Examining the Role of BTK Inhibitors in Mantle Cell Lymphoma

Akash Mukherjee, MD

Up to 10% of of all newly diagnosed non-Hodgkin lymphoma cases are mantle cell lymphoma (MCL). As part of the diagnostic work-up for a a patient with newly diagnosed MCL, it is important to establish prognostic disease biology factors such as classical nodal morphology vs blastoid variant vs leukemic variant, TP53 mutation status, and Ki-67 reflective of proliferation.¹

Approximately 10% to 15% of patients with MCL present with a leukemic variant exhibiting lymphocytosis, mild lymphadenopathy, mild cytopenia, and splenomegaly; they usually have an indolent course. These patients can be safely treated with a close wait-andwatch approach without any active treatment. Duration of observation depends on clinical course.²

The rest of the patients will need treatment at diagnosis dictated by the patient’s age, performance status, and disease biology. Ki-67 over 30% and blastoid variant exhibit an aggressive clinical course. Younger patients who are transplant eligible usually receive cytarabine-containing intensive chemotherapy followed by autologous stem cell transplant. With this aggressive approach, the median progression-free survival (PFS) is approximately 9 to 11 years; however, late relapses can occur.^3,4 Maintenance with rituximab (Rituxan) can be considered for 2 years post transplant to minimize relapse.

For older and transplant-ineligible patients, I recommend treatment with either bendamustine (Bendeka) plus rituximab (BR) for 6 cycles followed by rituximab maintenance for 2 years or BR plus 500 mg/m2 of cytarabine. These treatments showed 2-year PFS and overall survival (OS) rates of 81% and 86%, respectively.^5,6

However, patients with a TP53 mutation or high-risk Mantle Cell Lymphoma International Prognostic Index score have an increased relapse rate despite treatment with chemoimmunotherapy that warrants subsequent treatment with Bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors or immunomodulators, or CD19-directed cellular therapy. Findings from the phase 3 SHINE (NCT01776840), ACE-LY-308 (NCT02972840), and SYMPATICO (NCT03112174) clinical trials incorporating BTK inhibitors in combination with BR or using BTK inhibitor plus venetoclax (Venclexta) as frontline therapy could potentially change the treatment paradigm for elderly patients with MCL.

For patients with relapsed or refractory MCL treatment options include a BTK inhibitor plus ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) for patients who have received at least 1 prior therapy.^7-9 The combination of ibrutinib and venetoclax has also been studied in relapsed or refractory MCL with an 18-month PFS rate of 57% (95% CI, 40%-82%) among 24 patients in the phase 2 AIM trial (NCT02471391).¹⁰

Patients usually achieve a median PFS of approximately 16 to 22 months with a BTK inhibitor and have a median OS of approximately 6 to 10 months following disease progression with BTK inhibitor treatment. Findings from the phase 2 ZUMA-2 study (NCT02601313) showed promising efficacy and durability of response in this subset of patients using the CD19-directed chimeric antigen receptor T-cell therapy brexucabtagene autoleucel (Tecartus). Patients treated with the agent (n = 60) achieved a 67% (95% CI, 53%-78%) complete response rate and a 12-month PFS and OS rates of 61% and 83%, respectively, along with a manageable safety profile.¹¹ Allogeneic stem cell transplant could be offered to select patients with relapsed or refractory MCL who have a lower probability of transplant-related mortality as another potentially curative option.

References

1. Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol. 2019;94(6):710-725. doi:10.1002/ajh.25487
2. Abrisqueta P, Scott DW, Slack GW, et al. Observation as the initial management strategy in patients with mantle cell lymphoma. Ann Oncol. 2017;28(10):24892495. doi:10.1093/annonc/mdx333
3. Hermine O, Hoster E, Walewski J, et al; European Mantle Cell Lymphoma Network. Addition of highdose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565-575. doi:10.1016/S0140-6736(16)00739-X
4. Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the second Nordic mantle cell lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175(3):410-418. doi:10.1111/bjh.14241
5. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2
6. Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017;4(1):e15-e23. doi:10.1016/ S2352-3026(16)30185-5
7. Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015;126(6):739-745. doi:10.1182/ blood-2015-03-635326
8. 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. 2018;391(10121):659-667. doi:10.1016/ S0140-6736(17)33108-2
9. Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with zanubrutinib, a selective inhibitor of Bruton’s tyrosine kinase. Clin Cancer Res. 2020;26(16):42164224. doi:10.1158/1078-0432.CCR-19-3703
10. Tam CS, Anderson 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
11. 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