Options are growing in the treatment of mantle cell lymphoma after complete response. At the 2022 Pan Pacific Lymphoma Conference,1 the use of these newer strategies in older patients was discussed by Brad S. Kahl, MD, Professor of Medicine and Director of the Lymphoma Service at Washington University School of Medicine in Missouri. Julie M. Vose, MD, FASCO, MBA, Professor and Hematology/Oncology Division Chief at the University of Nebraska Medical Center, Omaha, provided recommendations for treating younger patients.
Brad S. Kahl, MD
Julie M. Vose, MD, FASCO, MBA
Survival Improving
The Surveillance, Epidemiology, and End Results (SEER) database of almost 9,000 patients treated between 2000 and 2013 shows overall survival has been steadily improving for younger patients, aged 50 to 64, and older ones, aged 65 to 74.2 The potential reasons for this could be greater use of autologous stem cell transplantation (ASCT), earlier diagnosis (ie, lead-time bias), use of rituximab and other more effective medications (including nonchemotherapy drugs), use of intensive induction, and identification of subsets of patients who can defer therapy. Improvements were being seen before the advent of chimeric antigen receptor (CAR) T-cell therapy, Dr. Vose noted.
Induction Options for Older Patients
Describing current and emerging treatments for older patients, Dr. Kahl noted that bendamustine plus rituximab (BR) is the most widely used regimen. Other nonintensive regimens include R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone), R-BAC (rituximab, bendamustine, and cytarabine), R2 (lenalidomide, rituximab), and BR plus ibrutinib.
These regimens vary in efficacy. In older populations, their reported median progression-free survival (without maintenance) is 14 months for R-CHOP, 25 months for VR-CAP, 35 to 42 months for BR, and, with the newer regimen RBAC500 (see below), more than 7 years in a small Italian study.3
RBAC500 uses a lower dose of bendamustine and a low dose of cytarabine, specifically consisting of rituximab at 375 mg/m2 on day 1, bendamustine at 70 mg/m2 on days 2 and 3, and cytarabine at 500 mg/m2 on days 2 to 4 every 4 weeks. Dr. Kahl has found this novel regimen to be active but also myelosuppressive. “I’m not sure about it yet, but it’s something to keep your eye on,” he commented.
Discussing his personal choices among these regimens, Dr. Kahl said that for older patients with highly proliferative disease, he would consider R-BAC or VR-CAP before BR. For older patients with a TP53 mutation or 17p deletion, he would consider a Bruton’s tyrosine kinase (BTK) inhibitor (if covered by insurance) or BR (expecting a shorter remission with BR).
Although more intensive strategies tend to produce remissions of 3 to 4 years in older patients, he said, “I think you can get these with nonintensive strategies now.” Intensive regimens are not ideal for the average older patient, though fit patients with highly proliferative disease may be candidates.
Benefit of Maintenance Following Complete Remission
Following a complete response, there are several options for next steps: observe, start maintenance rituximab, perform ASCT (with or without maintenance rituximab), start a BTK inhibitor, use BR plus ibrutinib, or start R2. Maintenance therapy has been shown to improve overall survival after R-CHOP but not yet for BR, he said.
The impact of maintenance rituximab after BR was studied in the small MAINTAIN trial, presented at the ASCO Annual Meeting in 20164 but still unpublished. It offered no significant overall survival benefit over observation (69.6 months vs not reached), leading to “pretty vigorous debate in the past 6 years” and variable use of this approach, he said.
Support for maintenance after BR did come from the phase II ECOG-ACRIN E1411 trial,5 which evaluated induction with BR vs BR plus bortezomib (BVR) for six cycles, followed by maintenance with rituximab alone or with lenalidomide. Both arms achieved a median progression-free survival of more than 5 years, “suggesting maintenance rituximab is adding something after BR-based therapy,” he said.
Interesting data have also recently come from 1,621 patients in the Flatiron database who were treated with BR or R-CHOP for induction, followed by maintenance rituximab or observation.6 Median time to next treatment was 37 months with BR alone and 22 months with R-CHOP alone, but medians were not reached for either arm when followed by maintenance in this real-world sample.
“Maintenance pulled both induction strategies up considerably [on the Kaplan Meier curves] for time to next treatment and overall survival,” Dr. Kahl observed. “Maintenance rituximab was similarly beneficial after BR as it was after R-CHOP. I think these data are pretty compelling in support of maintenance after BR.”
