CAR T-Cell Therapy Offers Potential Solution for Relapse in MCL, But With Toxicity Risk

Mantle cell lymphoma (MCL) accounts for 5% to 10% of all non-Hodgkin lymphomas (NHLs) and is commonly diagnosed when a patient’s disease is in an advanced stage with extranodal involvement, commonly including gastrointestinal mucosa and central nervous system involvement with blastoid variant. Disease relapse among patients with MCL is known to occur after prolonged remission, which leaves an unanswered question among oncologists in the field of how to approach treatment of relapsed MCL.¹

In a presentation during the 2020 Debates and Didactics in Hematology and Oncology conference, Amelia A. Langston, MD, professor and executive vice chair, Department of Hematology and Medical Oncology; director, Bone Marrow and Stem Cell Transplant Program; and medical director, Winship Cancer Network, at Winship Cancer Institute of Emory University, explained the issues with treating patients with relapsed MCL and how the integration of chimeric antigen receptor (CAR) T-cell therapy can be a solution to the problem.

Understanding MCL

Langston noted that MCL has multiple morphologic variants, including classical disease, aggressive or blastoid disease, and indolent disease. Although it is common for oncologists to treat patients with indolent tumors right after diagnosis, Langston highlighted that a small proportion of those patients do not require immediate treatment.

One method for understanding when to start treatment and to predict how patients with MCL will respond to treatment, is utilizing the MIPIc (Mantle Cell Lymphoma International Prognostic Index) prognostic score. Another method, Langston explained, is through gene expression profiles, karyotype, and mutation analysis, which can identify p53 mutations, NOTCH-1 mutations, complex karyotype, and overall poor prognosis.

Initial Treatment of MCL

The primary treatment for MCL is aggressive induction followed by autologous stem cell transplantation (ASCT), which has been shown to prolong survival in patients with MCL who are fit for aggressive treatment.

Research by Martin Dreyling, MD, PhD, et al presented in 2005 demonstrated the feasibility of early consolidation with myeloablative radiochemotherapy followed by ASCT. In the study, 62 patients underwent ASCT, and 122 patients received interferon (IFN) alpha. With ASCT, the median progression-free survival (PFS) was 39 months with ASCT versus 17 months with IFN-alpha (P = .0108). The 3-year overall survival (OS) rate with ASCT was 83% versus 77% with IFN-alpha (P = .18).²

Data presented at the American Society of Hematology Annual Meeting in 2009 showed a median OS of 90 months with ASCT compared with 54 months with IFN (P = .034).³

Next-Line Treatment for MCL

Once patients with MCL relapse, the treatment landscape includes FDA-approved targeted therapies, chemotherapy/immunotherapy combinations, and allogeneic hematopoietic stem cell transplant. The targeted therapies include Bruton’s tyrosine kinase (BTK) inhibitors, proteasome inhibitors, immunomodulatory drugs, mTOR inhibitors, venetoclax (Venclexta), as well as combination regimens.

The BTK inhibitor ibrutinib (Imbruvica) at a 560-mg daily dose level has led to an objective response rate (ORR) of 66% with a complete response (CR) rate of 20%, according to a pooled analysis of 3 open-label clinical trials, which were the PCYC‐1104 (NCT01236391), SPARK (NCT01599949), and RAY (NCT01646021) studies. The analysis included 370 patients with MCL who had a median of 2 prior lines of therapy before receiving ibrutinib. This analysis also showed that more than 1 line of prior therapy, p53 mutations, and blastoid histology were all predictors of poor response to ibrutinib.^4,5 

Acalabrutinib (Calquence), another BTK inhibitor, at a dose of 100 mg twice daily demonstrated efficacy in a single-arm multicenter, phase 2 clinical trial (ACE-LY-004, NCT02213926). The ACE-LY-004 study included 124 patients with a median 2 prior lines of therapy. The ORR achieved with acalabrutinib was 81% (95% CI, 73%-87%) per investigator assessment. The CR rate was 40% (95% CI, 31%-49%).⁶

In terms of survival, the 12-month PFS rate observed with acalabrutinib was 67% (range, 58%-75%) and the 12-months OS rate was 87% (range, 79%-92%).

The adverse events observed in ACE-LY-004 were considered tolerable and only led to treatment discontinuation in 6% of the study population.

