The Current Role of CAR T-Cell Therapy in Patients With Mantle Cell Lymphoma

Introduction

Mantle cell lymphoma (MCL) is a rare subtype of B-cell lymphoma, accounting for roughly 3% to 10% of all non-Hodgkin lymphomas in Western countries.¹ The annual incidence rate of MCL is approximately 4 to 8 cases per million persons per year in the United States; the median age at diagnosis is 68 years.² MCL occurs more frequently in men than women (3:1) and remains a largely incurable disease; the median overall survival (OS) is 5 years.³ Recently, the overexpression of CCND1, a hallmark feature of MCL, has become a valuable clinical marker for disease diagnosis and treatment.^3,4

High-Risk MCL

Determining disease risk is critical in predicting prognosis and guiding the management of MCL.² High-risk MCL is defined as a simplified MCL International Prognostic Index score of at least 6.2; it is commonly associated with features that include poor performance status, significant comorbidities, elderly age, central nervous system involvement, blastoid or pleomorphic morphology, Ki-67 index of 30% or more, TP53 aberrations, complex genomics and karyotype, Bruton tyrosine kinase inhibitor (BTKi)-refractory disease, and early disease progression (ie, 12-24 months after first-line therapy).^2,5 Molecular characteristics identified as high-risk genetic features include mutations of NOTCH1, NOTCH2, and KMT2D or copy number loss of CDKN2A.6 Patients with high-risk disease have a markedly lower 5-year OS (34%) than do those with low- and intermediate-risk disease (83% and 63%, respectively).⁷ Treatment and management of patients with high-risk MCL can be challenging, and they represent an unmet need in the current therapeutic landscape.⁴

First-line Treatment for MCL

Treatment for newly diagnosed MCL depends upon initial assessment of clinical factors (eg, age, performance status, comorbidities) and presence of high-risk features.⁵ Standard-of-care frontline therapy for previously untreated patients 65 years or younger typically includes intensive chemotherapy with or without autologous stem cell transplant followed by maintenance with rituximab, whereas bendamustine in combination with rituximab in usually preferred in patients aged at least 65 years.⁵ Nonchemotherapy options are also available; they include lenalidomide or ibrutinib in combination with rituximab.⁵

Treatment for Relapsed or Refractory MCL

In patients with disease that is refractory to frontline intensive chemoimmunotherapy, targeted therapies are usually prioritized over alternative chemoimmunotherapy regimens, andtreatment decisions are generally based upon exposure to BTKis.^2,6 In patients with no prior exposure to BTKis, the preferred treatment option is a covalent BTKi (eg, ibrutinib, acalabrutinib, zanubrutinib); these BTKis can be used as single-agent therapies or in combination.²

In BTKi-refractory MCL, anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has become a preferred next-line treatment option in some patient subsets due to the high response rates in this treatment setting.⁶ However, for patients who are not eligible for CAR-T therapy, standard-of-care treatment using triplet therapy with R-BAC (rituximab, bendamustine, and cytarabine) or doublet combinations of rituximab and the proteosome inhibitor bortezomib, rituximab and the immunomodulator lenalidomide, or rituximab and bendamustine is usually preferred. Other agents used in this treatment setting include the BCL2 inhibitor venetoclax and allogeneic hematopoietic cell transplant.^2,6

ZUMA-2 Trial

The phase 2, multicenter, open-label ZUMA-2 trial (NCT02601313) evaluated the efficacy of the anti-CD19 CAR T-cell therapy brexucabtagene autoleucel (brexu-cel) in patients with relapsed or refractory (R/R) MCL who had been treated with up to 5 prior regimens.^8,9 Based on initial trial findings in 74 patients, use of brexu-cel resulted in an objective response rate (ORR) of 87% (complete response [CR], 62%; minimum follow-up, 6 months). Brexu-cel was granted accelerated FDA approval on July 24, 2020, for the treatment of adult patients with R/R MCL.¹⁰

Three-year follow-up data involving the use of brexu-cel in 105 patients were presented at the 2022 American Society of Clinical Oncology Annual Meeting.^1,8 Investigators reported an ORR of 91% (95% CI, 81.8%-96.7%), with a 68% CR rate. The median duration of response (DOR), progression-free survival (PFS), and OS were 28.2 months (95% CI, 13.5-47.1 months), 25.8 months (95% CI, 9.6-47.6 months), and 46.6 months (95% CI, 24.6 months-not estimable), respectively.^1,8 The most frequently reported adverse events (AEs) of at least grade 3 were neutropenia (grade 3, 1%; grade 4, 10%); further, serious grade 3 drug-related infections were reported in 2 patients.¹

