Lisocabtagene Maraleucel (Breyanzi)

Number: 0986

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses lisocabtagene maraleucel (Breyanzi) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of lisocabtagene maraleucel (Breyanzi) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of lisocabtagene maraleucel (Breyanzi), contact National Medical Excellence (NME) at 877-212-8811.

1. Exclusions

   Aetna will not provide coverage for members with any of the following exclusions:

   1. Primary central nervous system lymphoma; or
   2. Previous treatment course with the requested medication or another CD19-directed chimeric antigen receptor (CAR) T-cell therapy; or
   3. ECOG performance status greater than or equal to 3 (see Appendix); or
   4. Inadequate and unstable kidney, liver, pulmonary or cardiac function; or
   5. Active hepatitis B, active hepatitis C or any active uncontrolled infection; or
   6. Active graft versus host disease; or
   7. Active inflammatory disorder.

2. Criteria for Initial Approval

   1. Adult Large B-cell lymphomas

      Aetna considers lisocabtagene maraleucel (Breyanzi) medically necessary for treatment of B-cell lymphomas in members 18 years of age or older when any of the following criteria are met:

      1. The member has received prior treatment with two or more lines of systemic therapy and has any of the following B-cell lymphoma subtypes: 

         1. Diffuse large B-cell lymphoma (DLBCL) [including DLBCL NOS, follicular lymphoma grade 3, DLBCL arising from indolent lymphomas]; or
         2. High grade B-cell lymphoma (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified); or
         3. Primary mediastinal large B-cell lymphoma; or
         4. Follicular lymphoma; or
         5. HIV-related B-cell lymphomas (including HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specified); or
         6. Monomorphic post-transplant lymphoproliferative disorder (B-cell type); or

      2. The member has received prior treatment with first-line chemoimmunotherapy and has any of the following B-cell lymphoma subtypes;

         1. Diffuse large B-cell lymphoma (DLBCL) [including DLBCL NOS and follicular lymphoma grade 3]; or
         2. High grade B-cell lymphoma (including high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 [double/triple hit lymphoma], high-grade B-cell lymphoma, not otherwise specified); or
         3. Primary mediastinal large B-cell lymphoma; or
         4. HIV-related B-cell lymphomas (including HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specified); or
         5. Monomorphic post-transplant lymphoproliferative disorder (B-cell type); or
            

      3. The member has received prior treatment with a covalent Bruton tyrosine kinase inhibitor (e.g., acalabrutinib [Calquence], ibrutinib [Imbruvica], zanobrutinib [Brukinsa] and has relapsed/refractory Mantle cell lymphoma.

   2. Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

      Aetna considers lisocabtagene maraleucel (Breyanzi) medically necessary for treatment of relapsed or refractory CLL/SLL in members 18 years of age or older when the member has received prior therapy with Bruton tyrosine kinase inhibitor (e.g., acalabrutinib [Calquence], ibrutinib [Imbruvica], zanubrutinib [Brukinsa])- and venetoclax-based regimens.

   3. Pediatric Primary Mediastinal Large B-cell Lymphoma

      Aetna considers lisocabtagene maraleucel (Breyanzi) medically necessary for treatment of pediatric primary mediastinal large B-cell lymphoma in members less than 18 years of age when the member has received prior therapy with at least two chemoimmunotherapy regimens and achieved partial response.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   See Dosage and Administration information.

Dosage and Administration

Lisocabtagene maraleucel (Breyanzi) is a cell suspension for infusion for autologous and intravenous use only administered in a certified healthcare facility. A single dose of Breyanzi consists of 1:1 CAR-positive viable T cells of CD8 and CD4 components, with each component supplied separately in one to four single-dose 5 mL vials. Each mL contains greater than or equal to 1.5 x 10⁶ to 70 x 10⁶ CAR-positive viable T cells.

Dosing of lisocabtagene maraleucel (Breyanzi) is based on the number of chimeric antigen receptor (CAR) positive viable T cells. 

