Medical Policy: 08.01.30 

Original Effective Date: October 2018 

Reviewed: October 2018 

Revised: November 2018 

 

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:

Kymriah™ (Tisagenlecleucel) is a genetically modified autologous cellular immunotherapy comprised of 0801 specific to CD19, a cell surface protein found on normal and malignant B-cells. It is a customized treatment that is prepared using an individual patient’s own T-cells. Steps for preparing Kyrimah (tisagenlecleucel) include: collecting a patient’s immune cells from blood via leukapheresis; sending the cells to a manufacturing facility; genetically modifying the patient’s T-cells to produce CD19-specific CARs on their surface; expanding the number of CAR T-cells; returning the cells to the treatment facility; and infusing the CAR T-cells back into the patient. This process takes about 2 weeks. Patients typically receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) prior to intravenous infusion of Kymriah (tisagenlecleucel). Once infused, the CAR T-cells selectively target and bind to CD19-expressing B-cells, thereby promoting T-cell expansion and activation, B-cell depletion, and persistence of the CAR T-cells.

 

Severe and life-threatening adverse reactions have occurred in patients receiving Kymriah (tisagenlecleucel), including cytokine release syndrome (CRS) and neurological toxicities. Due to these safety concerns, the FDA regulates Kymriah (tisagenlecleucel) through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Kymriah REMS. Under the REMS, only certified healthcare facilities can administer Kymriah (tisagenlecleucel). The prescribing information for Kymriah (tisagenlecleucel) also includes a black box warning. The required components of REMS are:

  • Healthcare facilities that dispense and administer CAR-T cell therapy Kymriah must be enrolled and comply with REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of toclizumab are available for each patient for infusion within 2 hours after Kymriah, if needed for treatment of CRS.
  • Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Kymriah are trained about the management of cytokine release syndrome (CRS) and neurological toxicities.

 

Kymriah (Tisagenlecleucel) is currently FDA approved for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse; and for the treatment of adult patients with relapsed and refractory large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DCBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Kymriah is not indicated for the treatment of patients with primary central nervous system lymphoma.

 

Kymriah (Tisagenlecleucel) for Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is a malignancy (clonal) of the bone marrow in which the early lymphoid precursors of the white blood cells (called lymphoblasts) proliferate and replace the normal hematopoietic cells of the marrow. This results in overcrowding of the bone marrow, as well as the peripheral organs (particularly the liver, spleen, and lymph nodes) by the lymphoblasts. As a consequence, the leukemic blasts displace the normal hematopoietic bone marrow and cause cytopenias in all 3 cell lineages (anemia, thrombocytopenia, granulocytopenia). Leukostasis affecting brain and lung may also occur. Death occurs commonly due to severe pancytopenia and resulting infections. Refractory (resistant) disease is defined as those patients who fail to obtain complete response with induction therapy, i.e., failure to eradicate all detectable leukemia cells (<5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (>25% marrow cellularity and normal peripheral blood counts).

 

Approximately 5000 cases of B-cell ALL are diagnosed every year in the United States, and approximately 620 pediatric and young adult patients with B-cell ALL will relapse each year in the United States. It is largely a disease of the young with approximately 60% of cases occurring in patients younger than 20 years old with a median age at diagnosis of 15 years. While it is treatable in 85% cases, approximately 15% of children and young adults with ALL will relapse while 2% to 3% of ALL patients are primary refractory. Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate. The 2-year survival rate among patients with ALL who relapse after hematopoietic cell transplantation is 15%. The Food and Drug Administration approved clofarabine (as a single agent or in combination) in 2004 and blinatumomab in 2014 for relapsed and refractory ALL. Reported median objective response rates in the pivotal trials of the 2 agents were 19.7% and 33%, the median durations of response was 2.5 months and 6 months, and median overall survival durations were 3 months and 7.5 months, respectively. Note that the percentages of patients treated with 3 or more prior treatments of clofarabine and blinatumomab trial were 62% and 7%, respectively. Nevertheless, treatment options for patients with relapsed or refractory ALL are limited, associated with poor outcomes and high toxicity and the disease remains incurable.

 

Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission. Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. MRD positivity is defined as the presence of 0.01% or more ALL cells and has been shown to be a strongest prognostic factor to predict the risk of relapse and death when measured during and after induction therapy in both newly diagnosed and relapsed ALL. In a 2017 meta-analysis of 20 studies of 11,249 pediatric ALL, the hazard ratio for event-free survival in MRD-negative patients compared with MRD-positive patients was 0.23 (95% confidence interval, 0.18 to 0.28).

 

Kymriah (Tisagenlecleucel) is now a treatment option for patients up through age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

 

Rationale

Assessment of efficacy for therapeutic intervention involves a determination of whether an intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes but are prone to biases such as non-comparability of treatment groups, placebo effect, and variable natural history of the condition.

 

Pivotal Trial

In the pivotal trial phase 2 single-arm, international, multicenter trial (study B2202), 68 patients ages 3 to 21 years at screening, with CD19-positive second or greater bone marrow relapse or primary refractory B-cell acute lymphoblastic leukemia were treated with Kymriah (tisagenlecleucel) and followed for 12 months. This trial has not been published; information was obtained from the Food and Drug Administration Oncologic Drugs Advisory Committee Meeting held in July 2017. Sixty-three patients received U.S.-manufactured product while 5 patients received EU-manufactured product. Patients were required to have more than 5% blasts at screening and either ineligible for, or have relapsed after, allogeneic cell transplant. Refractory was defined by not achieving an initial CR after 2 cycles of a standard chemotherapy regimen (primary refractory). Subjects who were refractory to subsequent chemotherapy regimens after an initial remission were considered chemo-refractory.

