multifocal, dense infiltrates of mast cells (≥ 15 mast cells in aggregates) detected in sections of bone marrow and/or other extracutaneous organ(s).

     

    Minor Criteria:

    • In biopsy sections of bone marrow or other extracutaneous organs, > 25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology of > 25% of all mast cells in bone marrow aspirate smears, are immature or atypical.
    • Detection of an activating point mutation at codon 816 of KIT in the bone marrow, blood, or another extracutaneous organ.
    • Mast cells in bone marrow, blood or other extracutaneous organs express CD25, with or without CD2, in addition to normal mast cell markers.
    • Serum total tryptase persistently > 20 ng/ml (unless there is an associated myeloid neoplasm, in which case this parameter is not valid).

     

    Systemic Mastocytosis with an Associated Hematological Neoplasm

    • Meets the general criteria for systemic mastocytosis
    • Meets the criteria for an associated hematologic neoplasm (i.e. a myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, lymphoma or another hematological neoplasm classified as a distinct entity in the WHO classification)

     

    Aggressive Systemic Mastocytosis

    • Meets the general criteria for systemic mastocytosis
    • ≥ 1 C finding
    • Does not meet the criteria for mast cell leukemia
    • Skin lesions are usually absent

     

    Mast Cell Leukemia

    • Meets the general criteria for systemic mastocytosis
    • Bone marrow biopsy shows diffuse infiltration (usually dense) by atypical, immature mast cells
    • Bone marrow aspirate smears show ≥ 20% mast cells
    • In classic cases, mast cells account for ≥ 10% of the peripheral blood white blood cells, but the aleukaemic variant (in which mast cells account for < 10% is more common)
    • Skin lesions are usually absent

     

    World Health Organization (WHO) Criteria for B-Findings and C-Findings in Patients with Systemic Mastocytosis (SM)

    B-Findings: Indicate a high burden of mast cells (MCs) and expansion of the neoplastic process into multiple hematopoietic lineages, without evidence of organ damage

    • High mast cells burden (shown on bone marrow biopsy): > 30% infiltration of cellularity by mast cells and (focal dense aggregates) AND serum total tryptase > 200 ng/ml
    • Signs of dysplasia or myeloproliferation in non-mast cell lineage(s), but criteria are not met for definitive diagnosis of an associated hematological neoplasm, with a normal or only slightly abnormal blood counts
    • Hepatomegaly without impairment of liver function, palpable splenomegaly without hyperslenism, and/or lymphadenopathy on palpation or imaging.

     

    C-Findings: Are indicative of organ damage produced by MC infiltration (should be confirmed by biopsy if possible)

    • Bone marrow dysfunction caused by neoplastic mast cell infiltration, manifested by ≥ 1 cytopenia; absolute neutrophil count < 1.0 x109/L, hemoglobin level <10 g/dl, and/or platelet count < 100 x 109/L
    • Palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension
    • Skeletal involvement, with large osteolytic lesions with or without pathologic fractures (pathologic fractures caused by osteoporosis do not qualify as a C finding)
    • Palpable splenomegaly with hypersplenism
    • Malabsorption with weight loss due to gastrointestinal mast cell infiltrates

     

    IWG-MRT-SCNM Criteria for Eligible Organ Damage to Assess Clinical Improvement (CI) and Treatment Response
    Nonhematologic
    Organ DamageOrgan Damage Eligible for CI ResponseCI Response Criteria
    Ascites or pleural effusions
    1. Symptomatic ascites or pleural effusion requiring medical intervention such as use of diuretics (grade 2), OR
    2. > 2 therapeutic paracenteses or thoracenteses at least 28 days apart over 12 weeks prior to study entry (grade 3), and one of the procedures is performed during the 6 weeks prior drug start
    1. Complete resolution of symptomatic ascites or pleural effusion AND no longer in need of diuretic(s) for > 12 weeks, OR
    2. No therapeutic paracentesis or thoracentesis for > 12 weeks
    Liver function abnormalities > Grade 2 abnormalities in direct bilirubin, AST, ALT, AP in the presence of ascites, and/or clinically relevant portal hypertension, and/or liver MC infiltration that is a biopsy-proven or other causes for abnormal liver function are not identified Reversion of 1 or more liver function tests to normal range for > 12 weeks
    Hypoalbuminemia > Grade 2 hypoalbuminemia (3.0 g/dL) Reversion of albumin to normal range for > 12 weeks
    Symptomatic marked splenomegaly Symptomatic marked splenomegaly: a spleen that is palpable > 5 cm below that left costal margin and the patient endorses symptoms of discomfort and/or early satiety > 50% reduction in palpable splenomegaly and no endorsement of discomfort and/or early satiety for > 12 weeks (3D computed tomography/magnetic resonance imaging evaluation may also be undertaken)

     

    IWG-MRT-ECNM Criteria for Eligible Organ Damage to Assess Clinical Improvement (CI) and Treatment Response
    Hematologic
    Organ Damage Organ Damage Eligible for CI Response CI Response Criteria
    ANC Baseline grade > ANC (<1 x109/L) A minimum 100% increase in the ANC and an ANC of at least 0.5 x 109/L for > 12 weeks
    Anemia (transfusion-independent) Grade > 2 anemia (Hb < 10 g/dL) An increase in Hb level of at lest 2 g/dL that is maintained for > 12 weeks
    Anemia (transfusion dependent) Transfusion of a minimum of 6 units of PRBC in the 12 weeks before the start of treatment with the most recent transfusion occurring in the previous 4 weeks. RBC transfusions are only considered as part of the baseline criteria if they are administered for an Hb level
    < 8.5 g/dL and not associated with bleeding, hemolysis, or therapy
    Transfusion independence for > 12 weeks and maintenance of a minimum Hb level of 8.5 g/dL at the end of the 12 week period of response duration
    Thromobocytopenia (transfusion-independent) Grade > 2 thrombocytopenia (<75 x 109/L) A minimum of 100% increase in the platelet count and an absolute platelet count increase of at least 50 x 109/L and no need for platelet transfusions for > 12 weeks
    Thrombocvtopenia (transfusion-dependent)
    1. Transfusion of a minimum of 6 units of apheresed platelets during the 12 weeks preceding treatment; and
    2. at least 2 units transfused in the previous 4 weeks; and
    3. transfusions are administered only for a platelet count < 20 x 109/L
    Transfusion independence for a minimal period of 12 weeks and maintenance of a platelet count of > 20 x 109/L

       

      Waldenstrom Macroglobulinemia

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for salvage therapy of chemosensitive Waldenstrom macroglobulinemia.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational to treat Waldenstrom macroglobulinemia.

