Allogeneic Hematopoietic Stem Cell Transplant*

Medical Policy: 08.01.02 
Original Effective Date: March 2004 
Reviewed: October 2011 
Revised: October 2011 

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: 

Transplantation of allogeneic hematopoietic stem cells, derived from bone marrow or peripheral blood, in conjunction with a myeloablative conditioning regimen, is an established therapy for a variety of malignancies including acute and chronic leukemias, Hodgkin’s lymphoma, and non-Hodgkin’s lymphomas. Immunologic compatibility between donor and patient is a crucial factor in achieving a successful outcome. The harvested stem cells are administered to the patient intravenously following conditioning with myeloablative chemotherapy with or without total body irradiation at high enough doses to cause bone marrow failure. The treatment effect results from chemotherapeutic ablation of malignant cells, as well as an associated immune-mediated graft versus malignancy effect.

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Prior Approval: 

Prior approval is recommended. Submit a prior approval now.

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Policy: 

Allogeneic hematopoietic stem cell transplant, in conjunction with a myeloablative conditioning regimen consisting of chemotherapy with or without total body irradiation, may be considered medically necessary for the following conditions:

Non-Hodgkin's Lymphoma (NHL)

For patients with non-Hodgkin lymphoma B-cell subtypes considered aggressive (except mantle cell lymphoma)

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

For patients with mantle cell lymphoma:

• Myeloablative or reduced-intensity conditioning (RIC) as salvage therapy

For patients with non-Hodgkin lymphoma B-cell subtypes considered indolent:

• As salvage therapy for patients who do not achieve complete remission after first-line treatment (induction) with a full course of standard-dose chemotherapy
• To achieve or consolidate complete remission for those in a first or subsequent relapse, whether or not their lymphoma has undergone transformation to a higher grade

Reduced-intensity conditioning (RIC) allogeneic HSCT may be considered medically necessary in patients who meet the criteria for an allogeneic HSCT but whose age (typically older than 55 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy) preclude use of a standard conditioning regimen.

The term salvage therapy describes chemotherapy given to patients who have either failed to achieve complete remission after initial treatment for newly diagnosed lymphoma; or, relapsed after an initial complete first remission.

A chemosensitive relapse is defined as relapsed non-Hodgkin lymphoma that does not progress during or immediately after standard-dose induction therapy (i.e., achieves stable disease or partial response).

Transformation describes a lymphoma whose histologic pattern has evolved to a higher-grade lymphoma. Transformed lymphoma typically evolves from a nodular pattern to a diffuse pattern.

High risk peripheral T-cell lymphoma is defined as one of the following histologic subtypes:

Nodal: peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-ALCL) or angioimmunoblastic lymphoma (AIL). High-risk patients may also include the rare patient with ALK+ALCL who is refractory to conventional chemotherapy.

Extranodal: T/NK cell lymphoma nasal type, enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma.

Acute Lymphoblastic Leukemia (ALL)

• Adults and children in first complete remission at high risk of relapse
• Adults or children in second or greater remission or refractory ALL
• Adults with relapsed ALL following conventional-dose chemotherapy

Several risk stratification schema exist, but, in general, the following findings help define children at high risk of relapse:

• Poor response to initial therapy including poor response to prednisone prophase defined as an absolute blast count of 1000/µL or greater, or poor treatment response to induction therapy at 6 weeks with high risk having ≥1% minimal residual disease measured by flow cytometry
• All children with T-cell phenotype
• Patients with either the t(9;22) or t(4;11) regardless of response measures

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 greater than 35 years
• Leukocytosis at presentation of >30,000/µL (B-cell lineage) and >100,000/µL (T-cell lineage)
• “Poor prognosis” genetic abnormalities like the Philadelphia chromosome (t(9;22))
• Extramedullary disease
• Time to attain complete remission longer than 4 weeks

Acute  Myeloid Leukemia (AML)

• Treatment of AML in any stage for individuals who have not had previous high dose chemotherapy with stem cell support
• Primary refractory (unable to achieve complete remission after conventional-dose chemotherapy)
• Relapse after attaining a first complete remission following conventional-dose chemotherapy

