Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	1998109
Category:	Pharmacy
Initiated:	February 1998
Last Review:	August 2025

Tisagenlecleucel (e.g., Kymriah)

Description:

Tisagenlecleucel is an adoptive immunotherapy in which the T cells of an individual are modified by genetic engineering using lentiviral vector. The resulting genetic modified cells express a CD-19 directed chimeric antigen receptor protein that consists of an extracellular portion that has a murine anti-CD19 single-chain antibody fragment as well as an intracellular portion that contains T-cell signaling and co-stimulatory domains. Once injected, the genetically modified T cells selectively target and bind to CD19 antigen expressed on the surface of B cells and tumors derived from B cells. Subsequently, the intracellular signaling domains play crucial roles in T-cell activation, persistence, and effector functions (Novartis Pharmaceuticals, 2017).

REGULATORY STATUS

On August 30, 2017, tisagenlecleucel (e.g., Kymriah™; Novartis) was approved by the FDA for the treatment of individuals up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

On May 1, 2018, tisagenlecleucel (e.g., Kymriah™; Novartis) was approved by the FDA for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

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 individuals with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Individuals should be monitored for neurologic events after treatment.

Tisagenlecleucel (e.g., Kymriah) is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS. The requirements for the REMS components are as follows:

Health care facilities that dispense and administer 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 individual for administration within 2 hours after tisagenlecleucel, axicabtagene ciloleucel, or brexucabtagene autoleucel infusion, if needed for treatment of cytokine release syndrome.
Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer tisagenlecleucel are trained to manage cytokine release syndrome and neurologic toxicities.

On May 27, 2022, the Food and Drug Administration approved tisagenlecleucel (e.g., Kymriah) for the treatment of adult individuals with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more lines of systemic therapy, and to include a major modification to the approved Risk Evaluation and Mitigation Strategy (REMS). This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in conformity trial(s).

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Please refer to AR policy # 2020001 for separate policy on Adoptive Immunotherapy.

Prior Approval is required for tisagenlecleucel (e.g., Kymriah).

The initial use of this drug requires documentation of direct physician (MD/OD) involvement in the ordering and evaluation as well as a signature in the medical records submitted for prior approval.

STANDARD REVIEW FOR DURATION OF TREATMENT COURSE OR 12 MONTHS (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.

Effective November 01, 2025

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Tisagenlecleucel (e.g., Kymriah) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:

The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”).

B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

STANDARD REVIEW:

Individual has confirmed diagnosis of *relapsed or **refractory CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts); AND
Individual is 25 years of age or less at the time of infusion; AND
Individual has adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis; AND
Individual has confirmed CD19 tumor expression (Kymriah, 2025); AND
Individual is using for one of the following types of disease:

6. Individual does not have ANY of the following:

Burkitt lymphoma; OR
Active central nervous system (CNS) 3 leukemia****; OR
Concomitant genetic syndrome with the exception of Down syndrome; OR
Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to tisagenlecleucel infusion; OR

7. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND

8. There is only one administration of tisagenlecleucel per individual per lifetime

NON-HODGKIN LYMPHOMA (non-follicular lymphoma)

STANDARD REVIEW:

Individual is 18 years of age or older at the time of infusion; AND
Individual has a histologically confirmed, aggressive diagnosis of ***relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, or high-grade B-cell lymphoma, or diffuse large B-cell lymphoma arising from follicular lymphoma; AND
Individual has received adequate prior therapy including ALL the following:

v. Anti-CD20 monoclonal antibody for CD20-positive tumor (e.g., rituximab); AND

vi. Anthracycline-containing chemotherapy regimen; AND

vii. For individuals with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma and subsequently have chemo refractory disease after transformation to diffuse large B-cell lymphoma; AND

4. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND

5. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND

6. Individual does not have primary central nervous system lymphoma; AND

7. There is only one administration of tisagenlecleucel per individual per lifetime

FOLLICULAR LYMPHOMA (FL)

STANDARD REVIEW:

Individual is 18 years of age or older at the time of infusion; AND
Individual has a histologically confirmed diagnosis of *relapsed or **refractory follicular lymphoma; AND
Individual has received at least two prior lines of therapy (Kymriah, 2025); AND
Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
Individual ****does not have primary central nervous system lymphoma; AND
Individual has no previous allogeneic HSCT; AND
Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
There is only one administration of tisagenlecleucel per individual per lifetime.