 

The prespecified primary efficacy end point was the proportion of patient who achieved objective remission rate (ORR; CR or CR with incomplete blood count recovery [CRi]) as assessed by an independent review committee within 3 months after Kymriah (tisagenlecleucel) infusion. The trial would meet its primary objective if the lower bound of the 2-sided 95% confidence intervals for ORR was greater than 20%. The key secondary outcome was proportion of patients who achieve best ORR (CR or CRi with an minimal residual disease [MRD]–negative bone marrow) within 3 months of receiving Kymriah (tisagenlecleucel). Key secondary end points were tested sequentially (after primary end point was significant) to control for overall type I error.

 

Of 107 patients who were screened, 88 met the trial inclusion criteria and of these 68 (77.3%) were infused with Kymriah (tisagenlecleucel). In 7 (8%) patients, Kymriah (tisagenlecleucel) could not be manufactured. The median time from enrollment to infusion was 44 days. Of the 68 patients, 63 patients received Kymriah (tisagenlecleucel) infusion at least 3 months prior to the data cutoff date. Patients received investigator choice bridging chemotherapy as needed to control their leukemia while waiting for Kymriah (tisagenlecleucel) infusion. Patients also received protocol mandated lymphocyte-depleting chemotherapy 2 to 14 days prior to Kymriah (tisagenlecleucel) infusion. The median age was 12 years (range, 3-23 years), 82% were male, 75% were white, median Karnofsky/Lansky Performance Status score was 90 (range, 50-100), 79% had relapsed disease, 12% had chemo-refractory disease, and 9% had primary refractory disease. The enrolled patient population was heavily pretreated as evident by the following statistics; 87% (59) of patients had received a prior hematopoietic cell transplant with a median of 3 previous treatments. Results summarized in Table 1 show that 52 (82.5%) patients who received Kymriah (tisagenlecleucel) infusion achieved a CR or CRi within 3 months. Of the 52 patients who achieved a CR or CRi within 3 months, 29 (56%) were still in remission,13 (25%) had relapsed, 12 (23%) were censored prior to the data cutoff. The reasons for censoring were six received hematopoietic cell transplant, five received a new cancer therapy, and one was lost to follow-up. The estimated relapse-free rate among responders at month 6 was 75.4% (95% CI, 57.2% to 86.7%). Among the responders, four died (three after disease relapse, one after new cancer therapy was initiated while in remission).

 

Table 1. Summary of Efficacy Results of 63 Patients in the Pivotal Study

OutcomesResults, n (%) (95% confidence internal) or %
Primary end point (3 mo)
Objective remission rate ( complete remission + complete remission with incomplete blood count recovery) 52 (82.5) (70.9 to 91.0)
complete remission 40 (63)
complete remission with incomplete blood count recovery 12 (19)
Not reported/unknown 11 (17.5)
Secondary end point (3 mo)
Best objective remission rate ( complete remission + complete remission with incomplete blood count recovery with minimal residual disease-positive) 52 (82.5) (70.9 to 91.0)
Other secondary end points
Median duration of remission Not reached
Median event-free survival Not reached
Percent relapse-free at 6 mo after remission 75
Percent survival at 6 mo 89
Percent survival at 9 mo 79
Percent survival at 12 mo 79

 

Supportive Studies

Two single-arm studies that included a total of 84 patients were conducted using product manufactured at University of Pennsylvania cell and vaccine production facility. The first study was a phase 1/2 a single-center study in 55 patients enrolled between March 2012 and November 2015. The objective remission rate (ORR) (CR or CRi) was 95% (52/55), and best ORR (CR or CRi with MRD-negative bone marrow) was 89% (49/55). Median OS was 32.7 months (95% CI, 21.0 to inestimable). First pediatric patient treated in the study has been in remission for 5 years. The second study was a phase 2 multi-centric study that enrolled 29 patients between August 2014 and February 2016. The objective remission rate (ORR) (CR or CRi) was 69% (20/29).

 

Safety

Safety data included 68 patients (63 patients received who U.S.-manufactured product plus 5 patients who received EU-manufactured product) and is summarized in Tables 2 and 3. Cytokine release syndrome (CRS) was the most common serious life-threatening adverse event in the pivotal study and required aggressive supportive measures. One fatality due to CRS-related coagulopathy was observed in the pivotal study. Any grade CRS occurred in 78% (53/68) patients while 47% (32/68) experienced a grade 3 or 4 CRS. The severity of CRS was associated with high tumor burden of greater than 50% blasts in the bone marrow at screening. CRS occurred after a median of 3 days (range, 1-22 days) after Kymriah (tisagenlecleucel) infusion and lasted for a median duration of 8 days. CRS resulted in significant morbidity burden as indicated by intensive care unit admission (31 [46%]), ventilatory support (10 [15%]), dialysis (7 [10%]), hypotension (35 [51%]), and hypotension requiring high-dose vasopressor support (17 [25%]).

 

The next most important adverse event of Kymriah (tisagenlecleucel) was neurotoxicity such as encephalopathy and seizures. Any grade neurotoxicity was reported in 44% (30/68) patients, and grade 3 neurotoxicity was reported in 15% (10/68) patients. No cases of grade 4 neurotoxicity were reported. Although neurotoxicity was reversible with the use of optimal and best supportive care, the severity of these toxicities requires monitoring for airway protection.