       

      Definitions
      Salvage therapy
      Salvage therapy is treatment that is given after the cancer has not responded to other treatment

       

      Amyloidosis

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat primary systemic amyloidosis.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational to treat primary systemic amyloidosis.

       

      Multiple Myeloma and POEMS Syndrome

      Multiple Myeloma

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      A single autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat multiple myeloma after primary therapy.

       

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the treatment of progressive or relapsed multiple myeloma who did not receive an autologous stem cell transplant as part of their initial treatment.

       

      A second autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat responsive multiple myeloma that has relapsed after a complete or partial remission following an initial autologous hematopoietic stem cell transplantation.

       

      Tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat multiple myeloma after primary therapy.

       

      Tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary in patients who fail to achieve at least a near complete or very good partial response (VGPR) after the first transplant in the tandem sequence.

       

      Tandem transplantation with an initial round of autologous hematopoietic stem cell transplantation (bone marrow transplantation) followed by a non-myeloabltive conditioning regimen and allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) (i.e. reduced intensity conditioning regimen) is considered medically necessary to treat relapsed or progressive disease.

       

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) including tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for all other indications not meeting the criteria above.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the following:

      • Tandem transplantation with an initial round of autologous hematopoietic stem cell transplantation (bone marrow transplantation) followed by a non-myeloablative conditioning regimen allogeneic hematopoietic stem cell transplantation (i.e. reduced-intensity conditioning regimen) to treat relapsed or progressive disease.

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) myeloablative or non-myeloablative is considered investigational for all other indications not meeting the criteria above.

       

      Definitions
      Myeloablative
      Myeloablative is a severe form of myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is a side effect of some cancer treatments.
      Non-myeloablative
      Non-myeloablative (also knowns as reduced intensity conditioning) is a bone marrow transplant in which the individual’s marrow is not completely destroyed prior to receiving the donor’s marrow or stem cells.

       

      Response criteria for multiple myeloma by International Myeloma Working Group (NCCN)
      • Complete response: negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow aspirates.
      • Very good partial response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 h.
      • Partial response: ≥ 50% reduction of serum M-protein please reduction in 24 h urinary M-protein by ≥ 90% or to < 200 mg per 24 h. If the serum and urine M-protein are unmeasurable, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria.

       

      If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥ 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥ 30%. In addition to these criteria, if present at baseline, a ≥ 50% reduction in the size (sum of the products of the maximal perpendicular diameters (SPD) of measure lesions) of soft tissue plasmacytomas is also required.

      • Minimal response: ≥ 25% but 49% reduction of serum M-protein and reduction in 24 h urine M-protein by 50%-89%. In addition to the above listed criteria, if present at baseline, a 25%-49% reduction in SPD of soft tissue plasmacytomas is also required.
      • Progressive disease: Increase of 25% from lowest confirmed response value in one or more of the following criteria:
        • Serum M-protein (absolute increase must be ≥ 0.5 g/dL);
        • Serum M-protein increase ≥ 1g/dL, if the lowest M component was ≥ 0.5 g/dL;
        • Urine M-protein (absolute increase must be ≥ 200 mg/24 h;
        • In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL);
        • In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be ≥ 10%);
        • Appearance of a new lesion(s), ≥ 50% increase from nadir in SPD of > 1 lesion, or ≥ 50% increase in the longest diameter of a previous lesion > 1 cm in short axis;
        • ≥ 50% increase in circulating plasma cells (minimum of 200 cells per uL) if this is the only measure of disease.
      • Clinical relapse: Clinical relapse requires one or more of the following criteria:
        • Direct indicators of increasing disease and/or end organ dysfunction (calcium elevation, renal failure, anemia, lytic bone lesions [CRAB features] related to the underlying clonal plasma-cell proliferative disorder. It is not used in calculation of time to progression or progression-free survival but is listed as something that can be reported optionally or for use in clinical practice;
        • Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression);
        • Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥ 1cm) increase as measured serially by the SPD of the measurable lesion;
        • Hypercalcemia (>11 mg/dL);
        • Decrease in hemoglobin of ≥ 2 g/dL not related to therapy or other non-myeloma related conditions;
        • Rise in serum creatinine by 2 mg/dL or more from the start of therapy and attributable to myeloma;
        • Hyperviscosity related to serum paraprotein.
      • Relapse from complete response (to be used only if the endpoint is disease-free survival) any one of the following criteria:
        • Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
        • Developmental of ≥ 5% plasma cells in the bone marrow;
        • Appearance of any other sign of progression (i.e. new plasmacytoma, lytic bone lesion, or hypercalcemia).
      • Relapse from MRD negative (to be used only if the endpoint is disease-free survival) any one of the following criteria:
        • Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive imaging study for recurrence of myeloma);
        • Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
        • Development of ≥ 5% clonal plasma cells in the bone marrow;
        • Appearance of any other sign of progression (i.e. new plasmacytoma, lytic bone lesion; or hypercalcemia).

       

      POEMS Syndrome (Polyneuropathy, Organmegaly, Endocrinopathy, Monoclonal Gammopathy and Skin Abnormalities)

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat disseminated POEMS syndrome.

       

      Note: Patients with disseminated POEMS syndrome may have diffuse sclerotic lesions or disseminated bone marrow involvement.

       

      Tandem autologous hematopoietic stem cell transplantation is considered investigational to treat POEMS syndrome.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (Bone Marrow Transplantation) is considered investigational to treat POEMS syndrome.

       

      Hodgkin Lymphoma

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary in patients with primary refractory or relapsed Hodgkin lymphoma.

       

      Tandem autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the following:

      • In patients with primary refractory Hodgkin lymphoma; or
      • In patients with relapsed disease with poor risk features who do not attain a complete remission after cytoreductive chemotherapy prior to transplantation.

       

      A second autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for relapsed Hodgkin lymphoma after a prior autologous hematopoietic stem cell transplantation.

       

      All other uses of autologous hematopoietic stem cell transplantation (bone marrow transplantation) for patients with Hodgkin lymphoma is considered investigational including, but not limited to, initial or up-front therapy for newly diagnosed disease to consolidate a first complete remission.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) using either myeloablativbe or reduced intensity conditioning regimens (non-myeloablative) is considered medically necessary for the following:

      • Individuals with primary refractory or relapsed Hodgkin lymphoma; or
      • Individuals who relapse after autologous hematopoietic stem cell transplantation that was used to treat primary refractory or relapsed disease

       

      Note: Reduced intensity conditioning regimens (non-myeloablative allogeneic transplantation) would be considered for individuals who would otherwise qualify for a myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), but would not tolerate standard myeloablative conditioning regimen. This may include the following age typically > 60 years or comorbidities (e.g. liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score).