Investigators led by Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, concluded from this study that acalabrutinib holds an important place in the treatment landscape of MCL and induces a high rate of durable responses with tolerable safety.

For combination therapies in the MCL paradigm, ibrutinib plus venetoclax was investigated in a single-arm, multicenter, phase 2 study (AIM, NCT02471391), which enrolled 24 patients with MCL, 23 of whom had relapsed or refractory disease and 1 patient with a p53 mutation who was ineligible for chemotherapy. The median number of prior lines of therapy for this study population was 2, and 46% of patients had a p53 mutation and/or deletion. Ibrutinib was administered at 560 mg per day for 4 weeks and then venetoclax was added with a gradual dose escalation up to 400 mg per day.⁷

The combination of ibrutinib and venetoclax achieved a CR rate of 42% at 16 weeks, which surpassed the historical result of ibrutinib monotherapy (9%; P < .001). In addition, the CR rate among patients who were negative for minimal residual disease was 38%, and for patients with a p53 mutation, the CR rate was 50%. Ibrutinib plus venetoclax also achieved a PFS rate of 78% at 15 months.

The safety analysis did reveal 2 cases of tumor lysis syndrome in patients, however, but overall, the combination was well tolerated.

Up and Coming Options for Relapsed MCL

CAR T-cell therapy has already been integrated into the treatment landscape of many hematologic malignancies and is now being considered as a treatment for different solid tumors. CAR T-cell therapy is also a valid option for treatment of R/R MCL, and one agent, KTE-X19 has been granted Priority Review by the FDA for this indication based on results from the phase 2 ZUMA-2 trial.¹

The multicenter study enrolled 74 patients and 68 of them received the CAR T-cell product. Among the MCL subjects, the subgroups included patients who relapsed after ASCT, relapsed after their most recent previous therapy, were refractory to BTK inhibition, relapsed during or after BTK inhibition, and could not receive BTK inhibition.⁸

In terms of efficacy, 85% of patients achieved an objective response, which included CRs in 59% of patients. In the various subgroups of patients with MCL included in the study, high rates of objective response were also observed. There were also 2 patients with stable disease and 2 with progressive disease.

Neither the median PFS nor OS were reached at the time of data cutoff, but the PFS rate at 1 year was estimated to be 61% in the study, and the OS rate was estimated to be 83% at 1 year.

The CAR T-cell agent led to grade 3 or higher AEs, the majority of which were cytopenias (94%); additionally, 32% were infections, 31% were neurologic events, 15% of patients had cytokine release syndrome, and 32% had hypogammaglobulinemia. The treatment-related mortality rate in this study was 3%, which was due to infections.

These data led to the conclusion that although KTE-X19 can induce durable remissions in patients with MCL, it causes serious toxicities that are common for CAR T-cell therapy. Thus, Langston noted in her presentation that CAR T-cell therapy for relapsed disease should only be considered for select patients.

Overall, BTK inhibition will likely remain a standard of care for R/R MCL, Langston stated, but CAR T-cell therapy should be carefully integrated into the landscape, once the first agent is granted FDA approval and depending on the indications of that approval. Finally, healthier patients with R/R MCL can continue to be considered for ASCT, which, she noted, has curative ability for heavily pretreated patients.¹

_References:

_{1. Langston AA. Integrating CAR t cell therapy into the management of relapsed mantle cell lymphoma. Presented at: 2020 Debates and Didactics in Hematology and Oncology; July 16-18, 2020; Sea Island, GA.}

_{2. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105(7):2677-2684. doi:10.1182/blood-2004-10-3883}

_{3. Hoster E, Metzner B, Forstpointner R, et al. Autologous Stem Cell Transplantation and Addition of Rituximab Independently Prolong Response Duration in Advanced Stage Mantle Cell Lymphoma. Blood. 2009;114(22):880. doi:10.1182/blood.V114.22.880.880}

_{4. Rule S, Dreyling M, Goy A, et al. Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies. Br J Haematol. 2019;179(3):430-438. doi:10.1111/bjh.14870}

_{5. Rule S, Dreyling M, Goy A, et al. Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis. Haematologica. 2019;104(5):e211-e214. doi:10.3324/haematol.2018.205229}

_{6. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2017;391(10121):659-667. doi:10.1016/S0140-6736(17)33108-2}

_{7. Tam CS, Andeson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211-1223. doi:10.1056/NEJMoa1715519}

_{8. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR t-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347}