Medical Policy


Subject: Tisagenlecleucel (Kymriah®)
Document #: MED.00124 Publish Date:    08/02/2018
Status: Revised Last Review Date:    07/26/2018


This document addresses uses of tisagenlecleucel (Kymriah, Novartis Pharmaceuticals Corporation, East Hanover, NJ), an autologous chimeric antigen receptor (CAR) T-cell immunotherapy that targets the CD19 surface antigen expressed in B cell malignancies. Tisagenlecleucel is produced by genetically engineering an individual’s own functioning immune cells to express tumor antigen recognition signals that target and destroy malignant cells in certain types of B-cell precursor cancer.

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

Tisagenlecleucel is considered medically necessary for the treatment of B-cell acute lymphoblastic leukemia (ALL), when all of the following criteria are met:

  1. Pediatric or young adult (25 years of age or younger); and
  2. Documentation of CD19 tumor expression; and
  3. Disease is considered refractory, or in second or later relapse, in any of the following scenarios:
    1. Second or later bone marrow relapse; or
    2. Bone marrow relapse after allogeneic stem cell transplant; or
    3. Primary refractory or chemo-refractory after relapse; and
  4. Performance score on Karnofsky or Lansky Scale is greater than or equal to 50% or Eastern Cooperative Oncology Group (ECOG) performance score is 0-3; and
  5. One-time, single administration treatment.

Tisagenlecleucel is considered medically necessary in individuals with large B-cell lymphoma when all of the following criteria in 1 through 7 are met:

  1. 18 years of age or older; and
  2. Histologically confirmed diagnosis of one of the following:
    1. Diffuse large B-cell lymphoma (DLBCL), not otherwise specified; or
    2. High-grade B-cell lymphoma; or
    3. Transformed follicular lymphoma; and
  3. Relapsed or refractory disease, defined as progression after two or more lines of systemic therapy (which may or may not include therapy supported by autologous stem cell transplant); and
  4. Must have received adequate prior therapy including at least one of the following:
    1. An anthracycline-containing chemotherapy regimen and rituximab; or
    2. Either failed autologous hematopoietic stem cell transplantation (ASCT), were ineligible for or refused consent to ASCT; and
  5. Documentation of all of the following clinical findings without transfusion:
    1. Absolute neutrophil count (ANC) ≥ 1000/uL; and
    2. Absolute lymphocyte count (ALC) > 300/uL; and
    3. Platelet count ≥ 50,000/uL; and
    4. Hemoglobin > 8.0 g/dl; and
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and
  7. One-time, single administration treatment.

Note: According to the black box warning in the FDA Product Information Label, tisagenlecleucel should be administered at a designated treatment center that has received site certification.

Investigational and Not Medically Necessary:

Tisagenlecleucel is considered investigational and not medically necessary when the medically necessary criteria are not met, and for all other indications, including but not limited to:

  1. Use in combination with other chemotherapy agents;
  2. Any central nervous system (CNS) disease (for example, brain metastases, CNS lymphoma, and a history or presence of CNS disorders such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement);
  3. History of allogeneic stem cell transplant, chimeric antigen receptor therapy or other genetically modified T-cell therapy;
  4. Active, uncontrolled infection;
  5. Human immunodeficiency virus (HIV);
  6. Hepatitis B or C (if viral load is detectable).

On August 30, 2017, tisagenlecleucel received approval by the U.S. Food and Drug Administration (FDA) for the treatment of children and young adults, 25 years of age or younger, with B-cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. On May 1, 2018, tisagenlecleucel received expanded approval by the FDA for the treatment of adults with relapsed or refractory large B-cell lymphoma (including diffuse large B-cell lymphoma [DLBCL] not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma ) after two or more lines of systemic therapy. Tisagenlecleucel was granted priority review and breakthrough therapy designations by the FDA (FDA Product Information [PI] Label, 2018).