       

      All other uses of allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) for patients with Hodgkin lymphoma is considered investigational including, but not limited to, initial or up-front therapy for newly diagnosed disease to consolidate a first complete remission.

       

      Definitions
      Karnofsky Performance Status
      Karnofsky Performance Status is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The scores on the scale range from 0 to 100. A higher score means the individual is better able to carry out daily activities. The Karnofsky Performance Status may be used to determine the individuals prognosis, to measure changes in an individual’s ability to function or to decide whether an individual could be included in a clinical trial.
      • 100 – normal no complaints
      • 90 – able to carry on normal activities. Minor signs or symptoms of disease
      • 80 – normal activity with effort
      • 70 – care for self, unable to carry on normal activity or do active work
      • 60 – requires occasional assistance, but able to care for most of his or her needs
      • 50 – requires considerable assistance and frequent medical care
      • 40 – disabled requires special care and assistance
      • 30 – severely disabled, hospitalization indicated though death not imminent
      • 20 – very sick, hospitalization necessary, active supportive treatment necessary
      • 10 - moribund (approaching death, deepening stupor and coma)
      Myeloablative
      Myeloablative is a severe form of myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is a side effect of some cancer treatments.
      Non-myeloablative
      Non-myeloablative (also knowns as reduced intensity conditioning) is a bone marrow transplant in which the individual’s marrow is not completely destroyed prior to receiving the donor’s marrow or stem cells.
      Poor-risk relapsed Hodgkin lymphoma
      Poor-risk relapsed Hodgkin lymphoma may be defined as 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV at relapse, and relapse within previously irradiated sites.
      Primary refractory Hodgkin lymphoma
      Primary refractory Hodgkin lymphoma may be defined as disease regression less than 50% after 4 to 6 cycles of doxorubicin-containing chemotherapy or disease progression during induction or within 90 days after the end of the first-line treatment.

       

      Non-Hodgkin Lymphoma (NHL)

      • See also medical policies
        • 08.01.29 Yescarta (Axicabtagene Ciloleucel)*
        • 08.01.30 Kymriah (Tisagenleleucel)*

       

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      For Patients with Non-Hodgkin Lymphoma (NHL) B-cell Subtypes Considered Aggressive (Except Mantle Cell Lymphoma)

       

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for patients with aggressive non-Hodgkin lymphoma B-cell subtypes (except mantel cell lymphoma) for any of the following:

      • As salvage therapy for patients who do not achieve complete remission after first-line treatment (induction) with a full course of standard-dose chemotherapy; or
      • To consolidate a first complete remission in individuals with diffuse large B-cell lymphoma, whose age adjusted International Prognostic Index score that predicts a high or high-intermediate risk of relapse; or
      • To achieve or consolidate a complete remission for those in a chemosensitive first or subsequent relapse.

       

      For Patients with Non-Hodgkin Lymphoma (NHL) B-cell Subtypes Considered Indolent

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for patients with indolent non-Hodgkin lymphoma B-cell subtypes for any of the following:

      • As salvage therapy for patients who do not achieve complete remission after first-line treatment (induction) with a full course of standard-dose chemotherapy; or
      • To achieve or consolidate complete remission in patients in a first or subsequent chemosensitive relapse, regardless of whether the lymphoma has progressed (transformed) to a higher grade.

       

      For Patients with Mantle Cell Lymphoma

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for patients with mantel cell lymphoma to consolidate a first remission.

       

      Patients with Mature T-Cell or Natural Killer Cell (Peripheral T-Cell) Neoplasms

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for patients with mature T-cell or NK-cell (peripheral T-cell) neoplasms:

      • To consolidate a first complete remission in high risk subtypes; or
      • As salvage therapy; or
      • To treat peripheral T-cell lymphoma in patients with relapsed or refractory disease

       

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for any of the following:

      • As initial therapy (i.e. without a full course of standard-dose induction chemotherapy) for any non-Hodgkin lymphoma; or
      • To consolidate a first complete remission in patients with diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index Score that predicts a low or low-intermediate risk of relapse; or
      • To consolidate a first complete remission in individuals with indolent (slow-growing) non-Hodgkin lymphoma B-cell subtypes; or
      • As salvage therapy for mantle cell lymphoma (MCL); or
      • Tandem transplants to treat individuals with any stage, grade, or subtype of non-Hodgkin lymphoma.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      For Patients with Non-Hodgkin Lymphoma (NHL) B-cell Subtypes Considered Aggressive (Except Mantle Cell Lymphoma)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for aggressive non-Hodgkin lymphoma B-cell subtypes (except mantel cell lymphoma) using a myeloablative conditioning regimen for any of the following:

      • As salvage therapy for patients who do not achieve complete remission after first-line treatment (induction) with a full course of standard dose chemotherapy; or
      • To consolidate a first complete remission in individuals with diffuse large B-cell lymphoma whose age-adjusted International Prognostic Index score predicts a high or high-intermediate risk of relapse; or
      • To achieve or consolidate a complete remission in patients in chemosensitive first or subsequent relapse.

       

      For Patients with Non-Hodgkin Lymphoma (NHL) B-cell Subtypes Considered Indolent

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for indolent non-Hodgkin lymphoma B-cell subtypes using a myeloablative conditions regimen for any of the following:

      • As salvage therapy for patients who do not achieve complete remission after first-line treatment (induction) with a full course of standard dose chemotherapy; or
      • To achieve or consolidate complete remission in individuals in a first or subsequent chemosensitive relapse, regardless of whether the lymphoma has progressed (transformed) to a higher grade.

       

      Reduced Intensity Conditioning (Non-Myeloablative) Allogeneic Stem Cell Transplantation

      Reduced intensity conditioning (non-myeloablative) allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for the treatment of non-Hodgkin lymphoma in patients who meet the criteria for an allogeneic hematopoietic stem cell transplantation but who do not qualify for myeloablative allogeneic hematopoietic stem cell transplantation.

       

      Note: Reduced intensity conditioning regimens (non-myeloablative allogeneic transplantation) would be considered for individuals who would otherwise qualify for a myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), but would not tolerate standard myeloablative conditioning regimen. This may include the following age typically > 60 years or comorbidities (e.g. liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score).

