The role of targeted therapies in the first-line treatment of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a rare B-cell malignancy with a heterogeneous clinical course with no true standard of care. To date, several treatment regimens have been used in the treatment of patients with newly diagnosed MCL. With few phase 3 randomized trials to pull data from, most treatments are generally dictated by region and institutional preference over clear scientific rationale. Nonetheless, there have been marked improvements in expected remission and overall survival (OS) rates, although a cure for this disease remains elusive.1.2

Treatment for most patients is a dichotomy based on transplant eligibility: high-dose chemotherapy, which invariably includes cytarabine (Nordic regimen, R-hyper-CVAD [rituximab, cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), dexamethasone]R-DHAOx/CHOP [rituximab, dexamethasone, high-dose cytarabine, oxaliplatin/cyclophosphamide, doxorubicin, prednisone, vincristine]), is followed by autologous stem cell transplantation (ASCT) followed by maintenance R or “less intense” chemoimmunotherapy (CIT) followed by maintenance R.

In a presentation titled “The Role of Targeted Therapies in the Frontline Treatment of Mantle Cell Lymphoma,” Tycel J. Phillips, MD, Associate Clinical Professor, University of Michigan Health in Ann Arbor, Michigan, discussed strategies care of high-risk patients.

Two points can be highlighted:

  1. Maintenance R is universally accepted as beneficial in MCL as it improves progression-free survival (PFS) and OS.
  2. Data from 2 studies found bendamustine-rituximab (BR) to be superior to R-CHOP2,3 as initial therapy in patients considered unsuitable for ASCT and the regimen is preferred for most of this patient population.

Additionally, BR has blurred the lines of our dichotomy and has been used as the preferred pre-transplant regimen for some patients due to its good combination of efficacy and tolerability.

High-risk patients

However, given the toxicities of CIT and the desire to improve outcomes in very high-risk patients, studies aimed at incorporating new therapies into the first-line treatment of patients with MCL have been undertaken. These have included combined studies of CIT plus new agents or agents without traditional chemotherapy.

One of the first studies aimed to improve the outcomes of patients treated with R-CHOP by replacing vincristine with the proteasome inhibitor bortezomib (Velcade). This regimen, VR-CAP (bortezomib, rituximab, epirubicin, cyclophosphamide, prednisone),4 was shown in a randomized study to be superior to R-CHOP in ASCT-unfit participants. Adding bortezomib to BR has also been explored in a phase 2 study.5 Despite positive results, none of the combinations has equivalent absorption to BR. The SHINE study (NCT01776840)6 explored combination therapy with BR in more detail and the results were presented at the 2022 Annual Meeting of the American Society of Clinical Oncology.

This study randomly assigned MCL patients not eligible for transplant to BR vs BR plus the Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib (Imbruvica). Although the study achieved its primary objective, demonstrating a marked difference in PFS in the experimental arm, its impact on the treatment landscape is less established.

There was no advantage in OS, probably due to higher than expected non-disease deaths in the experimental group. Questions about the comparison with sequential therapy and the lack of tangible benefit in patients with a TP53 the mutation makes the general adoption of the diet doubtful.

SHINE’s sister study, ECHO (NCT02972840), evaluating BR with acalabrutinib (Calquence), is in the process of maturing. We are eagerly awaiting the results before putting a nail in the coffin of the CIT and BTKi combination in frontline MCL.

Alternative diets

Other studies have explored BTKi without chemotherapy in front-line MCL. BGB-3111-306 (NCT04002297) is an ongoing trial that randomizes ASCT-unfit patients to receive zanubrutinib (Brukinsa) plus R vs BR. Additionally, researchers looked at R+ibrutinib (IR) in 2 studies conducted at the University of Texas MD Anderson Cancer Center, WINDOW-I and WINDOW II.

The WINDOW-I7 study (NCT02427620) evaluated one-year induction of IR followed by R-hyper-CVAD consolidation for up to 4 cycles. The data demonstrated a high ORR after one year’s treatment of IR and led to the development of WINDOW II (NCT03710772), which incorporates the BCL-2 inhibitor venetoclax into the induction. In an elderly population, researchers are again exploring IR.8 They noted impressive ORR but high rates of toxicity and discontinuation, suggesting that ibrutinib may not be the ideal BTKi for this patient population. The first truly chemotherapy-free regimen used not a BTKi but the immunomodulating agent lenalidomide, plus R. The R2 study9 by the Cornell group (NCT01472562) was the first to demonstrate a high and durable response rate without CIT with long-term follow-up. aptitude. How to manage the 20-30% of patients at high risk, including those with aberrations of TP53NOTCH, complex cytogenetics and other identified high-risk features,11 is a mystery, with a bad operating system noted with the previously discussed schemes.