Managing Toxicities With CAR-T Therapies

The in vivo expansion of CAR T cells can lead to a systemic inflammatory response known as cytokine release syndrome (CRS), which is characterized by the release of multiple cytokines.³ Symptoms can range from mild to severe life-threatening symptoms resulting in organ toxicity. CRS is graded (ie, grade 1-4) based on symptom severity and associated organ toxicity, oxygen requirement, and degree of hypotension. Supportive measures are generally used to manage grade 1 CRS; however, for higher grade CRS, the anti–IL-6 receptor antibody tocilizumab and glucocorticoids are often required.^11,12

Other toxicities of interest in CAR T-cell therapy include potential neurotoxicity, defined as immune effector cell–associated neurotoxicity syndrome (ICANS) and hematologic toxicity. ICANS can manifest with symptoms of delirium, encephalopathy, lethargy, tremor, seizures, agitation, and, in rare cases, cerebral edema. Intravenous corticosteroids (eg, methylprednisolone, dexamethasone) and other supportive measures are mainstays for managing ICANS.^11,13 Growth factors, such as filgrastim, can be used to manage cytopenias; however, use of myeloid growth factors, including granulocyte-macrophage colony-stimulating factor, are not recommended during the first 3 weeks following cell infusion, as their use may aggravate CRS.¹¹

Real-World Outcomes Data

Real-world outcomes data evaluating brexu-cel in 135 patients with R/R MCL was presented at the European Hematology Association 2022 Hybrid Congress.¹⁴ The reported ORR was 84% (95% CI, 77%-90%), with a CR of 71% for all patients; after at least 180 days of follow up, the ORR was 78% (95% CI, 67%-87%), with a CR of 68%. The estimated DOR at 3 months was 85%; the estimated PFS and OS at 6 months were 66% and 79%, respectively. Reported grade 3 AEs of interest included CRS (9%) and immune effector cell–associated neurotoxicity (29%), which, for the majority of patients, resolved within 21 days.¹⁴ These early findings are consistent with safety and efficacy results observed among patients in the clinical trial setting in a broader patient population.

A Role for Brexu-Cel in the MCL Treatment Paradigm

Although use of BTKis produces markedly improved outcomes in patients with R/R MCL, BTKi resistance can occur, and a proportion of patients experience disease progression during BTKi therapy.^5,9 Prognosis for this patient subset is poor, with a median OS of 6 to 10 months and a 30% response rate with later lines of therapy. Moreover, patients with high-risk or primary refractory disease may have suboptimal responses from BTKi treatment.⁶ Brexu-cel has shown considerable efficacy in patients with R/R MCL, and it offers a favorable treatment option for this patient subset.^1,8,14

References

1. Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol. Published online June 4, 2022. doi:10.1200/JCO.21.02370

2. Jain P, Dreyling M, Seymour JF, Wang M. High-risk mantle cell lymphoma: definition, current challenges, and management. J Clin Oncol. 2020;38(36):4302-4316. doi:10.1200/JCO.20.02287

3. Pu JJ, Savani M, Huang N, Epner EM. Mantle cell lymphoma management trends and novel agents: where are we going? Ther Adv Hematol. 2022;13:20406207221080743. doi:10.1177/20406207221080743

4. Tbakhi B, Reagan PM. Chimeric antigen receptor (CAR) T-cell treatment for mantle cell lymphoma (MCL). Ther Adv Hematol. 2022;13:20406207221080738. doi:10.1177/20406207221080738

5. Jain P, Wang ML. Mantle cell lymphoma in 2022—a comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments. Am J Hematol. 2022;97(5):638-656. doi:10.1002/ajh.26523

6. Bond DA, Martin P, Maddocks KJ. Relapsed mantle cell lymphoma: current management, recent progress, and future directions. J Clin Med. 2021;10(6):1207. doi:10.3390/jcm10061207

7. Hoster E, Klapper W, Hermine O, et al. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014;32(13):1338-1346. doi:10.1200/JCO.2013.52.2466

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

9. Study to evaluate the efficacy of brexucabtagene autoleucel (KTE-X19) in participants with relapsed/refractory mantle cell lymphoma (ZUMA-2). ClinicalTrials.gov. Updated May 24, 2022. Accessed September 15, 2022. https://clinicaltrials.gov/ct2/show/NCT02601313

10. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. Published July 27, 2020. Accessed September 15, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-mantle-cell-lymphoma

11. Maus MV, Alexander S, Bishop MR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events. J Immunother Cancer. 2020;8(2):e001511. doi:10.1136/jitc-2020-001511

12. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47-62. doi:10.1038/nrclinonc.2017.148

13. Castaneda-Puglianini O, Chavez JC. Assessing and management of neurotoxicity after CAR-T therapy in diffuse large B-cell lymphoma. J Blood Med. 2021;12:775-783. doi:10.2147/JBM.S281247

14. Locke F, Hu ZH, Gerson J, et al. P1454: real-world outcomes of brexucabtagene autoleucel (brexucel) for the treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL) in the United States (US). HemaSphere. 2022;6(suppl):1336-1337. doi:10.1097/01.HS9.0000848672.43673.8a