       

      For Patients with Mantle Cell Lymphoma

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for patients with mantel cell lymphoma as salvage therapy using myeloablative or reduce intensity conditioning (non-myeloablative).

       

      Patients with Mature T-Cell or Natural Killer Cell (Peripheral T-Cell) Neoplasms

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for patients with mature T-cell or NK-cell (peripheral T-cell) neoplasms as salvage therapy using myeloablative or reduced intensity conditioning (non-myeloablative).

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for any of the following:

      • As initial therapy (i.e. without a full course of standard dose induction chemotherapy) for any non-Hodgkin lymphoma; or
      • To consolidate a first complete remission in individuals with diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index score that predicts a low or low-intermediate risk of relapse; or
      • To consolidate a first complete remission in individuals with indolent (slow growing) non-Hodgkin’s lymphoma B-cell subtypes; or
      • Tandem transplants to treat individuals with any stage, grade, or subtype of non-Hodgkin lymphoma; or
      • To consolidate a first remission in individuals with mantel cell lymphoma; or
      • To consolidate a first remission in individuals with mature T-cell or NK-cell (peripheral T-cell) neoplasms.

       

      Definitions
      Aggressive NHL
      These types of non-Hodgkin’s lymphoma (NHL) may develop rapidly, and treatment is usually started immediately.
      Chemosensitive relapse
      Chemosensitive relapse is defined as relapsed non-Hodgkin’s lymphoma that does not progress during or immediately after standard dose chemotherapy (i.e. achieve stable disease or a partial response).
      Complete response
      Complete response (also known as complete remission) is the disappearance of all signs of cancer in response to treatment; this does not always mean the cancer has been cured.
      Indolent cancer
      Indolent cancer is a type of cancer that grows slowly.
      Karnofsky Performance Status
      Karnofsky Performance Status is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The scores on the scale range from 0 to 100. A higher score means the individual is better able to carry out daily activities. The Karnofsky Performance Status may be used to determine an individual’s prognosis, to measure changes in an individual’s ability to function, or to decide whether an individual could be included in the clinical trial.
      • 100 – normal no complaints
      • 90 – able to carry on normal activities. Minor signs or symptoms of disease
      • 80 – normal activity with effort
      • 70 – care for self, unable to carry on normal activity or do active work
      • 60 – requires occasional assistance, but able to care for most of his or her needs
      • 50 – requires considerable assistance and frequent medical care
      • 40 – disabled requires special care and assistance
      • 30 – severely disabled, hospitalization indicated though death not imminent
      • 20 – very sick, hospitalization necessary, active supportive treatment necessary
      • 10 - moribund (approaching death, deepening stupor and coma)
      Myeloablative
      Myeloablative is a severe form of myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is a side effect of some cancer treatments.
      Non-myeloablative
      Non-myeloablative (also knowns as reduced intensity conditioning) is a bone marrow transplant in which the individual’s marrow is not completely destroyed prior to receiving the donor’s marrow or stem cells.
      Salvage therapy
      Salvage therapy is a treatment that is given after the cancer has not responded to other treatments i.e. refractory or relapsed disease. For patients with peripheral T-cell lymphomas, salvage therapy includes patients who do not achieve a complete response (e.g. achieve only a partial response, have no response or have progressive disease) with first-line induction chemotherapy (refractory disease) or who relapse after achieving a complete response with first-line induction chemotherapy. For mantel cell lymphoma, salvage therapy includes patients with progressive disease with first-line induction chemotherapy (refractory disease) or in patients who relapse after a complete response or partial response after initial induction chemotherapy, or patients who fail a previous autologous hematopoietic stem cell transplantation.
      Transformation
      Transformation describes a lymphoma whose histologic pattern has evolved to a higher grade lymphoma. Transformed lymphomas typically evolve from a nodular pattern to a diffuse pattern.

       

      International Prognostic Index:

      Low Risk = 0-1 points; Low Intermediate = 2 points; High Intermediate = 3 points; High Risk = 4-5 points.

       

      0 Points for any of the following:

      • Age less than 60 years
      • Tumor stage I or II
      • Extranodal involvement (ENI) 0-1
      • Performance status (PS) Eastern Cooperative Oncology Group (ECOG) 0-1
      • Lactate dehydrogenase (LDH) normal

      1 Point for presence of each:

      • Age greater than 60 years
      • Tumor stage III or IV
      • Extranodal involvement (ENI) greater than 1
      • Performance status (PS) Eastern Cooperative Oncology Group (ECOG) 2-4
      • Lactate dehydrogenase (LDH) greater than normal

       

      Eastern Cooperative Oncology Group (ECOG) Performance Status

      • 0 - Fully active able to carry on all pre-disease performance without restriction
      • 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g. light house work, office work)
      • 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours.
      • 3 - Capable of only limited self-care. Confined to bed or chair more than 50% of waking hours.
      • 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
      • 5 - Dead

       

      WHO Classification of the Mature B-Cell, T-Cell and NK-Cell Neoplasms (2017) (NCCN)

      Mature B-Cell Neoplasms

      * denotes indolent types of lymphoma

      + denotes aggressive types of lymphoma

      • Chronic lymphocytic leukemia/small lymphocytic lymphoma*
      • Monoclonal B-cell lymphocytosis
      • B-cell prolymphocytic leukemia+
      • Splenic marginal zone lymphoma*
      • Hairy cell leukemia*
      • Splenic B-celllymphoma/leukemia unclassifiable
        • Splenic diffuse red pulp small B-cell lymphoma
        • Hairy cell leukemia variant
      • Lymphoplasmacytic lymphoma*
        • Waldenstrom’s macronglobulinemia
      • Monoclonal gammopathy of undetermined significance (MGUS), IgM
        • heavy-chain disease
      • Monoclonal gammopathy of undetermined significance (MGUS), IgG/A
      • Plasma cell myeloma
      • Solitary plasmacytoma of bone
      • Extraosseous plasmacytoma
      • Monoclonal immunoglobulin deposition diseases
      • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT type)
      • Nodal marginal zone lymphoma*
        • Pediatric nodal marginal zone lymphoma
      • Follicular lymphoma*
        • In situ follicular neoplasia
        • Duodenal type follicular lymphoma
      • Pediatric type follicular lymphoma
      • Large B-cell lymphoma with IRF4 rearrangement
      • Primary cutaneous follicle center lymphoma
      • Mantel cell lymphoma+
        • In situ mantel cell neoplasia
      • Diffuse large B-cell lymphoma (DLBCL), NOS+
        • Germinal center B-cell type
        • Activated B-cell type
      • T-cell/histocyte-rich large B-cell lymphoma
      • Primary DLBCL of the central nervous system (CNS)
      • Primary cutaneous DLBCL, leg type
      • EBV-positive DLBCL, NOS
      • EBV-positive mucocutaneous ulcer
      • DLBCL associated with chronic inflammation
      • Lymphomatoid granulomatosis
      • Primary mediastinal (thymic) large B-cell lymphoma+
      • Intravascular large B-cell lymphoma+
      • ALK-positive large B-cell lymphoma
      • Plasmablastic lymphoma
      • Primary effusion lymphoma+
      • HHV8-positive DLBCL, NOS
      • Burkitt lymphoma+
      • Burkitt-like lymphoma with 11q aberration+
      • High grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
      • High grade B-cell lymphoma, NOS
      • B-cell lymphoma, unclassified with features intermediate between DLBCL and classical Hodgkin lymphoma