The Food and Drug Administration also noted infection as a special adverse event of interest. In the first 8 weeks after infusion, 43% (29/68) of patients developed infection of which 24% (16/68) were grade 3 and 3% (2/68) were grade 4. Infection included gram-positive, gram-negative systemic infections, Clostridium difficile, candida, herpes simplex, and encephalitis due to herpesvirus 6. Three deaths occurring within 60 days and related to infection with herpesvirus 6, bacterial infection, and fungal sepsis was reported.

 

Other adverse events of special interest included prolonged cytopenia, cardiac disorders, and B-cell aplasia. Three patients experienced congestive heart failure that required treatment. Most patients in the pivotal trial had previously been treated with chemotherapy and radiotherapy that predisposed them to cardiotoxicity; it is an anticipated risk in the intended population that would receive treatment with Kymriah (tisagenlecleucel). Acquired hypogammaglobulinemia is an expected side effect of Kymriah (tisagenlecleucel) because it not only kills pre-B acute lymphoblastic leukemia cells but also normal B cells because they are CD19-positive. Patients in the trial were maintained on supplemental treatment with intravenous gamma globulin after Kymriah (tisagenlecleucel). It is unclear as to how long intravenous gamma globulin would be required.

 

Multiple design features of the Kymriah (tisagenlecleucel) retroviral vector such as minimal homology between packaging plasmids and vector sequences, segregation on 4 different DNA plasmids, deletion of HIV accessory genes, and use of “self-inactivating” vector design aim to reduce the risk the potential of replication competent virus generation and insertional mutagenesis. However, the theoretical risk of formation of replication competent virus, their clonal growth or neoplastic transformation of transduced cells cannot be ruled out. If approved each vector batch and production cells will be tested for the presence of replication competent retrovirus. However, Novartis does not plan to collect patient samples for replication competent retrovirus testing. It is expected that over next 5 years, approximately 5000 patients may be enrolled in the first 5 years in a post-marketing registry that will follow-up patients up to 15 years after Kymriah (tisagenlecleucel) infusion.

 

Table 2. Summary of Serious Adverse Events (>5% Patients) in 68 patients in the Pivotal Study

Serious Adverse Eventa Any adverse event that resulted in death or was life-threatening or required inpatient hospitalization or caused prolongation of existing hospitalization or resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect, or required intervention to prevent permanent impairment or damage.Results, n (%)
Cytokine release syndrome 43 (63)
Febrile neutropenia 14 (21)
Hypotension 8 (12)
Acute kidney injury 5 (7)
Fever 5 (7)
Hypoxia 4 (6)

 

Table 3. Summary of Serious Adverse Events of Special Interest in 68 patients in the Pivotal Study

Adverse EventsGrade 3, n (%)a Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care.Grade 4, n (%) Life-threatening consequences; urgent intervention indicated.All Grades, n (%)
Patients with at least 1 event 23 (34) 28 (41) 62 (91)
Cytokine release syndrome 14 (21) 18 (27) 53 (78)
Febrile neutropenia 23 (34) 2 (3) 25 (37)
Hematopoietic cytopenia not resolved by day 28 10 (15) 12 (18) 25 (37)
Infections 16 (24) 2 (3) 29 (43)
Transient neuropsychiatric events 10 (15) 0 30 (44)
Tumor lysis syndrome 3 (4) 0 3 (4)

 

Summary

For individuals who are up to 25 years of age with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) who receive Kymriah (tisagenlecleucel), the evidence includes single-arm prospective studies. The pivotal single-arm trial reported an 83% response rate (measured by complete response or complete remission with incomplete blood count) in heavily pretreated patients. All patients who achieved a complete remission with incomplete blood count were also minimal residual disease negative, which is predictive of survival in acute lymphoblastic leukemia patients. After a median follow-up of 4.8 months, the median duration of response was not reached. The observed benefits seen with Kymriah (tisagenlecleucel) were offset by a high frequency and severity of adverse events. Cytokine release syndrome (CRS) was observed in more than half (63%) of the patients, and approximately 40% had an adverse event at grade 4 or higher. Long term follow-up and real-world evidence are required to assess the generalizability of Kymriah (tisagenlecleucel) efficacy and safety outside of the clinical trial setting. The evidence is sufficient to determine this technology results in a meaningful improvement in the net health outcomes.

 

Kymriah (Tisagenlecleucel) for Large B-Cell Lymphomas

Non-Hodgkin’s lymphoma (NHL) is a type of cancer that originates in lymphoid tissue and can spread to other organs. Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes or natural killer cells. In 2018, an estimated 74,680 people will be diagnosed with NHL and there will be approximately 19,910 deaths due to the disease.

 

NHL can be divided into two prognostic groups: indolent lymphomas and aggressive lymphomas.

  • Indolent lymphomas: Grow slowly; considered low grade lymphomas
  • Aggressive lymphomas: Grow at a faster rate; considered high grade lymphomas

 

Sometimes lymphoma changes from a slow growing type into a faster growing type, this is known as transformation. The transformed lymphoma has to then be treated as a high grade lymphoma.

 

Non-Hodgkin’s lymphoma is called “high grade” when the cells appear to be dividing quickly. These may be called aggressive lymphomas.

 

Diffuse large B-cell lymphoma (DLBCL) are the most common lymphoid neoplasms in adults, accounting for approximately 32.5% of NHLs diagnosed annually. Subtypes include primary mediastinal large B-cell lymphoma, high grade B cell lymphoma and diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma (follicular lymphoma with histologic transformation to diffuse large B-cell Lymphoma).