Initial FDA approval of tisagenlecleucel for the treatment of ALL was based on a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of a single infusion of tisagenlecleucel in children and young adults with relapsed/refractory B-cell ALL (ELIANA; NCT 02435849). A total of 63 study participants were enrolled and included in the interim analysis (median follow-up 4.8 months). The study inclusion criteria included age 3 years at screening to 21 years at time of diagnosis, positive for CD19 tumor expression, adequate organ function, bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening, life expectancy of at least 12 weeks, and Karnofsky (participants age ≥ 16 years) or Lansky (participants age < 16 years) performance status of ≥ 50 at screening. Participants were excluded from the study based on criteria which included the following: isolated extra-medullary disease relapse, diagnosis of a concomitant genetic syndrome (for example, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome), Burkitt's lymphoma/leukemia (i.e. mature B-cell ALL), prior malignancy (except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease), treatment with a prior gene therapy product or anti-CD19/anti-CD3 therapy, active or latent hepatitis B or C, or any uncontrolled infection, human immunodeficiency virus (HIV) positive test, presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD), and active central nervous system (CNS) involvement by malignancy (defined by CNS-3 per National Comprehensive Cancer Network® [NCCN] guidelines). Study participants were primary refractory, chemo-refractory after first relapse, relapsed after second-line therapy or ineligible for allogeneic SCT. Most study enrollees received lymphodepleting chemotherapy (fludarabine and cyclophosphamide) prior to infusion with tisagenlecleucel (Grupp, 2017). A total of 63% (n=40) of study participants achieved a complete remission (CR) and 19% (n=12) achieved a CR with incomplete blood count recovery (CRi). The primary outcome, overall remission rate (ORR=CR+Cri), was 83% (n=54). Secondary objectives included minimal residual disease (MRD), relapse-free survival (RFS), overall survival (OS) and safety. The 6-month OS was 89% and the disease-free survival was 60%. All participants who achieved a CR or CRi also tested negative for minimal residual disease (95% confidence interval [CI], 71-91; p<0.0001). With a median follow-up of 4.8 months from response, the median duration of CR/CRi was not reached (range: 1.2-14.1+ months). A total of 11 participants died after receiving an infusion with tisagenlecleucel; 7 were disease-related, 3 were attributed to infections, and 1 to intracerebral hemorrhage. Cytokine release syndrome (CRS) occurred in a total of 79% of study participants; 49% of CRS was grade 3 or 4. Treatment with anti-cytokine therapy, high dose vasopressors, invasive ventilation, and dialysis were needed to stabilize participants that developed CRS. There were no CRS-related deaths and no cases of cerebral edema reported (FDA PI Label, 2017). In 2018, Maude and colleagues published the final analysis from this clinical trial with a median follow-up of 13.1 months (range, 2.1 to 23.5 months) and a total of 75 participants enrolled. The final ORR, the key endpoint, was 81% (95% CI, 71-89%); 60% (n=45) achieved a CR, and 21% (n=16) had CRi. As in the interim analysis, the median duration of CR/CRi was not reached. The rate of event-free survival was 73% (95% CI, 60-82%) at 6 months and 50% (95% CI, 35-64%) at 12 months; median event-free survival was also not reached. The OS among the 75 participants who were infused with tisagenlecleucel was 90% (95% CI, 81-95%) 6 months following infusion and 76% (95% CI, 63-86) after 12 months. In this final analysis, 88% (n=66) of the 75 study participants had a grade 3 or 4 adverse event; 73% (n=55) of which were tisagenlecleucel-related. CRS occurred in 77% (n=58) of participants, 60% (n=35) of which were admitted to the intensive care unit for management of the CRS. Of the 58 individuals with CRS, 67% (n=28) received tocilizumab for management. In addition to the 11 deaths reported in the interim analysis, an additional 8 participants died before the final analysis (n=19 deaths for study duration); 2 occurred within the first 30 days after transfusion.

In 2014, Maude and colleagues published the results of a phase II clinical trial in children and adults diagnosed with relapsed/refractory ALL (n=30). A total of 25 children and young adults (5-22 years of age) and 5 older adults (26-60 years of age) received tisagenlecleucel. CR was achieved in 27 study participants (90%), including 2 with blinatumomab-refractory disease and 15 who had previously undergone stem-cell transplantation. There was a 6-month event-free survival rate of 67% (95% CI, 51-88%) and an OS rate of 78% (95% CI, 65-95). All study participants developed CRS. Severe CRS developed in 27% of participants and was associated with a higher disease burden prior to infusion. CRS was effectively treated with the anti-interleukin-6 receptor antibody, tocilizumab (Maude, 2014).