Large B-cell Lymphoma (LBCL) 

• After one line of therapy, the dose is 90 to 110 x 10⁶ CAR-positive viable T cells
• After two or more lines of therapy, the dose is 50 to 110 x 10⁶ CAR-positive viable T cells.

Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), and Mantle Cell Lymphoma (MCL)

• The dose is 90 to 110 x 10⁶ CAR-positive viable T cells.

Source: Juno Therapeutics, 2024

Experimental, Investigational, or Unproven

Aetna considers repeat administration of lisocabtagene maraleucel (Breyanzi) experimental, investigational, or unproven because the effectiveness of this approach has not been established.

Aetna considers lisocabtagene maraleucel experimental, investigational, or unproven for the treatment of solid tumors.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
0537T	Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day
0538T	preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)
0539T	receipt and preparation of CAR-T cells for administration
0540T	CAR-T cell administration, autologous
96413 – 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
Q2054	Lisocabtagene maraleucel, up to 110 million autologous anti-cd19 car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Other HCPCS codes related to the CPB:
Acalabrutinib [Calquence], ibrutinib [Imbruvica], zanubrutinib [Brukinsa]), venetoclax –no specific code
ICD-10 codes covered if selection criteria are met:
C82.00 - C82.99	Follicular lymphoma
C83.00 – C83.09	Small cell B-cell lymphoma [Small Lymphocytic Lymphoma]
C83.10 – C83.19	Mantle cell lymphoma
C83.30 - C83.39	Diffuse large B-cell lymphoma
C83.80 - C83.89	Other non-follicular lymphoma [primary effusion lymphoma]
C85.20 - C85.29	Mediastinal (thymic) large B-cell lymphoma [Less than 18 years of age]
C91.10	Chronic lymphocytic leukemia of B-cell type not having achieved remission
C91.12	Chronic lymphocytic leukemia of B-cell type in relapse
D47.Z1	Post-transplant lymphoproliferative disorder (PTLD)
ICD-10 codes not covered for indications listed in the CPB:
A00 – B99.9	Certain infectious and parasitic diseases [active, uncontrolled]
C00.0 – C82.39, C82.50 – C83.09, C83.50 – C83.79, C83.90 – C85.19, C85.80 - C90.02, C90.20 – C90.32, C96.0 - D09.9	Malignant solid tumors
D68.61	Antiphospholipid syndrome
D89.810 - D89.813	Graft-versus-host disease
I00 – I99.9	Diseases of circulatory system [inadequate and unstable cardiac function]
J00 – J99	Diseases of respiratory system [inadequate and unstable pulmonary function]
K27.0 - K27.9	Peptic ulcer, site unspecified
K50.00 - K52.9	Noninfective enteritis and colitis
K70.0 – K77	Disorders of liver system [inadequate and unstable liver function]
L40.0 - L40.9	Psoriasis
M00.00 – M99.9	Diseases of musculoskeletal system and connective tissue [active inflammatory disorder]
N00.0 – N29	Disorders of kidney and ureter system [inadequate and unstable kidney function]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Adult patients with large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) (including DLBCL arising from indolent lymphoma), high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B who have:

  • Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or 
  • Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
  • Relapsed or refractory disease after two or more lines of systemic therapy

  Limitations of Use:

  Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.

• Adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including, a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor
• Adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy
• Adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor

Compendial Uses

• Human immunodeficiency virus (HIV)-related B-cell lymphomas (including HIV-related diffuse large B-cell lymphoma, primary effusion lymphoma, and human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma, not otherwise specified)
• Monomorphic post-transplant lymphoproliferative disorder (B-cell type)
• Pediatric primary mediastinal large B-cell lymphoma
• Mantle cell lymphoma

Lisocabtagene maraleucel is available as Breyanzi (Juno Therapeutics Inc., a Bristol-Myers Squibb Company) and is a T-cell product. Breyanzi is prepared from the patient's T-cells, which are obtained from the product of a standard leukapheresis procedure. The purified CD8-positive and CD4-positive T cells are separately activated and transduced with the replication-incompetent lentiviral vector containing the anti-CD19 CAR transgene. Breyanzi is a CD19-directed genetically modified autologous cell immunotherapy administered as a defined composition to reduce variability in CD8-positive and CD4-positive T cell dose. The CAR is comprised of an FMC63 monoclonal antibody derived single chain variable fragment (scFv), IgG4 hinge region, CD28 transmembrane domain, 4-1BB (CD137) costimulatory domain, and CD3 zeta activation domain. CD3 zeta signaling is critical for initiating activation and antitumor activity, while 4-1BB (CD137) signaling enhances the expansion T cell and persistence of Breyanzi. CAR binding to CD19 expressed on the cell surface of tumor and normal B cells induces activation and proliferation of CAR T cells, release of pro-inflammatory cytokines, and cytotoxic killing of target cells (Juno Therapeutics, 2024).

According to the prescribing information, lisocabtagene maraleucel (Breyanzi) carries the following black box warnings:

• Cytokine release syndrome (CRS), including fatal or life-threatening reactions. In clinical trial, any grade CRS occurred in 46% (122/268) of patients. Grade greater than or equal to 3 CRS occurred in 4% (11/268) of patients. One patient had fatal CRS and two had ongoing CRS at time of death.
• Neurologic toxicities, including fatal or life-threatening reactions. In clinical trial, grade neurologic toxicities (NT) occurred in 35% (95/268) of patients. Grade greater than or equal to 3 NT occurred in 12% (31/268) patients. Three patients had fatal neurologic toxicity and seven had ongoing neurologic toxicity at time of death.

Additional warnings and precautions include hypersensitivity reactions, serious infections, prolonged cytopenias, hyopgammaglobulnemia, secondary malignancies, and effects on ability to drive and use machines.

Per the prescribing information, the most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) in BREYANZI-treated patients were fatigue, cytokine release syndrome, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a fast growing, invasive disease and the most common form of non-Hodgkin lymphoma (NHL), responsible of 1 out of every 3 cases diagnosed; 73 % of patients will not respond to or will relapse following 2nd-line or later treatment.  In patients who relapse or are unresponsive to initial therapies, conventional treatment options providing sustained responses are limited with an estimated median life expectancy of 6 months.  The treatment goal in DLBCL is curative intent with definitive therapy.  Additional therapeutic options are needed in relapsed or refractory DLBCL with an aim to provide sustained responses in these patients (Juno Therapeutics, 2021).

On February 5, 2021, the FDA approved Breyanzi (lisocabtagene maraleucel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma (FL) grade 3B.  Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.  Breyanzi was granted orphan designation for DLBCL, follicular lymphoma and PMBCL.  Breakthrough therapy designation was granted for treatment of subjects with R/R large B-cell lymphoma, including DLBCL not otherwise specified-de novo or transformed from indolent lymphoma, PMBCL and grade 3B FL.  Regenerative medicine advanced therapy (RMAT) designation was granted for the same indication (as Breakthrough Therapy designation) (FDA, 2021a; Juno Therapeutics, 2021c).