 

Diffuse large B-cell lymphoma (DLBCL) are the most common lymphoid neoplasms in adults, accounting for approximately 32.5% of NHLs diagnosed annually. Subtypes include primary mediastinal large B-cell lymphoma, high grade B cell lymphoma and diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma (follicular lymphoma with histologic transformation to diffuse large B-cell Lymphoma).

  • Diffuse large B-cell lymphoma (DLBCL)/High Grade B-cell Lymphoma: The lymphoma cells look fairly large when seen with a microscope. DLBCL can affect people of any age. It usually starts as a quickly growing mass in the lymph node deep inside the body such as in the chest or abdomen, or in a lymph node such as in the neck or axilla. It may also start in other areas such as the intestines, bones or even the brain or spinal cord. DLBCL tends to be fast growing (aggressive) lymphoma.
  • Diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma – histological transformation to DLBCL: In patients with follicular lymphoma, histological transformation to DLBCL is generally associated with a poor clinical outcome. Histological transformation to DCBCL occurs at an annual rate of approximately 3% for 15 years and the risk of transformation falls after that time, for reasons that remain unclear. Follicular lymphoma is the most common subtype of indolent NHL. Usually this lymphoma occurs in many lymph nodes sites throughout the body, as well as in the bone marrow.

 

Defining Relapsed and Refractory Disease

Refractory (resistant) disease is suggested by a less than 50 percent decrease in lesion size with treatment in the absence of new lesion development. In contrast progressive disease usually manifests as the appearance of any new lesion, a 50 percent increase in the longest diameter of a previously identified lesion or new/recurrent involvement in the bone marrow. Relapsed disease reflects the appearance of any new lesion after attainment of an initial complete remission.

 

Refractory or progressive disease is identified during the post-treatment response evaluation. The majority of relapses occur during the first two years after completion of treatment. However, as many as 18 percent of relapses occur more than five years after initial treatment. Relapses are usually symptomatic and rarely identified solely on the basis of routine imaging. Progressive or relapse can present with systemic B symptoms (i.e. fever, night sweats, weight loss), cytopenias, the development of an extranodal mass, or as the symptomatic or asymptomatic enlargement of the lymph nodes, liver or spleen.

 

When relapse is suspected, a biopsy of the involved lymph node or mass is recommended to confirm relapse and evaluate a potential change in histology, for example indolent non-Hodgkin’s lymphoma to an aggressive non-Hodgkin’s lymphoma.

 

Treatment for Relapsed or Refractory Disease

Outcomes for patients with refractory diffuse large B-cell lymphoma (DLBCL) are poor.

 

Relapse or refractory diffuse large B-cell lymphomas is treated with systemic chemotherapy with or without rituximab with plans to proceed to high dose chemotherapy and hematopoietic stem cell transplantation (HCT) in those with chemotherapy sensitive disease. The treatment of patients who are not candidates for HCT, who fail to respond to second-line chemotherapy regimens, or who relapse after HCT is generally palliative.

 

In the absence of HCT, conventional chemotherapy regimens provide only transient disease control for the majority of patients with relapsed or refractory disease. Patients with primary refractory disease rarely achieve complete remission when treated with a second chemotherapy regimen. Following relapses from a first complete remission, a subset of patients will achieve a second complete remission with chemotherapy; however, these remissions are generally not durable, and long term disease free survivors are rare. In contrast, approximately half of patients who respond to a second chemotherapy regimen and proceed to HCT will maintain their response for two years.

 

Kymriah™ (tisagenlecleucel) is now a treatment option for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma (follicular lymphoma with histologic transformation to diffuse large B-cell lymphoma). Kymriah is not indicated in the treatment of patients with primary central nervous system lymphoma.

 

Rationale

Assessment of efficacy for therapeutic intervention involves a determination of whether an intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes but are prone to biases such as non-comparability of treatment groups, placebo effect, and variable natural history of the condition.

 

Pivotal Trial

The approval for Kymriah (tisagenlecleucel) for large B-cell lymphoma is supported by data from the phase II JULIET clinical trial (NCT02445248), the first multi-center global registration study for Kymriah in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). JULIET was conducted in collaboration with Penn, and is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the United States, Canada, Australia, Japan and Europe, including: Austria, France, Germany, Italy, Norway and the Netherlands. In the JULIET trial, patients were infused in the inpatient and outpatient setting.

 