Chronic Lymphocytic Leukemia (CLL)

Small Lymphocytic Lymphoma (SLL)

Multiple Myeloma

• As a component of a tandem transplant consisting of an autologous HSCT followed by a non-marrow ablative regimen and allogeneic HSCT in patients with newly diagnosed disease

Pediatric Neuroblastoma

• Initial treatment of high-risk neuroblastoma
• Primary refractory or recurrent neuroblastoma in individuals who have not previously undergone treatment with high dose chemotherapy with stem cell support
• Repeat transplant due to primary graft failure or failure to engraft

Myelodysplastic  Syndromes (MDS)

• Refractory anemia
• Refractory neutropenia
• Refractory thrombocytopenia
• Refractory anemia with ring sideroblasts
• Refractory cytopenia with multilineage dysplasia
• Refractory anemia with excess blasts
• Myelodysplastic syndrome with isolated del(5q)
• Myelodysplastic syndrome, unclassifiable
• Childhood myelodysplastic syndrome

Myeloproliferative Neoplasms (MPN)

• Chronic myelogenous leukemia (CML)
• Polycythemia vera
• Essential thrombocytopenia
• Primary myelofibrosis
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia, not otherwise categorized
• Hypereosinophilic syndrome
• Mast cell disease
• MPNs, unclassifiable

Myelodysplastic/myeloproliferative Neoplasms (MDS/MPN)

• Chronic myelomonocytic leukemia (CMML)
• Juvenile myelomonocytic leukemia
• Atypical chronic myeloid leukemia
• MDS/MPN, unclassifiable

Hodgkin’s Disease (Lymphoma)

• Primary refractory
• Relapsed after an initial first remission
• Relapsed after prior therapy with high-dose chemotherapy and autologous stem cell support

Genetic Diseases and Acquired Anemias

• Sickle cell anemia for children or young adults at increased risk of stroke or end-organ damage, and with an HLA-identical, related donor. 

Factors associated with a high risk of stroke or end-organ damage include recurrent chest syndrome, recurrent vaso-occlusive crisis, and red blood cell alloimmunization on chronic transfusion therapy.

• Severe aplastic anemia, including congenital (i.e., Fanconi’s anemia or Diamond-Blackfan syndrome) or acquired (i.e., secondary to drug or toxin exposure) forms.
• Homozygous beta-thalassemia
• Wiskott-Aldrich syndrome
• Severe combined immunodeficiencies
• Albers-Schönberg disease
• Mucopolysaccharidoses (including Hunter’s, Hurler’s, Sanfilippo, Maroteaux-Lamy variants)
• Mucolipidoses (including Gaucher’s disease, metachromatic leukodystrophy, globoid cell leukodystrophy, adrenoleukodystrophy) for patients who have failed conventional therapies.
• Kostmann’s syndrome
• Leukocyte adhesion deficiencies
• X-linked lymphoproliferative syndrome

• Acute Lymphocytic Leukemia (ALL)
  • Relapsing after a prior myeloablative conditioning regimen and autologous stem cell support 
• Acute Myelogenous Leukemia (AML)
  • Relapsing after a prior myeloablative conditioning regimen and autologous stem cell support 
• Epithelial Ovarian Cancer
• Breast Cancer
• Germ Cell Tumors (testicular, mediastinal, retroperitoneal, ovarian)
• Malignant astrocytomas and gliomas
• Multiple myeloma
• Pediatric neuroblastoma following failed autologous stem cell transplant
• Primitive neuroectodermal tumors (PNET), including medulloblastoma and ependymoma
• High-risk solid tumors of childhood, including but not limited to:
  • Ewing sarcoma
  • Wilms' tumor
  • Osteosarcoma
  • Retinoblastoma
  • Rhabdomyosarcoma
  • All high-risk pediatric tumors relapsing after a prior myeloablative conditioning regimen and autologous stem cell support 
• Solid tumors in adults
• Non-Hodgkin's Lymphoma (NHL)
  • As initial therapy (i.e., without a full course of standard-dose induction chemotherapy) for all NHL's subtypes
• Mantle cell lymphoma
  • To consolidate a first remission
• Hodgkin's lymphoma
  • As initial therapy for newly diagnosed disease
  • To consolidate a first complete remission
• Auto-immune diseases including, but not limited to:
  • Multiple Sclerosis
  • Rheumatoid Arthritis
  • Systemic Lupus Erythematosus 

