The Role of CAR T in Early Treatment Setting for MCL
Chimeric antigen receptor (CAR) T-cell therapies that target the CD19 surface protein have emerged as a highly effective treatment among patients with B-cell non-Hodgkin lymphoma and mantle cell lymphoma (MCL) with high efficacy demonstrated among patients with relapsed or refractory (R/R) disease.1-8 Early investigational studies have largely been focused on assessing CAR T as a therapeutic strategy following failed first and second lines of therapy. However, the need for more effective treatment options in the early disease course, especially those with high-risk disease (eg, blastoid morphology, TP53-mutated disease, high Ki-67, primary refractory disease), has prompted the investigation of CAR T in earlier lines of therapy.1,9
Studies evaluating CAR T in the second-line treatment setting for B-cell lymphoma have shown higher response rates, progression-free survival (PFS), and overall survival (OS) when compared with standard-of-care treatments.2,10-12 These findings may suggest a role for CAR T in earlier lines of therapy and highlight the need for future research to determine the use of these agents in this treatment setting.9
Emerging BTK Inhibitors in MCL
Covalent Bruton tyrosine kinase inhibitors (BTKis) have played a critical role in transforming the treatment and management of MCL. However, treatment-associated resistance or intolerance can lead to treatment failure and the need for additional therapy in some patients.13,14 C481 mutations that occur in the binding site region of BTK result in decreased drug binding affinity and are the most common cause of covalent BTKi-associated treatment resistance.15,16 Pirtobrutinib is a noncovalent or reversible BTKi that possesses equivalent potency for both wild-type and C481-mutated BTK variants.13 With demonstrated efficacy among patients with MCL and C481-mutant BTK status, pirtobrutinib may offer a potential strategy for overcoming resistance to BTKi therapy.13,15
The BRUIN trial (NCT03740529) is an open-label, multicenter phase 1/2 study investigating pirtobrutinib in patients with previously treated B-cell malignancies, including MCL.13,17 In patients who had received prior treatment with a BTKi, ORR was 62% (95% CI, 53%-71%). In patients with BTK C481 mutations, ORR was 75%. The most frequent adverse event (AE) of any grade was fatigue (20%), followed by diarrhea (17%) and contusion (13%). Neutropenia was the most common AE of grade 3 or higher, occurring in 10% (32 of 323 patients), and was not dose dependent. AEs of special interest included bruising, rash, and atrial fibrillation or flutter and were associated with low occurrence rates: grade 1 (15%, 9%, and 0%, respectively) and grade 2 (2%, 2%, and 1%, respectively).
Combination Therapy With Venetoclax in MCL
Although studies evaluating the efficacy of single-agent ibrutinib in MCL have reported ORRs of up to 68%, most treated patients (up to 79%) fail to achieve complete response (CR).18 Venetoclax is a potent, selective inhibitor of the antiapoptotic protein BCL-2, which is overexpressed in various hematological malignancies, including MCL.9,19 Studies investigating venetoclax in R/R MCL have reported favorable efficacy, with ORRs of 53% to 75% and CRs in 18% to 21% of patients.20,21
The action elicited by venetoclax appears to complement that of ibrutinib, with preclinical models demonstrating synergistic antitumor effects, including increased apoptosis reported with combination vs single-agent therapy (combination, 23.0%; ibrutinib, 3.8%; venetoclax, 3.0%).22,23 These findings have prompted further investigation of combination therapy with ibrutinib and venetoclax and may suggest a role for this dual treatment approach in patients with R/R MCL, including those with previous BTKi exposure.24
The open-label, randomized, double-blind phase 3 SYMPATICO study (NCT03112174) evaluated the safety and efficacy of ibrutinib in combination with venetoclax in patients with R/R MCL.22,25 At a median treatment duration of 20.1 months, ORR for all patients was 81% (95% CI, 58%-95%), with a CR in 62% of patients. Median duration of response (DOR), PFS, and OS were 32.3, 35.0, and 35.0 months, respectively. The most common treatment emergent AEs (TEAEs) (any grade) occurring in more than 20% of patients included diarrhea, fatigue, nausea, neutropenia, and thrombocytopenia. The most frequent AEs of at least grade 3 included infection (38%), diarrhea (33%), and neutropenia (33%).