The optimal duration of maintenance remains unclear. After ASCT, Dr. Kahl usually prescribes rituximab for 3 years, but out of concern for B-cell depletion (especially during the COVID-19 pandemic), he shortens this to 2 years in older patients who received BR induction. And, in this population, he strongly favors the use of tixagevimab/cilgavimab, a monoclonal antibody combination approved as preexposure prophylaxis to prevent COVID-19 in individuals with moderate to severe immune compromise.
Ibrutinib: Role Is Not Clear
Another new first-line option is the BTK inhibitor ibrutinib in combination with BR followed by rituximab maintenance, as was evaluated in the recent phase III SHINE trial in 523 older patients.7 “There was no question that ibrutinib helped control the disease. There were fewer treatment discontinuations for progressive disease in the ibrutinib arm (28 vs 91), but there were more treatment discontinuations for adverse events (103 vs 63),” Dr. Kahl noted.
The ibrutinib regimen resulted in a 25% reduction in the risk of disease progression or death, with median progression-free survival of 6.7 years vs 4.4 years (P = .011). Median overall survival was not reached in either arm, and rates at 7 years were 55% with ibrutinib and 57% with placebo.
“My conclusion is there is not a clear-cut outcome in this trial. I tell patients that with ibrutinib, they have a 5 in 10 chance of still being in remission 5 years from now, but without it there is no difference in overall survival. Although patients given ibrutinib were less likely to die of mantle cell lymphoma, this was offset by more fatal adverse events,” he said.
“There are pros and cons to adding ibrutinib. There is no question that it improves progression-free survival, but this is still modest. There’s more toxicity, it’s costly, and you’ve used up your BTK inhibitor in the first line. I don’t see myself recommending it as a front-line strategy,” Dr. Kahl commented.
Additional data will come from SHINE and E1411. Two other trials of BTK inhibitors with better safety profiles may be promising:
- ECHO is evaluating BR with and without acalabrutinib until disease progression.
- MANGROVE is evaluating zanubrutinib plus rituximab vs BR in the front-line setting.
Mantle Cell Lymphoma in Younger Patients: Role of Bendamustine
Historically, for typical disease in younger patients, Dr. Kahl said he would use the Nordic regimen (dose-intensified CHOP), R-CHOP with alternating DHAP (dexamethasone, cytarabine, cisplatin), or BR with alternating high-dose cytarabine, but he said recent data have suggested that BR might be as effective as high-dose cytarabine. “I can see myself, going forward, just using straight BR-type induction and following that with ASCT and rituximab maintenance,” he said.
Dr. Vose noted that, among the aggressive therapeutic options, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Onclogy list BR as an “other recommended regimen” rather than “preferred.” She predicted that based on emerging data of BR’s efficacy, this could change.
Clinical Trials of ASCT
The main debate today, Dr. Vose said, is whether patients in first complete remission should undergo ASCT? “Many centers, including ours, do that, while some others see ASCT as less favorable…. We still don’t have a lot of randomized data saying this is the right thing to do.”
Aggressive treatment with rituximab plus chemotherapy followed by ASCT for patients in first complete remission improves progression-free survival, but its effect on overall survival remains unclear. Its main advantage is the avoidance of additional or continuous therapy (for 8–10 years or more), and the possibility of reserving alternative treatments for salvage. Although short-term toxicities from ASCT are often overcome, late toxicities may emerge. Furthermore, the relapse risk remains high, though delayed. “I think transplant is still an open question,” Dr. Vose said.
The benefit of ASCT was assessed in a retrospective multicenter study of 1,254 transplant-eligible patients up to age 65 treated between 2000 and 2015.8 Median progression-free survival was 62 months (> 5 years), and median overall survival was 139 months (> 11 years). On multivariable analysis, transplantation was associated with improved progression-free survival (hazard ratio [HR] = = 0.54; P < .01) and a trend toward improved overall survival (HR = 0.77; P = .06). After propensity score–weighted analysis, progression-free survival remained significant, but the trend toward a survival benefit diminished (HR = 0.87; P = .2).
At the University of Nebraska, Dr. Vose and her colleagues are conducting a retrospective analysis of 586 patients from 23 sites, with full pathology review and molecular testing performed on all cases (data unpublished). They evaluated outcomes according to receipt of cytarabine-based or non–cytarabine-based regimens and ASCT or no ASCT. “We saw that patients who underwent autologous transplant, and those who had cytarabine-containing regimens, appeared to have improved outcomes [progression-free and overall survival], but in the multivariate analysis, some of that benefit did fall out,” she reported.