       

      Mature T-Cell and NK-Cell Neoplasms

      • T-cell prolymphocytic leukemia
      • T-cell large granular lymphocytic leukemia
      • Chronic lymphoproliferative disorder of NK-cells
      • Aggressive NK-cell leukemia
      • Systemic EBV-positive T-cell lymphoma of childhood
      • Hydroa vacciniforme-like lymphoproliferative disorder
      • Adult T-cell leukemia/lymphoma
      • Extranodal NK/T-cell lymphoma, nasal type
      • Enteropathy-associated T-cell lymphoma
      • Monomorphic epitheliotropic intestinal T-cell lymphoma
      • Indolent T-cell lymphoproliferative disorder of the GI tract
      • Hepatosplenic T-cell lymphoma
      • Subcutaneous panniculitis-like T-cell lymphoma
      • Mycosis fungoides
      • Sezary syndrome
      • Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
        • Lymphomatoid papulosis
        • Primary cutaneous anaplastic large cell lymphoma
      • Primary cutaneous gamma-delta T-cell lymphoma
      • Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma
      • Primary cutaneous acral CD8-positive T-cell lymphoma
      • Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder
      • Peripheral T-cell lymphoma NOS
      • Angioimmunoblastic T-cell lymphoma
      • Follicular T-cell lymphoma
      • Nodal peripheral T-cell lymphoma with TFH phenotype
      • Anaplastic large-cell lymphoma, ALK positive
      • Anaplastic large-cell lymphoma, ALK negative
      • Breast implant – associated anaplastic large cell lymphoma

       

      Staging Lugano Modification of Ann Arbor Staging System (for Primary Nodal Lymphomas)* (NCCN) Extent of disease is determined by PET/CT for avid lymphomas, and CT for non-avid histologies
      StageInvolvementExtranodal Status
      Limited Stage I One node or a group of adjacent nodes Single extranodal lesions without nodal involvement
      Stage II Two or more nodal groups on the same side of the diaphragm Stage I or II by nodal extent with limited contiguous extranodal involvement
      Stage II Bulky** Whether II bulky is treated as limited or advanced disease may be determined by histology and a number of prognostic factors II as above with “bulky” disease Not applicable
      Advanced Stage III

      Nodes on both sides of the diaphragm

      Nodes above the diaphragm with spleen involvement

      Not applicable
      Stage IV Additional non-contiguous extralymphatic involvement Not applicable

       

      RAI System
      StageDescriptionModified Risk Status
      O Lymphocytes in blood > 5 x 109/L clonal B-cells and >40% lymphocytes in the bone marrow Low
      I Stage 0 with enlarged node(s) Intermediate
      II Stage 0-1 with splenomegaly, hepatomegaly, or both Intermediate
      III Stage 0-II with hemoglobin < 11.0 g/dL or hematocrit <33% High
      IV Stage 0-III with platelets <100,000/mcL High

       

      Binet System
      StageDescription
      A Hemoglobin ≥ 10g/dL and platelets ≥ 100,000/mm3 and < 3 enlarged areas
      B Hemoglobin ≥ 10g/dL and platelets ≥ 100,000/mm3 and ≥ 3 enlarged areas
      C Hemoglobin < 10g/dL and/or platelets < 100,000/ mm3 and any number of enlarged areas

       

      SLL staging System (NCCN)
      StageInvolvementExtranodal Status
      Limited
      Stage I One node or a group of adjacent nodes Single extranodal lesions without nodal involvement
      Stage II Two or more nodal groups on the same side of the diaphragm Stage I or II by nodal extent with limited contiguous extranodal involvement
      Stage II bulky II as above with “bulky” disease
      Note:Whether II bulky is treated as limited or advanced disease may be determined by histology and a number of prognostic factors.
      Not applicable
      Advanced
      Stage III Nodes on both sides of the diaphragm/Nodes above the diaphragm with spleen involvement Not applicable
      Stage IV Additional non-contiguous extralymphatic involvement Not applicable

       

      Prognostic Information for CLL/SLL (NCCN)(Markers of Poor Prognosis in CLL/SLL)
      TP53 and Immunoglobulin Heavy-Chain Variable (IGHV) Region Gene Mutation and Surrogates by Flow Cytometry
       FavorableUnfavorable
      DNA sequencing
      TP53 Unmutated Mutated
      IGHV >2% mutation ≤2% mutation
      Flow Cytometry
      CD38 <30% ≥30%
      Zap 70 <20% ≥20%
      CD46d <30% ≥30%

       

      Interphase Cytogenetics (FISH)
      UnfavorableNeutralFavorable
      del(11q) Normal Del(13q) (as a sole abnormality)
      del(17p) +12  

       

      Complex Karyotype
      Unfavorable
      ≥3 unrelated chromosome abnormalities in more than one cell on karyotype

       

      Chronic Myeloid Leukemia

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is investigational as a treatment of chronic myeloid leukemia (CML).

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) using a myeloablative conditioning regimen is considered medically necessary as a treatment of chronic myeloid leukemia (CML).

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) using a reduced intensity conditioning regimen (non-myeloablative) is considered medically necessary as a treatment of chronic myeloid leukemia (CML) in patients who meet clinical criteria for an allogeneic hematopoietic stem cell transplantation but who are not considered candidates for myeloablative conditioning allogeneic hematopoietic stem cell transplantation.

       

      Note: Reduced intensity conditioning regimens (non-myeloablative allogeneic transplantation) would be considered for individuals who would otherwise qualify for a myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), but would not tolerate standard myeloablative conditioning regimen. This may include the following age typically > 60 years or comorbidities (e.g. liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score).