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Procedure Codes and Billing Guidelines: 

The following CPT codes may be used to report services/procedures related to allogeneic bone marrow or peripheral stem cell transplant:

• 38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogenic
• 38207 Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage
• 38208 Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing
• 38209 Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, with washing
• 38210 Transplant preparation of hematopoietic progenitor cells; specific cell depletion within harvest, T-cell depletion
• 38211 Transplant preparation of hematopoietic progenitor cells; tumor cell depletion
• 38212 Transplant preparation of hematopoietic progenitor cells; red blood cell removal
• 38213 Transplant preparation of hematopoietic progenitor cells; platelet depletion
• 38214 Transplant preparation of hematopoietic progenitor cells; plasma (volume) depletion
• 38215 Transplant preparation of hematopoietic progenitor cells; cell concentration in plasma, mononuclear, or buffy coat layer
• 38220 Bone marrow; aspiration only
• 38221 Bone marrow; biopsy, needle or trocar
• 38230 Bone marrow harvesting for transplantation
• 38240 Bone marrow or blood-derived peripheral stem cell transplantation; allogenic
• 38242 Bone marrow or blood-derived peripheral stem cell transplantation; allogeneic donor lymphocyte infusions

The following HCPCS code may be used to report allogeneic bone marrow or peripheral blood stem cell transplant:

• S2150 Bone marrow or blood-derived peripheral stem cell harvesting and transplantation, allogenic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical, surgical, diagnostic and emergency services)

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Selected References: 