Eligible patients were ≥ 18 years of age with relapsed or refractory DLBCL, who receive ≥ 2 lines of chemotherapy, including rituximab and anthracycline, or relapsed following autologous hematopoietic stem cell transplantation (HSCT). The study excluded patients with active central nervous system malignancy, prior allogeneic HSCT, and ECOG performance status ≥ 2, a creatinine clearance < 60, alanine aminotransferase > 5 times normal, cardiac ejection fraction < 45%, or absolute lymphocyte concentration less than 300/uL. Of the 160 patients enrolled, 106 patients received tisagenlecleucel, including 92 patients who received product manufactured in the U.S. and were followed for at least 3 months or discontinued earlier. Eleven out of 160 patients enrolled did not receive tisagenlecleucel due to manufacturing failure. Thirty-eight other patients did not receive tisagenlecleucel, primarily due to death (n=16), and adverse events (n=3). Of the 92 patients receiving Kymriah, 90% received physician’s choice of bridging chemotherapy in the interval between start of screening and Kymriah infusion, among whom the median number of bridging chemotherapy regimens was 1 (range: 1 to 5) with 83% of patients receiving ≤ 2 regimens. A retrospectively identified sub-group of 68 patients was evaluable for the major efficacy outcome measures. Patients included in this sub-group had either no bridging chemotherapy, or had imaging that showed measurable disease after completion of bridging chemotherapy, prior to Kymriah infusion. Of the 24 patients not included, 8 had no evidence of disease at baseline prior to Kymriah infusion, 15 did not have baseline imaging following bridging chemotherapy, and I was excluded because of initial misclassification of a neuroendocrine tumor as DLBCL. Among the efficacy evaluable population of 68 patients, the baseline characteristics were: median age 56 years (range 22 to 74 years); 71% male; 90% White, 4% Asian, and 3% Black or African American; 78% had primary DLBCL not otherwise specified (NOS) and 22% had DLBCL following transformation from follicular lymphoma, of whom 17% were identified as high grade; and 44% had undergone prior autologous HSCT. The median number of prior therapies was 3 (range 1 to 6), 56% had refractory disease and 44% relapsed after their last therapy. Ninety percent of patients received lymphodepleting chemotherapy (LD) (66% of patients received fludarabine and 24% received bendamustine) and 10% did not receive any LD chemotherapy. The median time from leukapheresis and cryopreservation to Kymriah infusion was 113 days (range 47 to 196 days). The median dose was 3.5 x 108 CAR-positive viable T cells (range 1.0 to 5.2 x 108 cells). Seventy-three percent of patietns receivd Kymriah in the inpatient setting. Efficacy was established on the basis of complete response (CR) rate and duration of response (DOR), as determined by an independent review committee. The median time to response to Kymriah (CR and PR (partial response)) was 0.9 months (range 0.7 to 3.3 months). The median duration of response was not reached. Response durations were longer in patients who achieved CR, as compared to patients with a best response of partial response (PR). Of the 22 patients who experienced a CR, 9 achieved this status by 1months, 12 more by month 3, and the last by month 6 after Kymriah infusion. In this Novartis-sponsored study, Kymriah showed an overall response rate (ORR) of 50% (95% confidence interval (CI), 38% to 62%), with 32% of patients achieving a complete response (CR) and 18% achieving a partial response (PR). In all patients infused with Kymriah severe or life threatening (grade 3/4) CRS (cytokine release syndrome), defined by the Penn Grading Scale a rigorous scale for grading this reaction, occurred in 23% of patients. CRS is known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm. Eighteen percent of all infused patients experienced grade 3/4 neurologic events, which were managed with supportive care. Encephalopathy, a distinctive neurotoxicity associated CAR-T therapies, was seen as severe or life-threatening in 11% of patients. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema have occurred. Grade 3/4 cytopenias lasting more than 28 days included thrombocytopenia (40%) and neutropenia (25%), and grade 3/4 infections occurred in 25%. The most common (> 20%) adverse events (AEs) in the JULIET study are CRS (cytokine release syndrome), infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema and headache.

 

To further evaluate the long-term safety and the risk of secondary malignancies occurring after treatment, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with Kymriah (Tisagenlecleucel). This study will include at least 1500 patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. The enrolled patients will be followed for 15 years after the product administration.

 

Summary

The approval for Kymriah (tisagenlecleucel) is supported by data from the JULIET phase II clinical trial (NCT02445248), the first multi-center global registration study for Kymriah (tisagenlecleucel) in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In this Novartis-sponsored study, Kymriah (tisagenlecleucel) showed an overall response rate (ORR) of 50% (95% confidence interval (CI), 38% to 62%), with 32% of patients achieving a complete response (CR) and 18% achieving a partial response (PR) in 68 patients evaluated for efficacy. The median duration of response was not reached among these patients, indicating sustainability of response. This FDA approval brings an additional treatment option for these patients with few other options that have not responded to previous treatments, to include unsuccessful autologous stem cell transplant. The most common (> 20%) adverse events (AEs) in the JULIET study are CRS (cytokine release syndrome), infections, pyrexia, diarrhea, nausea, fatigue, hypertension, edema, and headache. Due to the risk of CRS and neurologic toxicities, Kymriah (tisagenlecleucel) was approved with a Risk Evaluation and Mitigation Strategy (REMS), which includes elements of safe use. The manufacturer has agreed to a post-marketing requirement observational registry study to collect safety information for patients treated with the marketed product. The evidence is sufficient to determine that the technology results in a meaningful improvement in net health outcomes.

 

Practice Guidelines and Position Statements

Acute Lymphoblastic Leukemia Version 1.2018

Relapsed/Refractory Disease

  • Ph+ ALL (AYA & Adult) → ABL1 kinase domain mutation testing → Treatment
    • Clinical trial; or
    • TKI ± chemotherapy; or
    • TKI ± corticosteroids; or
    • Blinatumomab (TKI intolerant/refractory); or
    • Inotuzomab ozogamicin (TKI intolerant/refractory); or
    • Tisagenlecleucel (patients < 26 years and with refractory disease or ≥ 2 relapses and failure of 2 TKIs)
  • Ph- ALL (AYA & Adult) → Treatment
    • Clinical trial; or
    • Blinatumomab (category 1); or
    • Inotuzumab ozogamicin (category 1); or
    • Tisagenlecleucel (patients < 26 years and with refractory disease or ≥ 2 relapses); or
    • Chemotherapy

 

Patients with Relapsed/Refractory Ph Positive ALL

Tisagenlecleucel is also an option for patients up to age 25 years (age < 26 years) and with refractory disease or ≥ 2 relapses and failure of 2 TKIs.