The approval of Breyanzi was based on data from the TRANSCEND NHL 001 (017001) trial.  In this study, Abramson et al (2020) evaluated the efficacy of Breyanzi in an ope n-label, multi-center, single-arm trial in adult patients with relapsed or refractory large B-cell non-Hodgkin lymphoma (NHL) after at least 2 lines of therapy. Breyanzi was administered to 268 patients in the inpatient and outpatient settings.  The median time to 1st response (complete response [CR] or partial response [PR] was 1.0 month (range of 0.7 to 8.9 months).  The median time to 1st CR was 1.0 month (range of 0.8 to 12.5 months).  Specifically, 192 patients were treated with Breyanzi at the dose of 50 to 110 x 10⁶CAR-positive viable T cells and evaluated for efficacy.  Of these patients, 73 % achieved a response (95 % CI: 67 % to 80 %), including 54 % who had minimal or no detectable lymphoma remaining following treatment (CR; 95 % CI: 47 % to 61 %) and 19 % who achieved a PR (95 % CI: 14 % to 26 %).  Median duration of response was 16.7 months in all responders (95 % CI: 5.3 to NR), and for patients who achieved a comCR, median duration of response was not reached (95 % CI: 16.7 to NR); for patients with a best response of PR, median duration of response was 1.4 months (95 % CI: 1.1 to 2.2).  Of 104 patients treated with Breyanzi who achieved a best overall response of CR, 65 % had remission lasting at least 6 months and 62 % had remission lasting at least 9 months.

Abramson et al (2020) evaluated the safety of 268 patients treated with Breyanzi.  Any grade cytokine release syndrome (CRS) occurred in 46 % (122/268) of patients. Grade 3 or worse CRS occurred in 4 % (11/268) of patients.  The median duration of CRS was 5 days (range of 1 to 30 days) and median time of onset was 5 days (range of 1 to 15 days).  Any grade neurologic toxicities (NT) occurred in 35% (95/268) of patients receiving Breyanzi.  Neurologic toxicities resolved in 81 of 95 patients (85 %), with a median duration of 12 days (range of 1 to 87 days).  The median onset of the 1st event was 8 days (range of 1 to 46 days).  Median duration of neurologic toxicity was 15 days (range of 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cut-off.

On June 24, 2022, the U.S. Food and Drug Administration approved Breyanzi (lisocabtagene maraleucel) for the treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12months of first-line chemoimmunotherapy; or
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant (HSCT) due to comorbidities or age.

The approval for the above expanded indications was based on supporting data from the pivotal Phase 3 TRANSFORM study (Bristol Myers Squibb, 2022).

In the TRANSFORM study, a randomized, open-label, multicenter phase 3 trial, Kamdar and colleagues (2022) evaluated the efficacy of lisocabtagene (Breyanzi) in adult patients with relapsed or refractory LBCL after first-line chemoimmunotherapy. A total of 184 patients were randomized 1:1 to receive Breyanzi with a planned dose of 100 × 10⁶ CAR-positive viable T cells intravenously or receive standard therapy consisting of 3 cycles of salvage immunochemotherapy delivered intravenously-R-DHAP(rituximab 375 mg/m² on day 1, dexamethasone 40 mg on days 1-4, two infusions of cytarabine 2000mg/m² on day 2, and cisplatin 100 mg/m² on day 1), R-ICE (rituximab 375 mg/m² on day 1, ifosfamide 5000 mg/m² on day 2, etoposide 100 mg/m² on days 1-3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m² on day 1, dexamethasone 40mg on days 1-4, gemcitabine 1000 mg/m² on days 1 and 8, and cisplatin 75 mg/m² on day 1)-followed by high-dose chemotherapy and autologous HSCT in responders. The primary efficacy endpoint was event-free survival and other efficacy endpoints included progression-free survival. The median follow-up was 6.2 months and median event -free survival was significantly improved in the Breyanzi group (10.1 months [95% Confidence Interval [CI] 6.1-not reached]) compared with the standard therapy group (2.3 months [2.2-4.3]; stratified hazard ratio 0·35; 95% CI 0.23-0.53; stratified Cox proportional hazards model one-sided p<0.0001). The most frequent grade 3 or worse adverse events were neutropenia (74 [80%] of 92 patients in the Breyanzi group vs 46 [51%] of 91 patients in the standard therapy group), anemia (45 [49%] vs 45 [49%]), thrombocytopenia (45 [49%] vs 58 [64%]), and prolonged cytopenia (40 [43%] vs three [3%]). Grade 3 cytokine-release syndrome and neurological events associated with CAR T-cell therapy was noted in (1%) and four (4%) of 92 patients in the Breyanzi group, respectively (no grade 4 or 5 events). Serious treatment-emergent adverse events were noted in 44 (48%) patients in the Breyanzi group and 44 (48%) in the standard therapy group. No new Breyanzi safety issues were notable in the second-line setting. The investigators concluded that the results support Breyanzi as a new second-line treatment recommendation in patients with early relapsed or refractory LBCL.