Off-label Indications:

The use of this drug for off-label indications not listed below is subject to policy 2000030.

STANDARD REVIEW:

Individual is 18 years of age or older; AND
Individual has a histologically confirmed diagnosis of one of the following:
Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND
Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND
There is only one administration of tisagenlecleucel per individual per lifetime.

Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications. To view the most recent and complete version of the guideline or Compendium, go online to NCCN.org. Please note, NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Tisagenlecleucel (e.g., Kymriah), for any indication or circumstance not described above, does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals with contracts without primary coverage criteria, tisagenlecleucel (e.g., Kymriah) for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The repeat treatment of tisagenlecleucel (e.g., Kymriah) for the treatment of B-cell acute lymphoblastic leukemia or of non-Hodgkin lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals without primary coverage criteria, the repeat treatment of tisagenlecleucel (e.g., Kymriah) for treatment of B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Tisagenlecleucel (e.g., Kymriah) after administration of axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals without primary coverage criteria, tisagenlecleucel (e.g., Kymriah) after administration of axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Policy Guidelines

* 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 allogeneic cell transplant.

** Refractory (resistant) disease is defined as those individuals 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).

*** Relapsed or refractory disease, defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant). This can be defined by any of the following:

Second or later bone marrow relapse; OR
Bone marrow relapse after allogeneic stem cell transplant; OR
Primary refractory disease defined as failure to achieve complete response after two cycles of standard chemotherapy; OR
Chemo-refractory after relapse defined as failure to achieve complete response after 1 cycle of standard chemotherapy for relapse leukemia.

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

CNS 1: Absence of blasts on cerebrospinal fluid cytospin preparation, regardless of the white blood cell (WBC) count
CNS 2: WBC count of less than 5 per microliter of blood and blasts on cytospin findings
CNS 3: WBC count of 5 per microliter of blood or more and blasts on cytospin findings and/or clinical signs of CNS leukemia (e.g., facial nerve palsy, brain/eye involvement, hypothalamic syndrome, significant leptomeningeal disease).

Provider is responsible for assessing suitability for CAR-T therapy, including verification of adequate renal function (creatinine clearance is not less than or equal to 45 mL/min), adequate cardiovascular function (left cardiac ejection fraction (EF) is not less than 45%, or other clinically significant cardiac disease has not been present within in the past 6 months), adequate immunological status (no active hepatitis B, active hepatitis C, human immunodeficiency virus (HIV) positive, or other active, uncontrolled infection).

The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication above with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”)]. The use of this drug for off-label indications not listed above is subject to policy 2000030.

Dosage and Administration

Dosing per FDA Guidelines unless otherwise specified below.

B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

The recommended dosage of tisagenlecleucel for individuals 50 kg or less is 0.2 to 5.0×1 million chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously.
The recommended dosage of tisagenlecleucel for individuals above 50 kg, dose is 0.1 to 2.5×100 million total chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.

NON-HODGKIN LYMPHOMA (non-follicular lymphoma)

The recommended target dose of tisagenlecleucel for individuals with large B-cell lymphoma is 0.6 to 6.0 × 100 million chimeric antigen receptor−positive viable T cells intravenously.

FOLLICULAR LYMPHOMA (FL)

The recommended target dose of tisagenlecleucel for individuals with follicular lymphoma is 0.6 to 6.0 x 100 million CAR-positive viable T cells intravenously.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Effective August 21, 2024 to October 31, 2025

Effective August 21, 2024, coverage criteria for CAR-T therapies has been separated into individual drug policies [i.e., Tisagenlecleucel (e.g., Kymriah), Axicabtagene Ciloleucel (e.g., Yescarta), Brexucabtagene Autoleucel (e.g., Tecartus), Lisocabtagene Maraleucel (e.g., Breyanzi), Idecabtagene Vicleucel (e.g., Abecma), and Ciltacabtagene Autoleucel (e.g., Carvykti)]. For details of coverage, please see specific drug policies: 1998109, Tisagenlecleucel (e.g., Kymriah), 2024038, Axicabtagene Ciloleucel (e.g., Yescarta), 2024039, Brexucabtagene Autoleucel (e.g., Tecartus), 2024042, Lisocabtagene Maraleucel (e.g., Breyanzi), 2024041, Idecabtagene Vicleucel (e.g., Abecma), 2024040, Ciltacabtagene Autoleucel (e.g., Carvykti).