 

Patients with Relapsed/Refractory Ph Negative ALL

Tisagenlecleucel is also an option for patients up to age 25 years of age < 26 years and with refractory disease or ≥ 2 relapses

 

B-Cell Lymphomas Version 5.2018

Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell Therapy
Tisagenleucel

Patient Selection

  • Tisagenleucel is indicated in the treatment of adult patients with relapsed or refractory large B- cell lymphoma after two or more lines of systemic therapy including DLBCL and high grade B-cell lymphoma and DLBCL arising from follicular lymphoma
  • Clinical trials excluded patients who are ECOG PS ≥ 2, have CNS involvement, or have serious infections. Patients must have adequate organ and marrow function. Clinical judgement is required
  • Health care facilities that dispense and administer Tisagenleucel must be enrolled and comply with Risk Evaluation and Mitigation Strategies (REMS) requirements

 

Histologic Transformation to Diffuse Large B-Cell Lymphoma
  • Minimal or no prior chemotherapy
    • Chemoimmunotherapy (anthracycline or anthracenedione-based regimens preferred unless contraindicated) plus or minus ISRT (involved site radiation therapy)
      • Complete Response (CR):
        • Observation
        • Clinical trial
        • High dose therapy with autologous stem cell rescue plus or minus ISRT if not previously given
      • Partial Response (PR):
        • Autologous stem cell transplant plus or minus ISRT if not previously given
        • Axicabtagene ciloleucel or tisagenlecleucel (only after ≥ 2 prior chemoimmunotherapy regimens)
        • Clinical trial
        • ISRT for localized residual and/or residual FDG-avid disease not previously irradiated
        • Observation
        • Ibritumomab tiuxetan
      • No Response (NR) or Progressive Disease:
        • Clinical trial
        • Ibritumomab tiuxetan or second line therapy
        • Axicabtagene ciloleucel or tisagenlecleucel (only after ≥ 2 prior chemoimmunotherapy regimens)
        • Best supportive care

 

Regulatory Status

Adoptive immunotherapy is not a U.S. Food and Drug Administration‒regulated procedure.

 

On August 30, 2017, tisagenlecleucel (Kymriah™; Novartis) was approved by the Food and Drug Administration (FDA) for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Kymriah™ is not indicated for the treatment of patients with primary central nervous system lymphoma.

 

On May 1, 2018 tisagenlecleucel (Kymriah™; Novartis) was approved by the Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DCBCL), high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Kymriah™ is not indicated for the treatment of patients with primary central nervous system lymphoma.

 

Prior Approval:

Prior approval required

 

Policy:

See related medical policies:

  • 08.01.26 Adoptive Immunotherapy
  • 08.01.27 Cellular Immunotherapy for Prostate Cancer – Provenge (Sipuleucel-T)
  • 08.01.29 Yescarta (Axicabtagene Ciloleucel)

 

Kymriah™ (Tisagenlecleucel) as a one time, single administration intravenous infusion is considered medically necessary when ALL of the following criteria are met:

  • Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia (ALL) with morphologic bone marrow tumor involvement (≥5% lymphoblasts): AND
  • Refractory disease or 2 or more relapses to include relapse after allogeneic stem cell transplant (unless ineligible for or refused to consent to allogeneic stem cell transplant), AND one of the following subtypes:
    • Philadelphia chromosome-negative disease (Ph - ALL); or
    • Philadelphia chromosome-positive disease (Ph + ALL) and failure to 2 tyrosine kinase inhibitors (TKIs) (e.g. imatinib (gleevac), dasatinib (sprycel), nilotinib (tasigna), ponatinib (iclusig), bosutinib (bolsulif); AND
  • Are 25 years old or younger at the time of infusion; AND
  • Have not received prior treatment with Kymriah (tisagenlecleucel) or any other gene therapy; or are being considered for treatment with any other gene therapy; AND
  • Have adequate organ function
    • Creatinine clearance ≥ 60 mL/min
    • A serum creatinine of ≤ 1.5 times upper limit of normal
    • ALT (alanine aminotransferase) ≤ 5 times upper limit of normal for age
    • Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 times the upper limit of normal
    • Direct bilirubin ≤ 1.5 times upper limit of normal
    • Hemodynamically stable and left ventricular ejection fraction (LVEF) ≥ 45% confirmed by echocardiogram or multigated acquisition (MUGA) scan; AND
  • Kymriah (tisagenlecleucel) will be provided based on the FDA recommended dosing and administration:
    • If the patient is 50 kg or less in weight, they will receive weight-based dosing at 0.2 to 5.0 x 106 CAR-positive viable T-cells per kg of body weight intravenously; or
    • If the patient is above 50 kg in weight, the patient will not be treated with more than 2.5 x 108 total CAR-positive T cells intravenously; AND
  • The patient will be receiving Kymriah (tisagenlecleucel) at a treatment center that is certified to administer Kymriah (tisagenlecleucel); AND
  • Do not have any of the following:
    • Burkitt lymphoma
    • Active hepatitis B, C, or any uncontrolled infection
    • Eligible for and consenting to allogeneic stem cell transplant
    • Grade 2 to 4 graft-versus-host disease
    • Donor lymphocyte infusion within 6 weeks prior to Kymriah (tisagenlecleucel) infusion
    • Bone marrow relapse after allogeneic stem cell transplant less than 6 months from stem cell transplant at the time of Kymriah tisagenlecleucel infusion
    • Concomitant genetic syndrome with the exception of Down syndrome
    • Active central nervous system (CNS) involvement, NCCN guidelines define CNS involvement (CNS leukemia) as the following: a white blood cell (WBC) count of 5 leukocytes/mcL in the cerebrospinal fluid with the presence of lymphoblasts)

 

Note: Patient with central nervous system 2 disease [cerebrospinal fluid containing blasts, but <5 white blood cells per microliter] are eligible

 

Definitions: Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission with chemotherapy and/or stem cell transplant.