Follicular Lymphoma

On May 15, 2024, the U.S. Food and Drug Administration (FDA) granted accelerated approval for Breyanzi (lisocabtagene maraleucel) for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received two or more prior lines of systemic therapy. The FDA approval was based on supporting data from the TRANSCEND-FL study (FDA, 2024a).

In the TRANSCEND-FL study, a phase 2, open-label, multicenter, single-arm trial, investigators evaluated the efficacy of Breyanzi (lisocabtagene maraleucel) in adult patients with relapsed or refractory FL after two or more lines of systemic therapy (including an anti-CD20 antibody and an alkylating agent). The planned dose for the study patients was Breyanzi 100 x 106 CAR-positive viable T cells. Patients received a single dose of Breyanzi 2 to 7 days after completion of lymphodepleting chemotherapy (i.e., fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days) (Juno Therapeutics, 2024).

Out of the 114 patients completing leukapheresis, 107 received Breyanzi and the median dose was 100.02 x 106 CAR-positive viable T-cells (range: 93.4 to 109.2 x 106 CAR-positive viable T cells). The primary efficacy analysis included 94 patients with positron emission tomography (PET)-positive FL at baseline or following bridging therapy, received conforming product in the intended dose range, and had at least 9 months of follow up from first response (Juno Therapeutics, 2024).

The primary efficacy outcome measures were overall response rate (ORR), established as the percentage of patients with a best overall response (BOR) of either complete response or partial response after Breyanzi infusion, and duration of response (DOR), as determined by an independent review committee. The ORR was 95.7% (95% Confidence Interval [CI]: 89.5, 98.8). After a median follow up of 16.8 months (95% CI: 16.3, 17.0), the median DOR was not reached (NR) (95% CI: 18.04, NR) (FDA, 2024a; Juno Therapeutics, 2024).

Mantle Cell Lymphoma

Kumar et al (2022) stated that mantle cell lymphoma (MCL) is a rare B-cell NHL that is clinically and biologically heterogeneous.  Risk stratification at the time of diagnosis is critical.  One of the most powerful prognostic indices is the Mantle Cell Lymphoma International Prognostic Index-Combined, which integrates an estimate of proliferation (Ki67 index) with the standard Mantle Cell Lymphoma International Prognostic Index clinical factors.  Furthermore, the presence of TP53 mutation is associated with sub-optimal response to intensive chemoimmunotherapy and especially dismal survival outcomes.  Given their excellent activity in the relapsed/refractory setting, increasingly, biologically targeted therapeutics such as co-valent Bruton tyrosine kinase inhibitors (BTKi), lenalidomide, and venetoclax are being incorporated into "chemotherapy-free" regimens and in combination with established chemoimmunotherapy backbones for treatment-naïve MCL.  Additionally, risk-adapted treatment programs are increasingly being studied.  These programs tailor treatment according to baseline prognostic factors (e.g., presence of TP53 mutation) and may incorporate biomarkers of response such as minimal residual disease (MRD) assessment.  Although still investigational, these studies presented an opportunity to move beyond the biology-agnostic, historical fitness-based treatment selection paradigm and toward a more personalized, tailored treatment approach in MCL.  After BTKi failure, many promising standard or investigational therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene maraleucel), bi-specific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug conjugate that targets ROR1), and the non-covalent Bruton TKI pirtobrutinib.  The authors concluded that these new therapies show promising effectiveness, even among high-risk patients, and will likely translate to improvements in survival outcomes for patients with progressive MCL following treatment with a BTKi.