Intensive induction chemotherapy with a high-dose cytarabine-based regimen followed by autologous stem cell transplant (ASCT) and rituximab maintenance remains the preferred first-line treatment approach in young, fit patients. Preferred approaches in older patients and those not eligible for ASCT or intensive chemotherapy include less-intensive regimens.24,26
Upon first relapse in the second-line setting, single-agent BTKis using ibrutinib, acalabrutinib, or zanubrutinib have become the standard of care, with selection based on the AE profile of individual agents and other patient factors.24 Most patients eventually relapse following BTKi therapy, as optimal treatment approaches remain unclear. Next-line treatment options in eligible patients often favor CAR T with corticosteroids, lenalidomide, or venetoclax for bridging therapy.
Promising New Therapies in MCL
The bispecific T-cell engager NVG-111 is a small, flexible molecule composed of 2 tandem-linked, antibody-derived single-chain variable fragments: 1 arm binds ROR1, which is a surface antigen expressed by various hematological and solid tumor cancers, whereas the other binds CD3 on the surface of lymphocytes.27 Dual binding of NVG-111 triggers the release of perforins, granzyme B, and cytokines via MHC-independent immune mechanisms, ultimately leading to the targeted destruction of tumor cells.
Phase 1/2 Trial: NVG-111 in MCL
An ongoing, 2-part, open-label phase 1/2 trial (NCT04763083) is investigating the safety and efficacy of NVG-111 in patients with R/R chronic lymphocytic leukemia (CLL) and MCL.27,28 At the data cutoff of January 2022, 6 patients had been enrolled in the trial (CCL, 5; MCL, 1). All 5 evaluable patients achieved an observed response following 3 cycles of NVG-111. Two patients had undetectable minimal residual disease (MRD) in the blood, with 1 patient also showing negative MRD in the bone marrow.28 The most frequently observed AEs (all grade 1) were lethargy, headaches, nausea, vomiting, and thrombocytopenia. Grade 1 cytokine release syndrome occurred in all 3 patients who received a flat dose of NVG-111 (30 μg/day). Tocilizumab or dose interruptions were only required in 1 patient, who also developed transient grade 3 immune effector cell–associated neurotoxicity syndrome–like symptoms.
Tazemetostat inhibits EZH2, which is a subunit of the histone methyltransferase PRC2 that plays a critical role in the epigenetic regulation of genes involved in cell cycle progression, autophagy, and apoptosis.29,30 Dysregulation of EZH2 can prolong survival and accelerate the proliferation of cells, leading to tumorigenesis and the development of cancer. Mutations resulting in gain-of-function EZH2 enzyme activity have also been identified in hematological malignancies, such as B-cell lymphoma, and are shown to correlate with significantly worse OS in patients with myeloid neoplasms (HR, 2.37; 95% CI, 1.48-3.79; P = .003).30,31
Tazemetostat With Acalabrutinib in R/R MCL
A 2-part, open-label, multicohort phase 1b/2 study (NCT05205252) is currently recruiting patients with R/R MCL (active comparator arm 3) to receive investigational treatment with tazemetostat in combination with acalabrutinib.32,33 During phase 1b, all patients will be enrolled in 3 dose-escalation cohorts of tazemetostat (400 mg, 600 mg, 800 mg); the primary end points include recommended phase 2 dosing, TEAEs, DLTs, and AEs. Phase 2 will entail the dose expansion portion of the study; the primary end point is ORR, whereas secondary end points include PFS, OS, and DOR.
Future of MCL: Unmet Needs
Novel therapies, including CAR T, have played a key role in transforming the treatment landscape for MCL.24 However, optimal approaches for treatment sequencing remain unclear, and patients with high-risk, aggressive, or multiple relapse disease continue to experience relatively poor outcomes. High-risk patients often experience suboptimal responses with BTKi therapy following relapse, and the use of CAR T in earlier lines of therapy for this patient population is an important area of future research.1,9 Demonstrated efficacy of CAR T in high-risk subgroups and a tolerable safety profile may suggest a role for CAR T earlier in the course of treatment for this patient subgroup.
1. Bond DA, Martin P, and Maddocks KJ. Relapsed mantle cell lymphoma: current management, recent progress, and future directions. J Clin Med.2021;10(6):1207. doi:10.3390/jcm10061207
2. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022;28(4):735-742. doi:10.1038/s41591-022-01731-4
3. Vitale C, Strati P. CAR T-cell therapy for B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: clinical trials and real-world experiences. Front Oncol. 2020;10:849. doi:10.3389/fonc.2020.00849
4. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7
5. 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
6. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0
7. Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(10):1403-1415. doi:10.1016/S1470-2045(21)00375-2
8. Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91-103. doi:10.1016/S1470-2045(21)00591-X
9. 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
10. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. Published correction appears in Lancet. 2022;400(10347):160.