Data from several ongoing studies are encouraging but remain too immature to be fully commented on. Some promising treatments for these patients still need to be explored on the front line. Chimeric antigen receptor (CAR) T-cell therapy has mature and impressive efficacy in these high-risk groups, but follow-up data has indicated continued relapses, suggesting that this treatment may not be the “holy grail.” for these patients.12.13 However, this is confounded by the nature and complexity of recurrent disease as well as the impact of bendamustine and other therapies on T cell function used in CAR T-cell therapy. Based on a similar mechanism of action, CD20/CD3 bispecific antibodies show great promise in MCL, but so far large mature datasets are lacking. Although CAR T-cell therapy and the use of bispecific antibodies are intriguing options for the first-line management of MCL, especially in patients with high-risk disease, both treatments are associated with several obstacles. For CAR T-cell therapy, accessibility remains a crutch that we can’t seem to overcome outside of certain parts of the country. The adverse event profile with cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome is still not something that all hematologists/oncologists can manage and is largely hampered by patient hesitancy. patients to visit centers that offer CAR T-cell therapy. Bispecific antibodies promise greater accessibility with fewer worries about insurance approval, but still have immature data and an adverse event profile that includes CRS, which hampers their uptake in the community. Overall, several attempts have been made to move targeted agents into first-line treatment of MCL, with some success, but not the monumental paradigm shift that has occurred in other diseases. Nevertheless, the future for these patients is bright as several studies are still awaiting reading and several new treatments have yet to enter the frontline scene.

REFERENCES:

1. Le Gouill S, Thieblemont C, Oberic L, et al; Lysa Group. Rituximab after autologous stem cell transplantation in mantle cell lymphoma. N English J med. 2017;377(13):1250-1260. doi:10.1056/NEJMoa1701769

2. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in the first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944-2952. doi:10.1182/blood-2013-11-531327

3. Rummel MJ, Niederle N, Maschmeyer G, et al; Indolent Lymphoma Study Group (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line therapy for patients with indolent and mantle cell lymphoma: an open-label, multicenter, randomized, non-inferiority phase 3 trial. Lancet. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2

4. Robak T, Jin J, Pylypenko H, et al; LYM-3002 Investigators. Bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line therapy in patients not eligible for transplantation with newly acquired mantle cell lymphoma diagnosed: final overall survival results from a randomized, open-label, phase 3 study. Lancet Oncol. 2018;19(11):1449-1458. doi:10.1016/S1470-2045(18)30685-5

5. Gressin R, Daguindau N, Tempescul A, et al; Lymphoma Study Association. A Phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for the first-line treatment of elderly patients with mantle cell lymphoma. Haematological. 2019;104(1):138-146. doi:10.3324/haematol.2018.191429

6. Wang ML, Jurczak W, Jerkeman M, et al; SHINE investigators. Ibrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma. N English J med. 2022;386(26):2482-2494. doi:10.1056/NEJMoa2201817

7. Wang ML, Jain P, Zhao S, et al. Ibrutinib-rituximab followed by R-HCVAD as first-line treatment for young patients (≤ 65 years old) with mantle cell lymphoma (WINDOW-1): a single-arm phase 2 trial. Lancet Oncol. 2022;23(3):406-415. doi:10.1016/S1470-2045(21)00638-0

8. Jain P, Zhao S, Lee HJ, et al. Ibrutinib with rituximab in the first-line treatment of elderly patients with mantle cell lymphoma. J Clin Oncol. 2022;40(2):202-212. doi:10.1200/JCO.21.01797

9. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle cell lymphoma. N English J med. 2015;373(19):1835-1844. doi:10.1056/NEJMoa1505237

10. Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma. Blood. 2018;132(19):2016-2025. doi:10.1182/sang-2018-07-859769

11. 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

12. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T cell therapy in relapsed or refractory mantle cell lymphoma. N English J med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

13. 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

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