 

Refractory (resistant) disease is defined as those patients who fail to obtain complete response with induction therapy, i.e., failure to eradicate all detectable leukemia cells (<5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (>25% marrow cellularity and normal peripheral blood counts).

 

Kymriah (tisagenlecleucel) is considered investigational for all other indications not listed above as the safety and efficacy has not yet been established in the peer reviewed medical literature.

 

Repeat treatment of Kymriah (tisagenlecleucel) is considered investigational, the safety and efficacy beyond one dose has not been studied and also is not indicated in the current FDA approval for Kymriah. The evidence is insufficient to determine the effects on net health outcomes.

 

Kymriah (Tisagenlecleucel) for Relapsed or Refractory Large B-cell Lymphoma

Kymriah™ (tisagenlecleucel) as a one time, single administration intravenous infusion is considered medically necessary when ALL of the following criteria are met:

  • Adult patients 18 years and older; AND
  • Histologically confirmed large B-cell lymphoma including:
    • Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS); or
    • High grade B-cell lymphoma; or
    • Diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma; AND
  • Is relapsed or refractory disease after two or more lines of systemic therapy (defined as no response to last line of therapy; or disease progression or recurrent ≤ 12 months after prior autologous stem cell transplant (ASCT); if salvage therapy is given post ASCT, the patient must have had no response to or relapsed after the first line of therapy); AND
  • Patients must have received prior therapy including at a minimum:
    • Anti-CD20 monoclonal antibody (e.g. rituximab); and
    • An anthracycline containing chemotherapy regimen (e.g. doxorubicin); or
    • For patients with transformed follicular lymphoma (TFN) must have received prior chemotherapy for follicular lymphoma and subsequently have chemo-refractory disease after transformation to diffuse large B-cell lymphoma (DLBCL); AND
  • Renal function defined as:
    • A serum creatinine of ≤ 1.5 times upper limit of normal (ULN); or
    • Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2; AND
  • Liver function defined as:
    • ALT (alanine aminotransferase) ≤ 5 times upper limit of normal for age; and
    • Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 times the upper limit of normal; and
    • Direct bilirubin ≤ 1.5 times upper limit of normal; AND
  • Baseline oxygen saturation > 91% on room air; AND
  • Hemodynamically stable and left ventricle ejection fraction (LVEF) ≥ 45% confirmed by echocardiogram or multigated acquisition (MUGA) scan; AND
  • Adequate bone marrow reserve defined as:
    • Absolute neutrophil count (ANC) > 1000/uL; and
    • Absolute lymphocyte count (ALC) ≥ 300/uL; and
    • Platelets ≥ 50,000/uL; and
    • Hemoglobin > 8.0 g/dl; AND
  • Kymriah (tisagenlecleucel) will be provided based on the FDA recommended dosing and administration:
    • For patients 18 years of age through age 24 years of age:
      • If the patient is 50 kg or less in weight, they will receive weight based dosing at 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight intravenously; or
      • If the patient is above 50 kg in weight, the patient will not be treated with more than 2.5 x 108 total CAR-positive viable T cells intravenously.
    • For patients 25 years and older:
      • The patient will not be treated with more than 6.0 x 108 CAR-positive viable T cells intravenously; AND
  • The patient will be receiving Kymriah (tisagenlecleucel) at a treatment center that is certified to administer Kymriah (tisagenlecleucel); AND
  • Do not have any of the following:
    • Prior treatment with Kymriah (tisagenlecleucel) or Yescarta (axicabtagene ciloleucel); or are being considered for treatment with other gene therapy
    • Active central nervous system (CNS) involvement by malignancy
    • Eligible for and consenting to autologous stem cell transplant
    • Prior radiation therapy within 2 weeks of infusion
    • Active replication of or prior infection with hepatitis B or active hepatitis C (HCV RNA positive)
    • HIV positive
    • Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood cultures positive ≤ 72 hours prior to infusion)
    • History of carcinoma in-situ of the cervix or breast unless disease free for at least 3 years.
    • History of a primary malignancy unless completely resected and in complete remission for ≥ 5 years
    • Cardiac arrhythmia not controlled with medical management
    • Patients on oral anticoagulation therapy
    • Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis)

 

Definitions:Relapsed Disease reflects the appearance of any new lesion after attainment of an initial complete remission. When relapse is suspected a biopsy of the involved lymph node or mass is recommended to confirm relapse and evaluate for potential change in histology.

 

Refractory Disease or resistant DCBCL is suggested by less than 50 percent decrease in lesion size with treatment in the absence of new lesion development.

 

Kymriah™ (tisagenlecleucel) is considered investigational for all other indications not listed above as the safety and efficacy has not yet been established in the peer reviewed medical literature.

 

Repeat treatment of Kymriah™ (tisagenlecleucel) is considered investigational, the safety and efficacy beyond one dose has not been studied and also is not indicated in the current FDA approval for Kymriah. The evidence is insufficient to determine the effects on net health outcomes.