Mohty and Kharfan-Dabaja (2022) noted that patients with R/R FL and MCL have a poor prognosis with anticipated short progression-free survival (PFS) and overall survival (OS).  Two CD19-directed CAR T therapies are approved in the U.S. for R/R FL, namely, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel.  The results of the ZUMA-5 and ELARA Trials resulted in the approval of axi-cel and tisagenlecleucel, respectively, after demonstrating high overall (ORR) and complete response (CR) rates in this high-risk population of FL patients who had received a median of 3 (range of 2 to 4) and 4 (range of 2 to 13) prior lines of therapies, respectively.  For instance, the ORR for ZUMA-5 was 94 % (CR = 79 %), and for ELARA, it was 86 % (CR = 69.1 %).  Pertaining to MCL, brexucabtagene autoleucel is approved for R/R MCL based on results of the ZUMA-2 Trial.  In the latter study, despite the fact that all R/R MCL patients had been exposed to prior Bruton's tyrosine kinase inhibitors (BTKIs), the reported ORR was 91 %, with 68 % achieving a CR.  These results showed a strong efficacy of CAR T therapy in both R/R FL and MCL; however, one must acknowledge the relatively short follow-up time of all afore-mentioned studies.  These researchers stated that longer follow-up showing durability of responses and long-term safety is definitely needed.

These researchers stated that lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T product currently approved for R/R large B-cell lymphoma after 2 or more lines of systemic therapy but not approved for MCL.  Liso-cel has been studied in a small number of patients with MCL in the TRANSCEND NHL 001 phase-I clinical trial.  A total of 41 patients were included, but only 32 patients received liso-cel.  High-risk features including blastoid morphology, Ki67 of greater than 30 %, TP53 mutation, and complex karyotype were observed in 37.5 % (n = 12), 72 % (n = 23), 22 % (n = 7), and 34 % (n = 11) of patients, respectively.  Among patients exposed to BTKi (87.5 %), 34 % were refractory.  The ORR was 84 %, and CR rate was 59 %.  CRS and neurologic events were observed in 50 % and 28 %, and 3 % and 9 % had grade greater than 3 CRS and neurological event (NE), respectively.  These results indicated that liso-cel was associated with low rate of high-grade toxicity in patients with MCL with promising efficacy data.  The study is still ongoing, and longer follow-up data are keenly awaited.

On May 30, 2024, the U.S. Food and Drug Administration (FDA) approved Breyanzi (lisocabtagene maraleucel) for adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least two prior lines of systemic therapy, including a Bruton tyrosine kinase inhibitor (BTKi). The FDA approval was based on supporting data from the TRANSCEND-MCL study (FDA, 2024b).

In the TRANSCEND-MCL study, an open-label, multicenter, single-arm trial, investigators evaluated the efficacy of Breyanzi (lisocabtagene maraleucel) in adult patients with relapsed or refractory MCL who had received at least two prior lines of therapy including a Bruton tyrosine kinase inhibitor, an alkylating agent, and anti-CD20 agent. The planned dose for the study patients was Breyanzi 100 x 106 CAR-positive viable T cells. Patients received a single dose of Breyanzi 2 to 7 days after completion of lymphodepleting chemotherapy (i.e., fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day concurrently for 3 days) (Juno Therapeutics, 2024).

Out of the 89 patients completing leukapheresis, 71 received Breyanzi and the median dose was 99.8 x 106 CAR-positive viable T cells (range: 90 to 103 x 106 CAR-positive viable T cells). The primary efficacy analysis included a total of 68 patients with MCL who received at least 2 prior lines of therapy including a BTK inhibitor, had positron emission tomography (PET)-positive MCL at study baseline or after bridging therapy, received conforming product in the intended dose range, and had at least 6 months of follow up from the date of first response (Juno Therapeutics, 2024).