       

      Definitions
      Karnofsky Performance Status
      Karnofsky Performance Status is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The scores on the scale range from 0 to 100. A higher score means the individual is better able to carry out daily activities. The Karnofsky Performance Status may be used to determine an individual’s prognosis, to measure changes in an individual’s ability to function, or to decide whether an individual could be included in the clinical trial.
      • 100 – normal no complaints
      • 90 – able to carry on normal activities. Minor signs or symptoms of disease
      • 80 – normal activity with effort
      • 70 – care for self, unable to carry on normal activity or do active work
      • 60 – requires occasional assistance, but able to care for most of his or her needs
      • 50 – requires considerable assistance and frequent medical care
      • 40 – disabled requires special care and assistance
      • 30 – severely disabled, hospitalization indicated though death not imminent
      • 20 – very sick, hospitalization necessary, active supportive treatment necessary
      • 10 - moribund (approaching death, deepening stupor and coma)
      Myeloablative
      Myeloablative is a severe form of myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is a side effect of some cancer treatments.
      Non-myeloablative
      Non-myeloablative (also knowns as reduced intensity conditioning) is a bone marrow transplant in which the individual’s marrow is not completely destroyed prior to receiving the donor’s marrow or stem cells

       

      Acute Myeloid Leukemia

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Autologous Hematopoietic Stem Cell Transplantation (bone marrow transplantation) is considered medically necessary to treat acute myeloid leukemia (AML) in first complete remission or beyond, or relapsed acute myeloid leukemia, if responsive to intensified induction chemotherapy in patients who are not candidates for allogeneic hematopoietic stem cell transplantation (bone marrow transplantation).

       

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational to treat acute myeloid leukemia (AML) for all other indications except as indicated above.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) using a myeloablative conditioning regimen is considered medically necessary to treat patients with acute myeloid leukemia (AML) with one of the following:

       

      • Poor to intermediate risk acute myeloid leukemia (AML) in first complete remission; or
      • Acute myeloid leukemia (AML) that is refractory to standard induction chemotherapy but can be brought in complete remission with intensified induction chemotherapy; or
      • Acute myeloid leukemia (AML) that relapses following chemotherapy induced first complete remission but can be brought into a second complete remission or beyond with intensified induction chemotherapy; or
      • Acute myeloid leukemia (AML) who have relapsed following a prior autologous hematopoietic stem cell transplantation, but can be brought into complete remission with intensified induction chemotherapy and are medically able to tolerate the procedure.

       

      Allogeneic hematopoietic stem cell transplantation reduced intensity conditioning regimen (non-myeloablative) as a treatment for acute myeloid leukemia (AML) is considered medically necessary in patients who are in complete marrow and extramedullary remission (first complete remission or beyond), and who, for medical reasons, would be unable to tolerate a myeloablative conditioning regimen.

       

      Note: Reduced intensity conditioning regimens (non-myeloablative allogeneic transplantation) would be considered for individuals who would otherwise qualify for a myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), but would not tolerate standard myeloablative conditioning regimen. This may include the following age typically > 60 years or comorbidities (e.g. liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score).

       

      Allogeneic hematopoietic stem cell transplantation is considered investigational for all other indications except as indicated above.

       

      Definitions
      Karnofsky Performance Status
      Karnofsky Performance Status is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The scores on the scale range from 0 to 100. A higher score means the individual is better able to carry out daily activities. The Karnofsky Performance Status may be used to determine an individual’s prognosis, to measure changes in an individual’s ability to function, or to decide whether an individual could be included in the clinical trial.
      • 100 – normal no complaints
      • 90 – able to carry on normal activities. Minor signs or symptoms of disease
      • 80 – normal activity with effort
      • 70 – care for self, unable to carry on normal activity or do active work
      • 60 – requires occasional assistance, but able to care for most of his or her needs
      • 50 – requires considerable assistance and frequent medical care
      • 40 – disabled requires special care and assistance
      • 30 – severely disabled, hospitalization indicated though death not imminent
      • 20 – very sick, hospitalization necessary, active supportive treatment necessary
      • 10 – moribund (approaching death, deepening stupor and coma)
      Myeloablative
      Myeloablative is a severe form of myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is a side effect of some cancer treatments.
      Non-myeloablative
      Non-myeloablative (also knowns as reduced intensity conditioning) is a bone marrow transplant in which the individual’s marrow is not completely destroyed prior to receiving the donor’s marrow or stem cells
      Primary refractory acute myeloid leukemia (AML)
      Primary refractory acute myeloid leukemia is defined as leukemia that does not achieve a complete remission after conventionally dosed (nonmarrow ablative) chemotherapy.

       

      Risk Status Based on Validated Cytogenetics and Molecular Abnormalities (NCCN)
      Risk StatusCytogeneticsMolecular Abnormalities
      Favorable risk Core binding factor: inv(16) or t(16;16) or T(8;21) or t(15;17) Normal cytogenetics: NPM1 mutation in the absence of FLT3-ITD or isolated biallelic (double) CEBPA mutation
      Intermediate risk Normal cytogenetics
      8 alone
      t(9;11)
      Other non-defined
      Core binding factor with KIT mutation
      Poor risk Complex (≥ 3 clonal chromosomal abnormalities)
      Monosomal karyotype
      -5, 5q-, -7, 7q-
      11 q23 – non t(9;11)
      Inv(3), t(3;3)
      t(6;9)
      t(9;22)
      Normal cytogenetics:
      with FLT3-ITD mutation
      TP53 mutation

       

      Acute Lymphoblastic Leukemia

      • See also medical policy 08.01.30 Kymriah (Tisagelecleucel)*

       

      Childhood Acute Lymphoblastic Leukemia

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in first complete remission but at high risk for relapse.

       

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in second or greater remission, or refractory childhood acute lymphoblastic leukemia (ALL).

       

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for all other indications except as indicated above.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in first complete remission but at high risk for relapse.

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in second or greater remission, or children with refractory acute lymphoblastic leukemia (ALL).

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in relapse after prior autologous hematopoietic stem cell transplantation.

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for all other indications except as indicated above.

       

      Adult Acute Lymphoblastic Leukemia

      Autologous Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat adult acute lymphoblastic leukemia (ALL) in first complete remission but at high risk for relapse.

       

      Autologous hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational to treat adult acute lymphoblastic leukemia (ALL) in second or greater remission or for those patients with refractory disease and for all other indications except as indicated above.