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12. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
13. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5
14. Wang M, Shah NN, Alencar AJ, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in preciously treated mantle cell lymphoma: updated results from the phase 1/2 BRUIN study. Blood. 2021;138(suppl 1):381. doi:10.1182/blood-2021-149138
15. Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative analysis of BTK inhibitors and mechanisms underlying adverse effects. Front Cell Dev Biol. 2021;9:630942. doi:10.3389/fcell.2021.630942
16. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294. doi:10.1056/NEJMoa1400029
17. A study of oral LOXO-305 in patients with previously treated CLL/SLL or NHL. ClinicalTrials.gov. Updated August 17, 2022. Accessed September 27, 2022. https://clinicaltrials.gov/ct2/show/NCT03740529
18. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516. doi:10.1056/NEJMoa1306220
19. Venclexta. Prescribing information. AbbVie Inc; 2022. Accessed September 27, 2022. https://www.rxabbvie.com/pdf/venclexta.pdf
20. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/JCO.2016.70.4320
21. Eyre TA, Walter HS, Iyengar S, et al. Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy. Haematologica. 2019;104(2):e68-e71. doi:10.3324/haematol.2018.198812
22. Wang M, Ramchandren R, Chen R, et al. Concurrent ibrutinib plus venetoclax in relapsed/refractory mantle cell lymphoma: the safety run-in of the phase 3 SYMPATICO study. J Hematol Oncol. 2021;14(1):179. doi:10.1186/s13045-021-01188-x
23. Portell CA, Axelrod M, Brett K, et al. Synergistic cytotoxicity of ibrutinib and the BCL2 antagonist, ABT-199(GDC-0199) in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL): molecular analysis reveals mechanisms of target interactions. Blood. 2014;124(suppl 21):509. doi:10.1182/blood.V124.21.509.509
24. Romancik JT, Cohen JB. Sequencing of novel therapies for mantle cell lymphoma. Curr Treat Options Oncol. 2021;22(12):118. doi:10.1007/s11864-021-00907-3
25. Study of ibrutinib combined with venetoclax in subjects with mantle cell lymphoma (SYMPATICO). ClinicalTrials.gov. Updated September 10, 2022. Accessed September 27, 2022. https://clinicaltrials.gov/ct2/show/NCT03112174
26. Rule S, Cook G, Russell NH, et al. Allogenic stem cell transplantation as part of front line therapy for mantle cell lymphoma. Br J Haematol. 2019;l84(6):999-1005. doi:10.1111/bjh.15723
27. First in human study of NVG-111 in chronic lymphocytic leukaemia and mantle cell lymphoma. ClinicalTrial.gov. Updated September 30, 2022. Accessed September 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04763083
28. Jasani P, Townsend W, Asher S, et al. First-in-human phase I study of a ROR1-targeting bispecific T-cell engager (NVG-111) shows evidence of efficacy in patients with relapsed/refractory CLL and MCL. J Clin Oncol. 2022;40(16):7535. doi:10.1200/JCO.2022.40.16_suppl.7535
29. Tazverik. Prescribing information. Epizyme; 2020. Accessed September 27, 2022. https://www.tazverik.com/Content/pdf/prescribing-information.pdf
30. Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol. 2020;13(1):104. doi:10.1186/s13045-020-00937-8
31. Zhang Q, Han Q, Zi J, et al. Mutations in EZH2 are associated with poor prognosis for patients with myeloid neoplasms. Genes Dis. 2019;6(3):276-281. doi:10.1016/j.gendis.2019.05.001
32. Bessudo A, Greenwald D, Kazemi MH, et al. P1109: Trial in progress: phase 1b/2 of tazemetostat in combination with various treatments in patients with relapsed or refractory hematologic malignancies. HemaSphere.2022;6:999-1000. doi:10.1097/01.HS9.0000847304.04017.68
33. Multi cohort study of tazemetostat in combination with various treatments for R/R hematologic malignancies. ClinicalTrials.gov. Updated October 24, 2022. Accessed September 27, 2022. https://clinicaltrials.gov/ct2/show/NCT05205252