Other Intensive First-Line Treatments
Aside from high-dose therapy followed by ASCT and 3 years of rituximab maintenance, the NCCN also recommends these regimens as aggressive therapy in this setting:
- RDHA (rituximab, dexamethasone, cytarabine) plus platinum
- Alternating R-CHOP/R-DHAP (defined previously)
- NORDIC regimen (defined previously)
- HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) plus rituximab
- Rituximab, bendamustine followed by rituximab, and high-dose cytarabine.
Results are “excellent” with high-dose cytarabine induction and ASCT (Nordic MCL2 regimen). Median remission times were shown to be 8 to 9 years, reaching 11 years for patients receiving ASCT in the pivotal study.9 Median overall survival has exceeded 10 years, with about 50% of patients still alive at 14 years. Although she acknowledged this is a “fairly toxic” regimen, it is “one you can get your patients through,” Dr. Vose said.
The value of maintenance rituximab has become clear from studies such as the LyMa/LYSA trial.10 After 3 years of maintenance rituximab post-ASCT, overall survival at 4 years was 89% vs 80% with observation (P = .04). Thus, 3 years of maintenance rituximab became the standard of care for many patients, “at least before the pandemic,” she said.
Studies Aim to Define Optimal Treatment
Several important clinical trials by the ECOG-ACRIN intergroup are aiming to define the optimal aggressive treatment for mantle cell lymphoma:
- The EA4181 trial will evaluate the addition of acalabrutinib to BR in 369 patients up to age 70 with untreated mantle cell lymphoma.
- The EA4150 trial will look at clonal markers and randomly assign patients according to the achievement of response and measurable residual disease after 3 years of rituximab, preceded or not by ASCT.
- TRIANGLE, a European study, will study ibrutinib added to induction and as maintenance, with or without ASCT.
DISCLOSURE: Dr. Kahl has served as a consultant to AbbVie, Acerta, AstraZeneca, ADCT, BeiGene, BMS, Genentech, Genmab, Gilead Sciences, Incyte, Janssen, MEI, MorphoSys, and Pharmacyclics. Dr. Vose has received honoraria from AbbVie, Janssen, AstraZeneca, MEI Pharma, Johnson and Johnson, Daiichi Sankyo, Pharmacyclics, Genentech, MorphoSys, Eli Lilly, and Caribou.
REFERENCES
1. Kahl BS, Vose JM: Mantle cell lymphoma in first complete response. 2022 Pan Pacific Lymphoma Conference. Presented July 20, 2022.
2. Epperla N, Hamadani M, Fenske TS, et al: Incidence and survival trends in mantle cell lymphoma. Br J Haematol 181:701-706, 2018.
3. Visco C, Chiappela 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 Fondadzione Italiana Linfomi. Lancet Hematol 4:E15-E23, 2017.
4. Rummel MJ, Knauf W, Goerner M, et al: Two years rituximab maintenance vs observation after first-line treatment with bendamustine plus rituximab in patients with mantle cell lymphoma: First results of a prospective, randomized, multicenter phase II study (a subgroup study of the StiL NHL7-2008 MAINTAIN trial). 2016 ASCO Annual Meeting. Abstract 7503.
5. Smith MR, Jegede O, Martin P, et al: ECOG-ACRIN E1411 randomized phase 2 trial of bendamustine-rituximab-based induction followed by rituximab ± lenalidomide consolidation for mantle cell lymphoma: Effect of adding bortezomib to front-line BR induction on progression-free survival. 2021 ASCO Annual Meeting. Abstract 7503.
6. Martin P, Cohen JB, Wang M, et al: Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: Results from large real-world cohorts. J Clin Oncol. June 28, 2022 (early release online).
7. Wang ML, Jurczak W, Jerkeman M, et al: Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med 386:2482-2494, 2022.
8. Gerson JN, Handorf E, Villa D, et al: Outcomes of younger patients with mantle cell lymphoma treated in the rituximab era. J Clin Oncol 37:471-480, 2019.
9. 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 175:410-418, 2016.
10. Le Gouill S, Thieblemont C, Oberic L, et al: Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med 377:1250-1260, 2017.