       

      Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat adult acute lymphoblastic leukemia (ALL) in first complete remission for any risk level.

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat adult acute lymphoblastic leukemia (ALL) in second or greater remission, or in adults with relapsed or refractory acute lymphoblastic leukemia (ALL).

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary to treat adult acute lymphoblastic leukemia (ALL) in relapse after prior autologous hematopoietic stem cell transplantation.

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) reduced intensity conditioning (non-myeloablative) is considered medically necessary as a treatment for adult acute lymphoblastic leukemia (ALL) in patients who are in complete marrow and extramedullary first or second remission, and who, for medical reasons would be unable to tolerate a standard myeloablative conditioning regimen.

       

      Note: Reduced intensity conditioning regimens (non-myeloablative allogeneic transplantation) would be considered for individuals who would otherwise qualify for a myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), but would not tolerate standard myeloablative conditioning regimen. This may include the following age typically > 60 years or comorbidities (e.g. liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score).

       

      Allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational for all other indications except as indicated above.

       

      Definitions
      Complete response
      Complete response (also known as complete remission) is the disappearance of all signs of cancer in response to treatment; this does not always mean the cancer has been cured.
      Karnofsky Performance Status Score
      Karnofsky Performance Status Score is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The scores on the scale range from 0 to 100. A higher score means the individual is better able to carry out daily activities. The Karnofsky Performance Status may be used to determine an individua’ls prognosis, to measure changes in an individual’s ability to function, or to decide whether an individual could be included in a clinical trial.
      • 100 – normal no complaints
      • 90 – able to carry on normal activities. Minor signs or symptoms of disease
      • 80 – normal activity with effort
      • 70 – care for self, unable to carry on normal activity or do active work
      • 60 – requires occasional assistance, but able to care for most of his or her needs
      • 50 – requires considerable assistance and frequent medical care
      • 40 – disabled requires special care and assistance
      • 30 – severely disabled, hospitalization indicated though death not imminent
      • 20 – very sick, hospitalization necessary, active supportive treatment necessary
      • 10 - moribund (approaching death, deepening stupor and coma)
      Myeloablative
      Myeloablative is a severe form of myelosuppression. Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. It is a side effect of some cancer treatments.
      Non-myeloablative
      Non-myeloablative (also knowns as reduced intensity conditioning) is a bone marrow transplant in which the individuals marrow is not completely destroyed prior to receiving the donor’s marrow or stem cells
      Refractory
      Refractory is a cancer that does not respond to treatment. The cancer may be resistant at the beginning of treatment, or it may become resistant to treatment. Also called resistant cancer.
      Relapse
      Relapse is a cancer that recurs after prior complete response

       

      Relapse Risk Prognostic Factors

      Childhood Acute Lymphoblastic Leukemia (ALL)

      Adverse prognostic factors in children include the following: age younger than 1 year or more than 9 years, male sex, white blood cell count at presentation above 50,000/uL, hypodiploidy (<45 chromosomes), translocation involving chromosomes 9 and 22 (t(9;22)) or BCR/ABL fusion, translocation involving chromosomes 4 and 11 (t(4;11)) or MLL/AF4 fusion, and ProB or T-lineage immunophenotype. Several risk-stratification schema exist, but in general the following findings help define children at high risk of relapse: 1) poor response to initial therapy including poor response to prednisone prophase defined as an absolute blast count of 1000/uL or greater, or poor treatment response to induction therapy at 6 weeks with high risk having 1% or higher minimal residual disease measured by flow cytometry; 2) all children with T-cell phenotype; and 3) patients with either the t(9;22) or t(4;11) regardless of early response measures.

       

      Adult Acute Lymphoblastic Leukemia (ALL)

      Risk factors for relapse are less well defined in adults, but a patient with any of the following may be considered at high risk for relapse: age older than 35 years, leukocytosis at presentation of greater than 30000/uL (B-cell lineage) or greater than 100000/uL (T-cell lineage), “poor prognosis” genetic abnormalities like the Philadelphia chromosome (t[9;22]), extramedullary disease, and time to attain complete remission longer than 4 weeks.

       

      Cytogenetic Risk Groups for ALL (NCCN)
      Risk GroupsCytogenetics
      Good Risk Hyperdiploidy (51-65 chromosomes; cases with trisomy of chromosomes 4, 10, and 17 appear to have the most favorable outcome); t(12;21) (p13;q22): ETV6-RUNX1
      Poor Risk Hypodiploidy (< 44 chromosomes); t(v;11q23):t(4;11) and other KMT2A rearranged
      t(--;11q23); t(9;22)(q34;q11.2): BCR-ABL 1 (defined as high risk in the pre-TKI era); complex karyotype (5 or more chromosomal abnormalities); Ph-like ALL; intrachromosomal amplification of chromosome 21 (iAMP21)

       

      Reduced Intensity Conditioning Regimen (Non-Myeleoblative) Allogeneic Hematopoietic Stem Cell Transplantation (Bone Marrow Transplantation)

      Reduced intensity conditioning regimen (non-myeloablative) allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered medically necessary for patients unable to tolerate a myeloablative conditioning regimen who would otherwise meet the medical necessity criteria for myeloablative allogeneic hematopoietic stem cell transplantation as indicated above for each of the following conditions:

       

      • Adult Acute lymphoblastic leukemia
      • Acute myeloid leukemia
      • Chronic myeloid leukemia
      • Hodgkin lymphoma
      • Myelodysplastic syndrome
      • Myeloproliferative neoplasms
      • Non-Hodgkin’s lymphoma

       

      Note: Reduced intensity conditioning regimens (non-myeloablative allogeneic transplantation) would be considered for individuals who would otherwise qualify for a myeloablative allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), but would not tolerate standard myeloablative conditioning regimen. This may include the following age typically > 60 years or comorbidities (e.g. liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score).

       

      All other indications for reduced intensity condition regimen (non-myeloablative) allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is considered investigational.

       

      Definitions

      Karnofsky Performance Status Score
      Karnofsky Performance Status Score is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The scores on the scale range from 0 to 100. A higher score means the individual is better able to carry out daily activities. The Karnofsky Performance Status may be used to determine an individua’ls prognosis, to measure changes in an individual’s ability to function, or to decide whether an individual could be included in a clinical trial.
      • 100 – normal no complaints
      • 90 – able to carry on normal activities. Minor signs or symptoms of disease
      • 80 – normal activity with effort
      • 70 – care for self, unable to carry on normal activity or do active work
      • 60 – requires occasional assistance, but able to care for most of his or her needs
      • 50 – requires considerable assistance and frequent medical care
      • 40 – disabled requires special care and assistance
      • 30 – severely disabled, hospitalization indicated though death not imminent
      • 20 – very sick, hospitalization necessary, active supportive treatment necessary
      • 10 - moribund (approaching death, deepening stupor and coma)

       

      Umbilical Cord Blood

      The collection and storage of cord blood stem cells from a newborn may be considered medically necessary when an allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) is imminent in an identified recipient with a condition that is medically appropriate for allogeneic hematopoietic stem cell transplantation.