For coverage criteria prior to August 21, 2024 for Tisagenlecleucel (e.g., Kymriah), Axicabtagene Ciloleucel (e.g., Yescarta), Brexucabtagene Autoleucel (e.g., Tecartus), Lisocabtagene Maraleucel (e.g., Breyanzi), Idecabtagene Vicleucel (e.g., Abecma), and Ciltacabtagene Autoleucel (e.g., Carvykti), please email codespecificinquiry@arkbluecross.com for a hardcopy print of the coverage policy.

Please refer to AR policy # 2020001 for separate policy on Adoptive Immunotherapy.

Prior Approval is required for tisagenlecleucel (e.g., Kymriah).

Effective August 21, 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Tisagenlecleucel meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following conditions:

1. B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA:

a. Individual has a confirmed diagnosis of *relapsed or **refractory CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts); AND

b. Individual is 25 years of age or less at the time of infusion; AND

c. Individual has adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis; AND

d. Individual does not have ANY of the following:

i. Burkitt lymphoma; OR

ii. Active hepatitis B, C, or any uncontrolled infection; OR

iii. Grade 2 to 4 graft-versus-host disease; OR

iv. Concomitant genetic syndrome with the exception of Down syndrome; OR

v. Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to tisagenlecleucel infusion; OR

e. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND

f. There is only one administration of tisagenlecleucel per individual per lifetime; AND

g. Must be dosed in accordance with the FDA label; OR

2. NON-HODGKIN LYMPHOMA (non-follicular lymphoma):

a. Individual is 18 years of age or older at the time of infusion; AND

b. Individual has a histologically confirmed, aggressive diagnosis of ***relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, or high-grade B-cell lymphoma, or diffuse large B-cell lymphoma arising from follicular lymphoma; AND

c. Individual has received adequate prior therapy including ALL the following:

i. Anti-CD20 monoclonal antibody for CD20-positive tumor; AND

ii. Anthracycline-containing chemotherapy regimen; AND

iii. For individuals with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma and subsequently have chemo refractory disease after transformation to diffuse large B-cell lymphoma; AND

d. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND

e. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND

f. Individual does not have primary ****central nervous system lymphoma; AND

g. There is only one administration of tisagenlecleucel per individual per lifetime; AND

h. Must be dosed in accordance with the FDA label; OR

3. FOLLICULAR LYMPHOMA (FL):

a. Individual is 18 years of age or older at the time of infusion; AND

b. Individual has a histologically confirmed diagnosis of *relapsed or **refractory follicular lymphoma; AND

c. Individual has adequate organ and bone marrow function as determined by the treating oncologist/hematologist; AND

d. Individual **Does not have primary central nervous system lymphoma; AND

e. Individual has no previous allogeneic HSCT; AND

f. Individual has not received prior treatment with CAR T-cell therapy or other genetically modified T-cell therapy and is not or has not been a subject of a clinical trial for any of the therapies listed in this policy; AND

g. There is only one administration of tisagenlecleucel per individual per lifetime; AND

h. Must be dosed in accordance with the FDA label.

* 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 allogeneic cell transplant.

** Refractory (resistant) disease is defined as those individuals 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).

*** Relapsed or refractory disease, defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).

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

CNS 1: Absence of blasts on cerebrospinal fluid cytospin preparation, regardless of the white blood cell (WBC) count
CNS 2: WBC count of less than 5/mL and blasts on cytospin findings
CNS 3: WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia (e.g., facial nerve palsy, brain/eye involvement, hypothalamic syndrome)

The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).

Dosage and Administration

Dosing per FDA Guidelines

B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

The recommended dosage of tisagenlecleucel for individuals 50 kg or less is 0.2 to 5.0×1 million chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously.
The recommended dosage of tisagenlecleucel for individuals above 50 kg, dose is 0.1 to 2.5×100 million total chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.