• Robinet E, Lapierre V, Tayebi H, et al., Blood versus marrow hematopoietic allogeneic graft. Transfus Apheresis Sci. 2003 Aug; 29(1): 53-9.
• Anagnostopoulos A, Giralt S. Critical review on non-myeloablative stem cell transplantation (NST). Crit Rev Oncol Hematol. 2002;44(2):175-190.
• Berdeja JG, Jones RJ, et al. Allogeneic bone marrow transplantation in patients with sensitive low-grade lymphoma or mantle cell lymphoma. Biol Blood Marrow Transplant. 2001;7(10):561-567.
• Bleakley M, Lau L, Shaw PJ, Kaufman A. Bone marrow transplantation for paediatric AML in first remission: a systematic review and meta-analysis. Bone Marrow transplant. 2002 May; 29(10): 843-52.
• Branson K, Chopra R, et al. Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies. J Clin Oncol. 2002;20(19):4022-4031.
• Storek J, Viganego F, Dawson MA, et al. Factors affecting antibody levels after allogeneic hematopoietic cell transplantation. Blood. 2003 Apr 15; 101(8):3319-24. Epub 2002 Dec 27.
• Levine JE, Uberti JP, Ayash L, et al. Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy. Biol Blood Marrow Transplant. 2003 Mar; 9(3): 189-97.
• Passweg JR, Meyer-Monard S, Gregor M, et al. High stem cell dose will not compensate for t-cell depletion in allogeneic non-myeloablative stem cell transplantation. Bone Marrow Transplant. 2002 Sep; 30(5): 267-71.
• ECRI. High-Dose Chemotherapy (HDC) with Autologous or Allogeneic Stem Cell Transplantation (SCT) or Bone Marrow Transplantation (BMT) for Medulloblastoma. Plymouth Meeting (PA): ECRI Health Technology Information Service; 2002 May 29. (ECRI Hotline Response).
• Hale GA, Tong X, Benaim E et al. Allogeneic bone marrow transplantation in children failing prior autologous bone marrow transplantation. Bone Marrow Transplant 2001; 27(2):155-62.
• Acute Myeloid Leukemia. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. v.2.2005.
• Non-Hodgkin's Lymphoma. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. v.1.2005.
• 2000 Technology Evaluation Center Assessments. Tab 9; Salvage HDC/AlloSCS for Relapse or Incomplete Remission Following HDC/AuSCS for Hematologic Malignancies.
• Perez-Martinez A, Quintero V, Vicent MG et al. High-dose chemotherapy with autologous stem cell rescue as first line of treatment in young children with medulloblastoma and supratentorial primitive neuroectodermal tumors. J Neurooncol. 2004; 67(1-2):101-6.
• Cogliatti S, Schmid U. Who is WHO and what was REAL? A review of the new WHO classification (2001) for malignant lymphoma. Swiss Med Wkly 2002;132:607-617.
• Hahn T, Wingard JR, Anderson KC et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant. 2003 Jan;9(1);4-37.
• Bruno B, Rotta M, Patriarca F et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J med 2007;356:1110-20.
• Kuruvilla J, Shepherd JD, Sutherland HJ et al. Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant. 2007 Aug;13(8):925-31. E-pub 2007 May 29.
• Rosinol L, Perez-Simon JA, Sureda A et al. A prosptective pethema study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008 Jul 8. [E-pub ahead of print].
• Chevallier P, Mohty M, Lioure B et al. Allogeneic Hematopoietic Stem Cell Transplantation for Myeloid Sarcoma: A Retrospective Study from the SFGM-TC. J Clin Oncol 2008 Jul 7 [E-pub ahead of print].
• Vardiman JW, Thiele J, Arber DA et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. July 2009; 114(5): 937-51.
• Lim ZY, Brand R, Martino R et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndrome or secondary acute myeloid leukemia. J Clin Oncol. 2010; 28(3):405-11.
• Sorror ML, Storer BE, Sandmaier BM et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol 2008; 26(30):4912-20.
• Dreger P, Corradini P, Kimby E et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21(1):12-7.
• Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111(12):5446-56.
• Laport GG. The role of hematopoietic cell transplantation for follicular non-Hodgkin’s lymphoma. Biol Blood Marrow Transplant 2006; 12(1 suppl 1):59-65. 
• The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: a predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329(14):987-94.
• Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009:523-31.
• Tam CS, Bassett R, Ledesma C et al. Mature results of the MD Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood 2009; 113(18):4144-52.
• Geisler C. Mantle cell lymphoma: are current therapies changing the course of the disease? Curr Oncol Rep 2009; 11(5):371-7. 
• Gahrton G. Progress in allogeneic transplantation for multiple myeloma. Eur J Hematol 2010; 85(4):279-89.
• Lokhorst H, Einsele H, Vesole D et al. International Myeloma Working Group consensus statement regarding current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol 2010; 28(29):4521-30.
• Pulsipher MA, Boucher KM, Wall D et al. Reduced-intensity allogeneic transplantation  in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow transplant Consortium Study ONC0313. Blood 2009; 114(7):1429-36.
• Cho BS, Lee S, Kim YJ et al. Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study. Leukemia 2009; 23(10):1763-70.
• Ringden O, Shrestha S, da Silva GT et al. Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma. Bone Marrow Transplant. 2011 Sep 26. doi: 10.1038/bmt/2011.192. [Epub ahead of print].
• Zimmerman A, Scott BL, Gopal AK et al. Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and concurrent lymphoid malignancy. Bone Marrow Transplant. 2011 Sep 12. doi: 10.1038/bmt.2011.180. [Epub ahead of print].

• Lazarus HM, Luger S. Which patients with adult acute lymphoblastic leukemia should undergo a hematopoietic stem cell transplantation? Case-based discussion.

  Hematology Am Soc Hematol Educ Program 2007:444-52.
• Fielding AK, Rowe JM, Richards SM et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the international ALL trial MRC UKALLXII/ECOG2993.  

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Policy History: 

Date                                        Reason                               Action

October 2011                         Annual review                    Policy revised

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Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

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