 

Policy Guidelines

Required Documentation

The patient’s medical records submitted for review should document the above medical necessity criteria is met for the indication being requested and should also include the following:

  • Office notes that contain the relevant history and physical and prior cancer treatment history
  • Include patients weight for dosing and administration review
  • Lab work within 7 to 14 days of the approval request

 

Harvesting

Autologous lymphocytes used as part of adoptive immunotherapy may be harvested in a pheresis (leukapheresis) procedure or may be isolated from resected tumor tissue.

 

Central Nervous System (CNS) Disease for B-Cell Acute Lymphoblastic Leukemia

Central nervous system (CNS) disease for B-cell acute lymphoblastic leukemia is defined by the following groups:

  • CNS 1: No lymphoblasts in the cerebrospinal fluid (CSF), regardless of the white blood cell (WBC) count
  • CNS 2: A white blood cell (WBC) count of less than 5 leukocytes/mcL in the cerebral spinal fluid (CSF) with the presence of blasts
  • CNS 3: A white blood cell (WBC) count of 5 leukocytes/mcL or greater with the presence of blasts

 

Black Box Warning

Kymriah™ (tisagenlecleucel) has a black box warning because of the risk of cytokine release syndrome and neurologic toxicities that include fatal or life-threatening reactions. It should not be administered to patients with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Patients should be monitored for neurologic events after treatment.

 

Kymriah™ (tisagenlecleucel) is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). The requirement for the REMS components are as follows:

  • Health care facilities that dispense and administer Kymriah (tisagenlecleucel) must be enrolled and comply with the REMS requirements.
  • Certified health care facilities must have onsite, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hours after Kymriah (tisagenlecleucel), if needed for treatment of cytokine release syndrome (CRS).
  • Certified health care facilities must ensure that health care providers who prescribe, dispense or administer Kymriah (tisagenlecleucel) are trained about the management of cytokine release syndrome (CRS) and neurologic toxicities.

 

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.

  • Q2042 Tisagenlecleucel, up to 600 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose (Kymriah)
  • 0537T Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day
  • 0538T Chimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)
  • 0539T Chimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration
  • 0540T Chimeric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous

 

Selected References:

  • Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. Jul 13 2017;3(7):e170580. PMID 28494052
  • Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. Oct 15 2015;373(16):1541-1552. PMID 26465987
  • Maude SL, Teachey DT, Porter DL, et al. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. Jun 25 2015;125(26):4017-4023. PMID 25999455
  • Pui CH, Carroll WL, Meshinchi S, et al. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. Feb 10 2011;29(5):551-565. PMID 21220611
  • Tallen G, Ratei R, Mann G, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. May 10 2010;28(14):2339-2347. PMID 20385996
  • Bajwa R, Schechter T, Soni S, et al. Outcome of children who experience disease relapse following allogeneic hematopoietic SCT for hematologic malignancies. Bone Marrow Transplant. May 2013;48(5):661-665. PMID 23128573
  • Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. Apr 20 2006;24(12):1917-1923. PMID 16622268
  • von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. Dec 20 2016;34(36):4381-4389. PMID 27998223
  • UpToDate. Overview of the Treatment of Acute Lymphoblastic Leukemia in Children and Adolescents. Terzah M. Horton M.D., PhD, C. Philip Steuber M.D. Topic last updated July 5, 2017.
  • UpToDate. Treatment of Relapsed or Refractory Acute Lymphoblastic Leukmia in Adults. Richard A. Larson M.D.. Topic last updated September 8, 2017.
  • Kymriah.
  • Kymriah Package Insert – FDA.
  • FDA News Release. FDA Approval Brings First Gene Therapy to the United States. Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form or acute lymphoblastic leukemia (ALL).
  • FDA News Release – FDA approves CAR-T cell therapy to treat adults with certain tuypes of large B-cell lymphoma.
  • Novartis Press Release: Kymriah (Tisagenlecleucel) receives second FDA approvals to treat appropriate relapsed or refractory patients with large B-cell lymphoma.
  • Kymriah package insert – FDA revised May 2018.
  • U.S. Food and Drug Administration FDA Supplement Approval May 1, 2018 for Kymriah for relapsed or refractory large B-cell lymphoma.
  • U.S. FDA Advisory Committee Briefing Document Tisagenlecleucel (CTL019) for the treatment of pediatric and young adult patietns with relapsed/refractory B-cell acute lymphoblastic leukemia. July 12, 2017
  • National Comprehensive Cancer Network (NCCN) Acute Lymphoblastic Leukemia Version 1.2018.
  • National Comprehensive Cancer Network (NCCN) B-Cell Lymphomas Version 5.2018.
  • ECRI. Panel Providers Guidelines for Managing CAR-T Cell Toxicities. Published November 30, 2017.
  • ECRI. FDA Expands Kymriah Immunotherapy Approval for Large B-Cell Lymphoma. Published May 8, 2018.
  • ECRI. Kymriah (Tisagenlecleucel) (Novartis Pharmaceuticals Corp.) for Treatment Diffuse Large B-Cell Lymphoma. Published June 25, 2018.
  • Friedberg JW. Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Hematology Am Soc Hematol Educ Program. 2011:2011:498-505
  • Crump M, Neelapu SS, Farooq U. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood 2017 Oct 19:130(16):1800-1808.
  • Porter D, Hwang WT, Frey NV, et. al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia Sci. Transl Med 2015 Sep 2:7(303):303ra139. PMID 26333935
  • JULIET phase II clinical trial (NCT02445248)

 

Policy History:

  • November 2018 - Interim Review, Policy Revised
  • October 2018 - Content moved from medical policy 08.01.26 - New policy created

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.

 

*CPT® is a registered trademark of the American Medical Association.