Expanded FDA approval of tisagenlecleucel for the treatment of DLBCL was based on the Phase II JULIET clinical trial, a single-arm, open-label, multi-center study in adults with relapsed or refractory DLBCL (NCT 02445248). Eligible participants were ≥ 18 years of age with histologically confirmed diagnosis of DLBCL; not otherwise specified, high-grade B-cell lymphoma; or transformed follicular lymphoma, who had relapsed after at least two lines of chemotherapy (including rituximab and anthracycline or relapsed following autologous HSCT [or were ineligible for transplant]). Participants also demonstrated adequate organ function and adequate bone marrow reserves without transfusion (absolute neutrophil count ≥ 1000/uL, absolute lymphocyte count > 300/uL, platelet count ≥ 50,000/uL, and hemoglobin > 8.0 g/dl). The study excluded individuals with any CNS disease, prior allogenic HSCT, an ECOG performance status ≥ 2, uncontrolled infection, HIV and hepatitis B or C (if viral load was detectable). At the time of interim analysis (median follow-up of 9.4 months), upon which approval was based, there were 68 evaluable study participants; 78% had primary DLBCL not otherwise specified, 22% had transformed follicular lymphoma, 17% had high-grade B-cell lymphoma; and 44% had a history of autologous HSCT. Efficacy was established on the basis of a CR rate (CR=32%; 95% CI: 21.5%-44.8%) and duration of response which was not reached (determined by an independent review committee). The overall response rate (ORR=[CR+partial response]) was 50% (95% CI: 37.6%-62.4%). Encephalopathy was seen as severe or life-threatening in 11% of participants. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema occurred. Grade 3 or 4 cytopenias lasting more than 28 days included thrombocytopenia (40%) and neutropenia (25%), and grade 3 or 4 infections occurred in 25% of participants. The most common adverse reactions (incidence >20%) were CRS, infections-pathogen unspecified, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache (FDA PI Label, 2018).

In 2017, Schuster and colleagues conducted a case series in 28 individuals diagnosed with CD19+ DLBCL or follicular lymphoma with no curative treatment options, <2 years of anticipated survival, and a partial response to or stable disease after the most recent therapy. The primary outcome of the study was the ORR at 3 months. At 3 months, 18 of 28 study participants had a response (ORR=64%; 95% CI: 44-81). Complete remission occurred in 6 of 14 individuals with DLBCL (43%) and 10 of 14 with follicular lymphoma (71%). At a median follow-up of 28.6 months, 86% of those with DLBCL who had a response and 89% of those with follicular lymphoma who had a response had sustained the response. All who were in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months). Grade 3 or 4 CRS occurred in 5 participants (18%) and grade 3 or 4 encephalopathy in 3 (11%) participants; 2 cases were self-limiting and 1 was fatal. In this case series, tisagenlecleucel demonstrated efficacy in the treatment of advanced DLBCL and follicular lymphoma with a durable complete response.

Tisagenlecleucel is also being investigated for safety and efficacy in adult ALL, multiple myeloma, lymphocytic leukemia and Hodgkin’s lymphoma.


ALL is an aggressive type of leukemia characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. In 2018, there will be an estimated 5960 new cases of ALL and 1470 deaths (American Cancer Society, 2018). ALL is the most common cancer diagnosed in children in the United States and occurs at an annual rate of approximately 41 cases per 1 million people aged 0 to 14 years and approximately 17 cases per 1 million people aged 15 to 19 years. On average, approximately 3100 children and young adults (<20 years old) are diagnosed with ALL each year (National Cancer Institute, 2018). Although more than 80% of individuals treated for ALL achieve a CR, approximately 15-20% will relapse (Oskarsson, 2016). At this time, hematopoietic stem cell transplant (HSCT) is the most effective treatment option for relapsed/refractory ALL. Achievement of CR is a vital step in the transplantation process, but many individuals are ineligible due to failure to achieve this remission (Topp, 2015).

Non-Hodgkin’s lymphoma (NHL) is one of the most common cancers in the United States, accounting for approximately 4% of all cancer diagnoses. The National Cancer Institute estimates that approximately 75,000 new cases of NHL will be diagnosed in 2018 (NCI, 2018). DLBCL is the most common type of NHL; 1 out of every 3 cases. While DLBCL is a relatively treatable malignancy, response rates to second-line therapy and beyond are much poorer and vary from about 14% to 60% (American Cancer Society, 2018).

