Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2024040
Category:	Pharmacy
Initiated:	August 2024
Last Review:	August 2024

Ciltacabtagene Autoleucel (e.g., Carvykti)

Description:

The spontaneous regression of certain cancers e.g., renal cell carcinoma, melanoma) supports the idea that an individual’s immune system can delay tumor progression and, on rare occasions, can eliminate tumors altogether. These observations have led to research into various immunotherapies designed to stimulate an individual’s own immune system. Chimeric antigen receptor T-cell therapy is a specific form of adoptive immunotherapy that involves harvesting cells from an individual or donor, a manufacturing process during which cells are genetically modified with engineered CAR protein to permit targeted activation and therapy, and infusion of cells into the individual.

ACUTE LYMPHOBLASTIC LEUKEMIA

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 individuals who fail to obtain complete response with induction therapy, e.g., 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 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 individuals compared with MRD-positive individuals was 0.23 (95% confidence interval, 0.18 to 0.28) (Berry, 2017).

Approximately 5000 cases of B-cell ALL are diagnosed every year in the United States,4 and approximately 620 pediatric and young adult individuals with B-cell ALL will relapse each year in the United States (Maude, 2015). It is largely a disease of the young with approximately 60% of cases occurring in individuals younger than 20 years old with a median age at diagnosis of 15 years.4 While it is treatable in 85% cases, approximately 15% of children and young adults with ALL will relapse while 2% to 3% of ALL individuals are primary refractory (Pui, 2011). Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate.7 The 2-year survival rate among individuals with ALL who relapse after hematopoietic cell transplantation is 15% (Bajwa, 2013). 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 were 2.5 months and 6 months, and median overall survival durations were 3 months and 7.5 months, respectively (Jeha, 2006; von Stackelberg, 2016). Note that the percentages of individuals treated with 3 or more prior treatments of clofarabine and blinatumomab trial were 62% and 7%, respectively. Nevertheless, treatment options for individuals with relapsed or refractory ALL are limited, associated with poor outcomes and high toxicity and the disease remains incurable.

DIFFUSE LARGE B-CELL LYMPHOMA

Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and accounts for approximately 25% of non-Hodgkin lymphoma cases (Swerdlow, 2016). DLBCL exhibits large heterogeneity in morphologic, genetic, and clinical aspects and multiple clinicopathologic entities are defined by the 2016 World Health Organization classification, which are sufficiently distinct to be considered separate diagnostic categories.

It has been estimated that 27,650 new cases of DLBCL were diagnosed in the United States in 2016 (Teras, 2016). Treatment in the first-line setting (particularly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) is associated with a 5-year survival rate ranging from 60% to 70%.14 However, based on a number of prognostic factors, 20% to 50% of DLBCL cases are refractory or relapse after first-line chemotherapy (International Non-Hodgkin's Lymphoma Prognostic Factors P., 1993; Sehn, 2007). The response to subsequent salvage chemotherapy and consolidation with autologous cell transplantation is suboptimal. A 2017 retrospective analysis of the SCHOLAR-1 study, which pooled data from 2 phase 3 clinical trials and 2 observational cohorts, included 636 individuals with refractory DLBCL (Crump, 2017). The objective response rate to the next line of therapy was 26%, with 7% achieving a complete response. Median overall survival was 6.3 months, and 2-year survival was 20%. Refractory DLBCL was defined as progressive disease or stable disease as best response at any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-line therapy) or as relapse 12 or fewer months after autologous cell transplantation.

ADOPTIVE CELL TRANSFER

The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing individuals. In current trials, 2 methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions.

Adoptive cellular therapy is “the administration of an individual’s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lympho-depleting preparative regimen” (Rosenberg, 2008). Protocols vary, but include these common steps:

1. Lymphocyte harvesting (either from peripheral blood or from tumor biopsy)

2. Propagation of tumor-specific lymphocytes in vitro using various immune modulators

3. Selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay

4. Lymphodepletion of the host with immunosuppressive agents

5. Adoptive transfer (e.g., transfusion) of lymphocytes back into the tumor-bearing host

CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY

Due to difficulties in expanding innate TILs, genetic modification techniques have been harnessed to decorate propagated T cells with engineered chimeric antigen receptors (CARs) that are composed of several functional components: a tumor antigen-targeting single chain variable fragment (scVF) (e.g., anti-CD19), a hinge region, a T-cell activation domain (e.g., CD3), and one or more costimulatory domains (e.g., CD28, 4-1 BB). Viral vector genetic modification approaches (e.g., retroviral, lentiviral) have traditionally been used to transfect T cells with CAR genes.

CILTACABTAGENE AUTOLEUCEL

Ciltacabtagene autoleucel is a BCMA (B cell maturation antigen)-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming an individual’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. The CARVYKTI CAR protein features two BCMA-targeting single-domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3-zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA-expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells.

REGULATORY STATUS

Ciltacabtagene autoleucel 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.

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

Health care facilities that dispense and administer ciltacabtagene autoleucel 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 ciltacabtagene 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 ciltacabtagene autoleucel are trained to manage cytokine release syndrome and neurologic toxicities.

On February 28, 2022, the Food and Drug Administration approved ciltacabtagene autoleucel (e.g., Carvykti) for the treatment of adult individuals with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

For coverage criteria prior to August 21, 2024 for 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 ciltacabtagene autoleucel (e.g., Carvykti).

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.

Effective August 21, 2024

CILTACABTAGENE AUTOLEUCEL (E.G., CARVYKTI) FOR MULTIPLE MYELOMA

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

Ciltacabtagene autoleucel meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of adults with relapsed or refractory multiple myeloma when ALL the following criteria are met:

1. Individual is 18 years of age or older; AND

2. Individual has a diagnosis of multiple myeloma; AND

3. Individual has received one prior lines of therapy including ALL the following:

a. Immunomodulatory agent; AND

b. Proteasome inhibitor; AND

4. Individual is refractory to lenalidomide; 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 is not the subject of a clinical trial for any of the therapies listed in this policy; AND

6. Individual does not have any of the following circumstances:

a. Combination use with other chemotherapy agents (not including the use of lymphodepleting chemotherapy prior to infusion) and/or biologic agents; OR

b. Prior allogeneic stem cell transplant; OR

c. Prior treatment with chimeric antigen receptor therapy or other genetically modified T-cell therapy; OR

d. Creatinine clearance less than or equal to 45 mL/min; OR

e. Left cardiac ejection fraction (EF) less than 45%, or other clinically significant cardiac disease within in the past 6 months; OR

f. Active hepatitis B, active hepatitis C, human immunodeficiency virus (HIV) positive, or other active, uncontrolled infection; OR

g. Repeated administration of idecabtagene vicleucel or ciltacabtagene autoleucel; AND

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

8. Individual does not have evidence of myeloma involving the central nervous system; AND

9. There is only one administration of idecabtagene vicleucel or ciltacabtagene autoleucel per individual per lifetime; AND

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

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

The recommended dose range is 0.5 - 1.0 x 1 million CAR-positive viable T cells per kg of body weight, with a maximum dose of 1 x 100 million Car-positive viable T cells per single infusion.

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

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

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

Rationale:

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.

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.

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)

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2024.

CPT/HCPCS:

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2025 American Medical Association.