NON-HODGKIN LYMPHOMA (non-follicular lymphoma)

The recommended target dose of tisagenlecleucel for individuals with large B-cell lymphoma is 0.6 to 6.0 × 100 million chimeric antigen receptor−positive viable T cells intravenously.

FOLLICULAR LYMPHOMA (FL)

The recommended target dose of tisagenlecleucel for individuals with follicular lymphoma is 0.6 to 6.0 x 100 million CAR-positive viable T cells intravenously.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Tisagenlecleucel, for any indication or circumstance not described above, does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals with contracts without primary coverage criteria, tisagenlecleucel for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The repeat treatment of tisagenlecleucel for the treatment of B-cell acute lymphoblastic leukemia or of non-Hodgkin lymphoma does not meet member certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals without primary coverage criteria, the repeat treatment of tisagenlecleucel for treatment of B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Tisagenlecleucel after administration of axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy for any indication does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals without primary coverage criteria, tisagenlecleucel after administration of axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel or any other CD-19 autologous T-cell immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

For coverage criteria prior to August 21, 2024 for Tisagenlecleucel (e.g., Kymriah, Axicabtagene Ciloleucel (e.g., Yescarta), Brexucabtagene Autoleucel (e.g., Tecartus), Lisocabtagene Maraleucel (e.g., Breyanzi), Idecabtagene Vicleucel (e.g., Abecma), and Ciltacabtagene Autoleucel (e.g., Carvykti), please email codespecificinquiry@arkbluecross.com for a hardcopy print of the coverage policy.

Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when randomized clinical trials show efficacy. The selected studies included only new randomized clinical trials.

Tisagenlecleucel

B-Cell Acute Lymphoblastic Leukemia (ALL)

In the pivotal trial phase 2 single-arm, international, multicenter trial (ELIANA), 92 patients ages 3 to 21 years of screening with CD19-positive relapsed or refractory B-cell ALL were treated with tisagenlecleucel and followed for a median duration of 13.1 months. Trial results were published by Maude et al (2018).

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

Of the 107 patients who were screened, 92 met the trial inclusion criteria and of these 75 (81.5%) were infused with tisagenlecleucel. Patients received investigator choice bridging chemotherapy as needed to control their leukemia while waiting for tisagenlecleucel infusion. Patients also received protocol mandated lymphocyte-depleting chemotherapy 2 to 14 days prior to tisagenlecleucel infusion. An overall response rate of 81% was reached for patients who had at least three months of follow-up data available at data cutoff. Median overall survival (OS) was not reached but OS at 6 months post-infusion was 90% and 76% (95% CI: 63 to 86) at 12 months after infusion. Any grade CRS was observed in 77% of patients.

Observed outcomes in single-arm study design cannot be attributed solely to the intervention itself because they could occur as a result of a placebo effect, the natural course of the disease, or confounding by time-varying factors. However, it is unlikely that the 81% response rate (measured by CR or CRi) seen in the pivotal single-arm trial of tisagenlecleucel in patients with relapsed or refractory ALL could be the result of noninterventional effect. An unbiased estimate of the safety of tisagenlecleucel cannot be ascertained from this evidence base because of the lack of control arm, which makes it difficult to determine whether the observed adverse reactions are a consequence of background disease or the drug itself. However, tisagenlecleucel is a biologic drug and therefore observed adverse reactions that have immunologic basis are likely drug mediated. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse reactions. CRS was observed in more than half (77%) of the patients and approximately 88% had an adverse event at grade 3 or higher. Long-term follow-up, real-world evidence, and post-marketing studies are required to assess the generalizability of tisagenlecleucel efficacy and safety outside of a clinical trial setting.

Diffuse Large B-Cell Lymphoma (DLBCL)

The pivotal trial phase 2 single-arm, multicenter trial (JULIET; NCT02445248) enrolled 165 patients with relapsed or refractory DLBCL. Data were obtained from Schuster et al (2019) containing published outcomes at a median data cutoff of 14 months.