       

      For patients who do not have a hematopoietic stem cell donor, transplantation of cord blood stem cells from a related or unrelated donor is considered medically necessary if the patient meets the medical necessity criteria outlined above for both the medical condition and allogeneic hematopoietic stem cell transplantation.

       

      Prophylactic collection and storage of cord blood stem cells for future allogeneic or autologous hematopoietic stem cell transplantation is considered not medically necessary when proposed for an unspecified future use as an autologous hematopoietic stem cell transplantation in the original donor, or in a related or unrelated donor for allogeneic hematopoietic stem cell transplantation.

       

      Transplantation of cord blood stem cells from related or unrelated donors in all other situations is considered investigational because the safety and/or efficacy cannot be established by review of the available peer reviewed medical literature.

       

      Syngeneic Transplantation

      Syngeneic hematopoietic stem cell transplantation (transplantation between identical twins) is considered medically necessary when the patient’s condition meets the medical necessity criteria outlined above for allogeneic  hematopoietic stem cell transplantation.

       

      Haploidentical Transplantation

      Haploidentical hemtopoietic stem transplantation is considered medically necessary when ALL of the following criteria is met:

      • The patient’s condition meets the medical necessity criteria outlined above for an allogeneic hematopoietic stem cell transplantation and there is an urgent need for transplant; AND
      • There is no fully HLA matched sibling available (6/6 HLA match); AND
      • The unrelated donor search does not identify an alterantive donor source i.e. a low likelihood of finding an eight of eight allele matched unrelated donor; AND
      • The HLA-haploidentical donor is one of the following: a biological parent, a biological child or a full or half sibling.

       

      Policy Guidelines

      The following factors may be considered as part of the patient’s eligibility for the proposed transplant subject to the judgement of the transplant center:

       

      • Karnofsky score ≥ 70 or Eastern Cooperative Oncology Group (ECOG) 0-2
      • No active infection or infection treated
      • No pulmonary insufficiency
      • No drug or alcohol misuse by history or drug and alcohol free period ≥ 4 weeks
      • Patient understands procedural risk and post procedure compliance of follow-up
      • Patient has adequate social and family support

       

      Notes:

      • Karnofsky Performance Status Score is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The scores on the scale range from 0 to 100. A higher score means the individual is better able to carry out daily activities. The Karnofsky Performance Status may be used to determine an individua’ls prognosis, to measure changes in an individual’s ability to function, or to decide whether an individual could be included in a clinical trial
        • 100 – normal no complaints
        • 90 – able to carry on normal activities. Minor signs or symptoms of disease
        • 80 – normal activity with effort
        • 70 – care for self, unable to carry on normal activity or do active work
        • 60 – requires occasional assistance, but able to care for most of his or her needs
        • 50 – requires considerable assistance and frequent medical care
        • 40 – disabled requires special care and assistance
        • 30 – severely disabled, hospitalization indicated though death not imminent
        • 20 – very sick, hospitalization necessary, active supportive treatment necessary
        • 10 - moribund (approaching death, deepening stupor and coma)
      • Eastern Cooperative Oncology Group (ECOG) status
        • 0- fully active, able to carry on all pre-disease performance without restriction
        • 1 – restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature e.g. light house work, office work
        • 2 – ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
        • 3 – capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
        • 4 – Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
      • Prior to transplantation, all active infections should be treated. Fungal infections often require long-term transplant; however, stem cell transplantation may be appropriate under the guidance of infectious disease specialist if the infection is responding to treatment.
      • Pulmonary insufficiency (abnormal lung function) is a risk factor for poor outcomes following hematopoietic stem cell transplantation
        • Pulmonary insufficiency as evidenced by either forced expiratory volume in one second (FEV1) or diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 50% of predicted value (when applicable DLCO is corrected for hemoglobin level).
          • A left ventricular shortening fraction considered in the normal range at the ordering institution may be substituted in the pediatric population.
          • Pulmonary function tests are generally not performed in the pediatric population given the difficulty in cooperating with the test. Provided the child has an adequate oxygen saturation on room air, a transplant program would consider the child eligible as far as lung function is concerned.
      • A psychosocial evaluation assesses the ability of the patient and his or her support system to cope and adhere to the treatment plan. A psychiatric or substance abuse disorder warrants further evaluation and follow-up.
      • The benefits and potential risks associated with transplantation should be fully explained to patients both verbally and in writing. Patients need to understand the importance of adherence to treatment protocols and follow-up appointments.

       

      Procedure Codes and Billing Guidelines:

      To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

      • 38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
      • 38241 Autologous transplantation

       

      Selected References:

      • Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015;21(11):1863-1869. PMID 26256941
      • Centers for Medicare and Medicaid Services. National Coverage Determination (NCD) for STEM CELL Transplantation (110.8.1). 2010; Version 5
      • Nikolov NP, Pavletic SZ. Technology Insight: hematopoietic stem cell transplantation for systemic rheumatic disease. Nat Clin Pract Rheumatol. Apr 2008;4(4):184-191. PMID 18285764
      • Milanetti F, Abinun M, Voltarelli JC, et al. Autologous hematopoietic stem cell transplantation for childhood autoimmune disease. Pediatr Clin North Am. Feb 2010;57(1):239-271. PMID 20307720
      • Sullivan KM, Muraro P, Tyndall A. Hematopoietic cell transplantation for autoimmune disease: updates from Europe and the United States. Biol Blood Marrow Transplant. Jan 2010;16(1 Suppl):S48-56. PMID 19895895
      • Mancardi GL, Sormani MP, Gualandi F, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. Mar 10 2015;84(10):981-988. PMID 25672923
      • Reston JT, Uhl S, Treadwell JR, et al. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler. Feb 2011;17(2):204-213. PMID 20921236
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      • UpToDate. HLA-Haploidentical Hematopoietic Cell Transplantation. Ephraim J. Fuchs M.D., MBA, Leo Luznik M.D., Topic last updated July 2, 2019.

       

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