CAR-T therapy may play an important role as a bridge to transplant by providing another therapeutic option to induce remission in individuals who would otherwise have been ineligible for a HSCT due to progression of disease; tisagenlecleucel is a type of CAR-T therapy (NCCN, 2018).

The process of producing tisagenlecleucel begins with harvesting peripheral blood cells from an individual. The T-cells are isolated and genetically engineering to recognize CD19 on targeted tumor cells (the genetically engineered cells are called CAR-T cells). These cells are then stimulated to multiply and the resulting product is infused back into the individual, reengineered to target and destroy malignant cells expressing CD19 (NCCN, 2018).

Adverse Events and Warnings 

Black box warnings from the FDA PI Label (2018) include the following information and recommendations:

Additional warnings from the FDA PI Label (2018) include the following information and recommendations:


Allogeneic cells: Harvested from a histocompatible donor.

Autologous cells: Harvested from the individual's own cells.

Bone marrow: A spongy tissue located within flat bones, including the hip and breast bones and the skull. This tissue contains stem cells, the precursors of platelets, red blood cells, and white cells.

Chemotherapy: The medical treatment of a disease, particularly cancer, with drugs or other chemicals.

Chimerism: Cell populations derived from different individuals; may be mixed or complete.

Complete response/remission (CR): The disappearance of all signs of cancer in response to treatment; this does not always mean the cancer has been cured; also called a complete response.

Cytotoxic: Destructive to cells.

ECOG (Eastern Cooperative Oncology Group) Performance Status: A scale used to determine the individual's level of functioning; this scale may also be referred to as the WHO (World Health Organization) or Zubrod score; based on the following scale:


Fully active, able to carry on all pre-disease performance without restriction


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


Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours


Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours


Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair



Graft versus host disease: A life-threatening complication of bone marrow transplants in which the donated marrow causes an immune reaction against the recipient's body.

Hematopoietic stem cells: Primitive cells capable of replication and formation into mature blood cells in order to repopulate the bone marrow.

Karnofsky Score: A measure of the individual's overall physical health, judged by their level of activity; the score uses the following scale (generally reserved for individuals 16 years of age and older):


Normal, no complaints, no signs of disease


Capable of normal activity, few symptoms or signs of disease


Normal activity with some difficulty, some symptoms or signs


Caring for self, not capable of normal activity or work


Requiring some help, can take care of most personal requirements


Requires help often, requires frequent medical care


Disabled, requires special care and help


Severely disabled, hospital admission indicated but no risk of death


Very ill, urgently requiring admission, requires supportive measures or treatment


Moribund, rapidly progressive fatal disease processes



Lansky Score: A measure of the individuals overall physical health, judged by their level of activity; the score uses the following scale (generally reserved for individuals less than 16 years of age): 


Fully active, normal


Minor restrictions in physically strenuous activity


Active, but tires more quickly


Both greater restriction of and less time spent in play activity


Up and around, but minimal active play; keeps busy with quieter activities


Gets dressed but lies around much of the day, no active play but able to participate in all quiet play and activities


Mostly in bed; participates in quiet activities


In bed; needs assistance even for quiet play                                         


Often sleeping; play entirely limited to very passive activities


No play; does not get out of bed



Refractory: Tumors that show less than 50% reduction in tumor burden in response to chemotherapy upon or during the course(s) of chemotherapy.

Relapse: The return of signs and symptoms of cancer after a period of improvement.


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:




Tisagenlecleucel, up to 250 million CAR-positive viable T cells, including leukapheresis and dose preparation procedures, per infusion [Kymriah]



ICD-10 Procedure



Introduction of engineered autologous chimeric antigen receptor T-cell immunotherapy into peripheral vein, percutaneous approach, new technology group 3 [when specified as Kymriah]


Introduction of engineered autologous chimeric antigen receptor T-cell immunotherapy into central vein, percutaneous approach, new technology group 3 [when specified as Kymriah]



ICD-10 Diagnosis




Follicular lymphoma



Diffuse large B-cell lymphoma



Mediastinal (thymic) large B-cell lymphoma



Acute lymphoblastic leukemia (ALL)



Encounter for antineoplastic immunotherapy


When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.