Of the 165 patients enrolled in the study, 95 patients were retrospectively identified and analyzed for the major efficacy outcome. The prespecified primary efficacy endpoint was ORR based on Lugano criteria (NCCN 2019), as assessed by an independent review committee and duration of response. Patients were heavily pretreated with a median of 3 prior therapies (range, 1-6), 56% had refractory disease and 44% relapsed after their last therapy. Response durations were longer in patients who achieved CR, as compared with patients with the best response of partial response. The response was consistent across subgroups (2 antineoplastic therapies, nongerminal or germinal cancer, rearranged MYC/BCL2/BCL6 or not)

Supportive Studies

Two single-arm studies that included a total of 84 patients were conducted using product manufactured at a university cell and vaccine production facility (Novartis Briefing Document, 2017; Novartis Presentations for the July 12, 2017, Meeting of the Oncologic Drugs Advisory Committee, 2017). The first study was a phase 1/2a single-center study in 55 patients enrolled between March 2012 and November 2015. The ORR rate (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 multicentric study that enrolled 29 patients between August 2014 and February 2016. The ORR rate (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) (FDA, 2017). 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 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 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 FDA 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 tisagenlecleucel. Acquired hypogammaglobulinemia is an expected side effect of 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 tisagenlecleucel. It is unclear as to how long intravenous gamma globulin would be required.

Multiple design features of the 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 tisagenlecleucel infusion.

SUMMARY OF EVIDENCE

Tisagenlecleucel

For individuals who are up to 25 years of age with relapsed or refractory B-cell acute lymphoblastic leukemia who receive tisagenlecleucel, the evidence includes multiple single-arm prospective trials. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trials reported an 81% response rate (measured by complete response or complete remission with incomplete blood count) in heavily pretreated patients. All patients who achieved a complete remission or 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 13.1 months, the median duration of response was not reached. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome was observed in more than half (77%) of the patients, and approximately 40% had an adverse event at grade 4 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of tisagenlecleucel efficacy and safety outside of a clinical trial setting. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are adults with a histologically confirmed diagnosis of aggressive Non-Hodgkin’s Lymphoma (eg, DBLCL not otherwise specified, high-grade B-cell lymphoma, transformed follicular lymphoma) who receive tisagenlecleucel, the evidence includes a single-arm prospective trial. The relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trial reported a 52% overall response rate (measured by complete or partial remission) in heavily pretreated patients. After a median follow-up of 14 months, the median duration of response was not reached. The observed benefits were offset by a high frequency and severity of adverse events. Any grade cytokine release syndrome was observed in 58% of the patients, and 63% had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence are required to assess the generalizability of tisagenlecleucel efficacy and safety outside of the clinical trial setting. 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 the net health outcome.

PRACTICE GUIDELINES AND POSITION STATEMENTS

Current guidelines from the National Comprehensive Cancer Network do not include recommendations for adoptive immunotherapy to treat cancers of the bladder, central nervous system, head and neck, hepatobiliary system, kidney, pancreatic, stomach, or thyroid, melanoma, Hodgkin lymphoma, or non-small-cell lung cancer (NCCN, 2017).

Current NCCN guidelines for acute lymphoblastic leukemia (v.2.2019) recommend (category 2A) tisagenlecleucel as a treatment option for:

Philadelphia chromosome-positive patients 26 years or less in age with refractory disease or 2 or more relapses and failure of 2 tyrosine kinase inhibitors.
Philadelphia chromosome-negative patients 26 years or less in age with refractory disease or 2 or more relapses.

Current Network guidelines for B-cell non-Hodgkin lymphoma (v.5.2019) recommend (category 2A) axicabtagene ciloleucel or tisagenlecleucel as a treatment option for:

For histological transformation to diffuse large B-cell lymphoma after multiple lines of prior therapies which include ≥2 chemo-immunotherapy regimens for the indolent or transformed disease.
For relapsed or refractory disease diffuse large B-cell lymphoma after multiple lines of prior therapies which include ≥2 chemo-immunotherapy regimens for the indolent or transformed disease

December 2020 Update

In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.

A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.

KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (NCT02601313). (Wang M, Munoz J, Goy A, et. al., 2020)

August 2021 Update

From UpToDate: “Chimeric antigen receptor (CAR)-T cell therapy is an option for patients with MM relapsed after four or more lines of systemic therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The use of CAR-T therapy is individualized weighing disease tempo, availability of other treatments, and expected toxicity. While initial studies suggest that CAR-T therapy has activity against relapsed or refractory MM, the quality of the evidence is low, treatment is associated with substantial toxicity, and the manufacturing process is complex and expensive.”

In a phase 2 study of the anti-BCMA CAR-T cell product idecabtagene vicleucel (ide-cel) in 128 patients with RRMM, objective responses were seen in 73 percent with an estimated median progression-free survival of 8.8 months. All but one patient experienced at least one grade 3 or 4 toxicity, with hematologic toxicity being most common. Cytokine release syndrome occurred in 84 percent and was usually grade 1 or 2. Grade ≥ 3 CRS occurred in 5% (7/128) of patients (Munshi et al., 2021).

Neurologic toxicities, including severe or life-threatening. In clinical trial, neurological toxicities (NT) occurred in 18% (23/128) of patients. Grade 3 neurologic toxicities occurred in 3% (4/128) of patients and no NT greater than grade 3 occurred (Munshi et al. 2021). Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), including fatal and life-threatening reactions. In clinical trial, HLH/MAS occurred in 4% (5/127) of patients (Celgene, 2021a).

Persistent cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery. In clinical trial, neutropenia occurred in 91% (117/128) of patients, anemia occurred in 70% (89/128), and thrombocytopenia occurred in 63% (81/128) (Munshi et al., 2021).

Response durations were longer in patients who achieved a stringent complete response (CR) as compared to patients with a partial response (PR) or very good partial response (VGPR). Of the 28 patients who achieved a stringent CR, it is estimated that 65% (95% CI: 42%, 81%) had a remission lasting at least 12 months. The median duration of response for VGPR patients (n=25) was 11.1 months (95% CI: 8.7, 11.3) and the median duration of response for PR patients (n=19) was 4.0 months (95% CI: 2.7, 7.2). Results of the KarMMa study support Abecma (idecabtagene vicleucel) induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma.

The NCCN guideline for Multiple Myeloma version 6.2021 idecabtagene vicleucel was added to therapy for previously treated multiple myeloma other recommended regimens and is indicated for patients who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

November 2021 Update

Leahy et al, 2021 published a post hoc analysis of 195 patients (aged 1–29 years) with relapsed or refractory CD19-positive ALL from 5 clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022). All 5 trials were performed at the Children’s Hospital of Philadelphia in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. Of the 5 trials, only 2 trials (ENSIGN and ELIANA) used tisagenlecleucel as the interventional CAR-T cell therapy. Of the 195 patients included in the analysis, 34% (n=66) were categorized as having central nervous system (CNS)-positive disease while the remaining 66% (n=129) were classified as having CNS-negative disease with a median follow-up of 39 months and 36 months, respectively. The proportion of patients in the CNS-positive stratum with a CR at 28 days after infusion was 97% versus 94% in the CNS-negative stratum (p=.74) with no significant difference in relapse-free survival (60% vs 60%) or OS (83% vs 71%) at 2 years between the 2 groups. Authors concluded that the preliminary findings of their study support the use of CAR T-cell therapies for patients with CNS relapsed or refractory B-cell ALL. However, among the 66 patients with CNS-positive disease, only 1 patient was from the ENSIGN trial who received tisagenlecleucel. Therefore, data demonstrating clinical efficacy and safety of tisagenlecleucel among patients with CNS-positive disease are lacking.

Levine at al 2021 published a pooled analysis of 137 patients from the ELIANA (n=79) and ENSIGN (n=58) trials reporting comprehensive safety data for tisagenlecleucel. Grade 3 or 4 treatment-related adverse events were reported in 77% of patients. Specific adverse events of interest that occurred ≤8 weeks post-infusion included CRS (any grade: 79% and grade 4: 22%), infections (any grade: 42% and grade 3 or 4: 19%), prolonged (not resolved by day 28) cytopenias (any grade: 40%; grade 3 or 4: 34%), neurologic events (any grade: 36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). It is important to note that Levine et al 2021 used the University of Pennsylvania (Penn) CRS grading scale while other studies have used the CRS Revised Grading System developed by Lee et al 2014 or the ASTCT CRS Consensus Grading scale.