The primary efficacy outcome measures were overall response rate (ORR), established as the percentage of patients with a best overall response (BOR) of either complete response or partial response after Breyanzi infusion, as determined by an independent review committee (IRC). Other efficacy outcome measures included complete response rate (CRR) and duration of response (DOR), as determined by IRC. The ORR was 85.3% (95% Confidence Interval [CI]: 74.6, 92.7) and the CRR was 67.6% (95% CI: 55.2, 78.5). After a median follow-up of 22.2 months (95% CI: 16.7, 22.8), the median DOR was 13.3 months (95% CI: 6.0, 23.3) (FDA, 2024b; Juno Therapeutics, 2024).

Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)

Siddiqi et al (2022) stated that BTKi and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).  However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies.  These investigators reported results of the phase-I, dose-escalation portion of the multi-center, open-label, phase-I/II TRANSCEND CLL 004 study of lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory CLL/SLL.  Patients with standard- or high-risk features treated with greater than or equal to 3 or greater than or equal to 2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 10[6] or 100 × 10[6] CAR+ T cells).  Primary objectives included safety and determining recommended dose; anti-tumor activity by 2018 International Workshop on CLL guidelines was exploratory; MRD was examined in blood and marrow; 23 of 25 enrolled patients received liso-cel and were evaluable for safety.  Patients had a median of 4 (range of 2 to 11) prior therapies (100 % had ibrutinib; 65 % had venetoclax) and 83 % had high-risk features including mutated TP53 and del(17p); 74 % of patients had CRS (9 % grade 3) and 39 % had neurological events (22 % grade 3/4).  Of 22 efficacy-evaluable patients, 82 % and 45 % achieved overall response and CR, respectively.  Of 20 MRD-evaluable patients, 75 % and 65 % achieved undetectable MRD in blood and marrow, respectively.  Safety and effectiveness were similar between dose levels.  The authors concluded that the phase-II portion of the study is ongoing at 100 × 10[6] CAR+ T cells.

According to information found on the Drugs.com website, on March 14, 2024, the U.S. Food and Drug Administration (FDA) granted accelerated approval of Breyanzi (lisocabtagene maraleucel) for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. The FDA approval was based on supporting data from the TRANSCEND CLL 004 study, a Phase 1/2 open label, single arm, pivotal multicenter trial.

In TRANSCEND CLL 004, Siddiqi et al. (2023) evaluated the efficacy of Breyanzi in adult patients with relapsed or refractory CLL or SLL who had received at least 2 prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor. Patients received and intravenous infusion of Breyanzi at one of two target dose levels: 50 x 106 (dose level 1) or 100 x 106 (dose level 2) chimeric antigen receptor-positive T cells. Efficacy was based on overall response rate (ORR) (including complete response [CR] and partial response [PR]) and duration of response (DOR) as determined by an independent review committee (IRC) using 2018 International Workshop CLL (iwCLL) criteria. The CR rate associated with Breyanzi treatment was 20% (95% confidence interval [CI]: 11.1-31.8). Among patients who achieved a CR, median duration of response was not reached (95% CI: 15 months-NR) at the time of data cutoff. Among all responders (ORR = 45%; 95% CI: 32.3-57.5), median duration of response was 35.3 months (95% CI: 12.4-NR). High rates of minimal residual disease (MRD) negative status were observed across patients treated with Breyanzi who achieved a CR, with an MRD-negativity rate of 100% in the blood (95% CI: 75.3-100) and 92.3% in the bone marrow (95% CI: 64-99.8).

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Appendix

Table: ECOG Performance Status

Grade	ECOG
0	Fully active, able to carry on all pre-disease performance without restriction
1	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)
2	Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3	Capbable of only limited self-care, confined to bed or chair more than 50% of waking hours
4	Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5	Dead

Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.

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References