Peer Reviewed Publications:

  1. Grupp S, Laetsch T, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young Adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood. 2016; 128(22):221. Available at: Accessed on June 12, 2018.
  2. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014; 371(16):1507-1517.
  3. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Engl J Med. 2018; 378(5):439-448.
  4. Maude S, Pulsipher M, Boyer M, et al. Efficacy and safety of CTL019 in the first US phase II multicenter trial in pediatric relapsed/refractory acute lymphoblastic leukemia: results of an interim analysis. Blood. 2016: 128:2801. Available at: Accessed on June 12, 2018.
  5. Oskarsson T, Söderhäll S, Arvidson J, et al. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. Haematologica. 2016; 101(1):68-76.
  6. Porter DL, 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; 7(303):303.
  7. Schuster S, Bishop M, Tam C, et al. Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2017. 30:577. Available at: Accessed on June 19, 2018.
  8. Schuster SJ, Svoboda J, Chong EA, et al.  Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017; 377(26):2545-2554.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Kymriah [Product Information], Novartis Pharmaceuticals Corporation, East Hanover, NJ; May 2018. Available at: Accessed on June 12, 2018.
  2. National Marrow Donor Program and the Medical College of Wisconsin. Center for International Blood and m Marrow Transplant Research: Karnofsky/Lansky Performance Status. 2009. Available at: Accessed on June 12, 2018.
  3. NCCN Clinical Practice Guidelines in Oncology®. © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: Accessed on June 12, 2018.
    • Acute Lymphocytic Leukemia (V1.2018). Revised March 12, 2018.
    • B-Cell Lymphomas (V7V4.20172018). Revised May 15, 2018.
  4. Novartis Pharmaceuticals. Determine efficacy and safety of CTL019 in pediatric patients with relapsed and refractory B-cell ALL (ELIANA). NCT 02435849. Updated March 21, 2018. Available at: Accessed on June 12, 2018.
  5. Novartis Pharmaceuticals. Risk Evaluation and Mitigation Strategy (REMS) program: Kymriah treatment centers. Available at: Accessed on June 12, 2018. 
  6. Tisagenlecleucel. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated June 05, 2018. Available at: Accessed on June 19, 2018.
Websites for Additional Information
  1. American Cancer Society. Key Statistics for Acute Lymphocytic Leukemia. Updated on January 04, 2018. Available at: Accessed on June 08, 2018.
  2. American Cancer Society (ACS). What Are the Key Statistics About Non-Hodgkin Lymphoma? Available at: Updated on January 04, 2018. Accessed on June 13, 2018.
  3. National Cancer Institute (NCI). Adult acute lymphoblastic leukemia treatment (PDQ®). Updated March 22, 2018. Available at: Accessed on June 08, 2018.
  4. National Cancer Institute (NCI). Adult Non-Hodgkin Lymphoma Treatment (PDQ®). Updated April 20, 2018. Available at: Accessed on June 13, 2018.
  5. NCI. CAR T Cells: Engineering patients’ immune cells to treat their cancers. Updated December 14, 2018. Available at: Accessed on June 08, 2018.
  6. NCI. Childhood acute lymphoblastic leukemia treatment (PDQ®). Updated April 5, 2018. Available at: Accessed on June 08, 2018.
Document History






Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. Updated title with registered trademark symbol. Revised MN and NMN criteria to include DLBCL. Updated Rationale, Background/Overview, Coding and References sections.



MPTAC review.



Hematology/Oncology Subcommittee Review. Updated Rationale, Background/Overview and References sections.



MPTAC review.



Hematology/Oncology Subcommittee Review. Updated Description/Scope. Added a “Note” referencing designated treatment centers to the MN Statement. Updated Rationale, Background/Overview, Coding and References sections.



MPTAC review.



Hematology/Oncology Subcommittee review. Updated header language from “Current Effective Date” to “Publish Date.” Updated Coding section to include 01/01/2018 HCPCS changes.



MPTAC review.



Hematology/Oncology Subcommittee review. Initial document development.

Preliminary Discussion


MPTAC Pre-FDA approval review.

Preliminary Discussion


Hematology/Oncology Subcommittee review. Pre-FDA approval review.