April 2022 Update

In an international, phase 3 trial, patients were randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.

A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred.

Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Filosto S, Shah J, Schupp M, et.al., 2021)

May 2022 Update

CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.

This single-arm, open-label, phase 1b/2 study done at 16 centers in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.

Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020, clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Hematological adverse events were common; grade 3-4 hematological adverse events were neutropenia (92 [95%] of 97 patients), anemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and hemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study: six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.

A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. (Berdeja JG, Madduri D, Usmani SZ, et.al., 2021)

August 2022 Update

The efficacy of KYMRIAH was evaluated in a multicenter, single-arm, open-label trial (ELARA, Study 3; NCT03568461) that included patients who were refractory to or relapsed within 6 months after completion of two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent), relapsed during or within six months after completion of an anti-CD20 antibody maintenance therapy following at least two lines of therapy, or relapsed after autologous hematopoietic stem cell transplant (HSCT). The trial excluded patients with active or serious infections, transformed lymphoma, or other aggressive lymphomas, prior allogeneic HSCT, or disease with active CNS involvement. Following lymphodepleting (LD) chemotherapy, KYMRIAH was administered as a single dose intravenous infusion with Duration of Response Results Overall DOR for responders (months) N = 34 Median DORa,b NE (95% CI) (5.1, NE) Rangec (0.03+ – 11.3+) Median Follow-up (95% CI)b 9.4 (7.9, 10.8) DOR if BOR is CR N = 22 Median DORa,b NE (95% CI) (10.0, NE) Rangec (1.5+ – 11.3+) DOR if BOR is PR N = 12 Median DORa,b 3.4 (95% CI) (1.0, NE) Rangec (0.03+ – 11.3+) a target dose of 0.6 to 6.0 × 108 CAR-positive viable T cells. The median dose administered was 2.06 × 108 CAR-positive viable T-cells (range: 0.1 to 6.0 × 108 CAR-positive viable T cells). The LD chemotherapy regimen consisted of either fludarabine (25 mg/m2 intravenously daily for 3 days) and cyclophosphamide (250 mg/m2 intravenously daily for 3 days starting with the first dose of fludarabine) or bendamustine (90 mg/m2 IV daily for 2 days); bridging chemotherapy between leukapheresis and LD chemotherapy was permitted as needed. Of the 90 patients included in the primary efficacy analysis, 40 patients (45%) were treated with bridging therapies. The most commonly used agents (in ≥ 5% of patients) were rituximab (22%), dexamethasone (13%), gemcitabine (12%), prednisone (11%), oxaliplatin (8%), etoposide (8%), and vincristine (6%). Of 98 patients who were enrolled and underwent leukapheresis, 97 patients received infusion with KYMRIAH and one patient without measurable disease did not receive KYMRIAH. There were no manufacturing failures for the 98 enrolled patients. Of the 97 patients infused with KYMRIAH, the efficacy evaluable population, as specified in the protocol, included the first 90 patients with measurable disease who received KYMRIAH consecutively and had at least 9 months follow-up from first objective response or discontinued earlier. Among the 90 patients with FL included in the efficacy analysis, the median age was 58 years (range: 29 to 73 years), 31% were female, 78% were White, 10% were Asian, and 1% were Black or African American. The median number of prior therapies was 4 (range: 2 to 13), with 24% receiving 2 prior lines, 21% receiving 3 prior lines, and 54% receiving ≥4 prior lines. Eighty-seven percent had Stage III-IV disease at study entry, 64% had bulky disease, 36% had a prior autologous HSCT, 79% were refractory to the most recent regimen, and 66% had progression within 24 months of initiating their first anti-CD20 combination therapy (POD24). Efficacy was established on the basis of objective response rate and duration of response (DOR) as determined by an independent review committee. The first disease assessment was scheduled to be performed at Month 3 post-infusion; the median time to first response was 2.9 months (range: 0.6 to 6.0 months). All responders achieved their response (complete response [CR] or partial response [PR]) at the first performed post-infusion disease assessment. (FDA, 2022)

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2024. No new literature was identified that would prompt a change in the coverage statement.

2025 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2025. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

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