Rituximab Plus Bendamustine Proves Promising in Young Patients With MCL

The combination of bendamustine and rituximab (Rituxan; BR) plus autologous stem cell transplantation (ASCT) and maintenance rituximab was shown to be an effective first-line treatment with comparable outcomes to R-CHOP/R-DHAP plus ASCT and observation in young patients with transplant-eligible mantle cell lymphoma (MCL), according to data published in Blood Advances.¹

Findings from the study showed an overall response rate (ORR) of 90% for patients treated with BR, with 54% achieving complete response (CR). Of these patients, 77% (n = 75) proceeded to ASCT, and 78% received maintenance rituximab. The ORR for patients treated with R-CHOP/R-DHAP was 94%, with 54% achieving CR. Of these patients, 78% (n = 181) proceeded to ASCT, and 2% received maintenance rituximab.

Moreover, at a median follow-up of 4.3 years (range, 0.2-7.6) in the BR cohort and 7.1 years (range, 0.1-14.8) in the R-CHOP/R-DHAP cohort, the unadjusted hazard ratio (HR) for progression-free survival (PFS) was 0.87 (95% CI, 0.53-1.41; P = .56), and the adjusted HR was 0.79 (95% CI, 0.45-1.37; P = .40), reflecting no distinct differences between unadjusted and adjusted comparisons.

The current first-line standard of care for young, fit patients with MCL is the combination of rituximab and cytotoxic chemotherapy followed by high-dose chemotherapy and ASCT, followed by maintenance rituximab.

Previously, the phase 3 MCL Younger trial (NCT00209222) found that alternating R-CHOP/R-DHAP and ASCT can lead to a longer time to treatment failure (HR, 0.60; 95% CI, 0.47-0.76) and a longer overall survival (OS; MCL International Prognostic Index [MIPI]-adjusted HR, 0.74; 95% CI, 0.56-0.98) compared with R-CHOP and ASCT alone. Additionally, the phase 3 LYMA trial (NCT00921414) found that 3 years of maintenance rituximab after 4 cycles of R-DHAP plus ASCT can improve PFS and OS over observation. These data, as well as results from other previous trials, indicate the potential benefits of BR in the transplant-eligible MCL population.

This populated-based cohort study investigated ORR rates and compared the HRs of PFS rates between two cohorts of transplant-eligible patients ages 18 to 65 years with stage II to IV MCL. These results were adjusted for MIPI as a continuous variable, Ki67 index (≥30% vs <30%), and blastoid/pleomorphic morphology as primary effect measure. Each cohort was independent and retrospectively identified from previously treated patient groupings, using shared baseline characteristics for enrollment.

Both cohorts were formed using the retrospectively applied eligibility criteria from the MCL Younger trial, which included previously untreated patients ages 18 to 65 years with stage II to IV (Ann Arbor) histologically proven diagnosis of MCL, measurable disease, and a World Health Organization (WHO) performance of less than 2.²

Both groups had similar Ann Arbor stage, lactate dehydrogenase ratios to the upper limit of normal, MCL35 risks, and blastoid/pleomorphic morphology.

Patients were excluded from the study if they had an EGOC performance status (PS) between 3 and 4, if they were pregnant or lactating, or if they had severely impaired pulmonary, cardiac, renal, or hepatic function unrelated to lymphoma.

The real-world BR cohort enrolled 97 patients with stage II to IV MCL who had been treated with first-line BR between June 2013 and January 2020. These patients were retrospectively identified using the British Columbia Cancer Centre for Lymphoid Cancer clinical and pathology databases. Compared with the R-CHOP/R-DHAP cohort, the patients in this cohort were older, had slightly worse performance statuses, had a greater proportion of Ki67 levels greater than or equal to 30%, and trended toward higher MIPI risk.

The BR cohort received 6 cycles of first-line BR, followed by ASCT and maintenance rituximab.

The R-CHOP/R-DHAP cohort was composed of the 232 patients in the R-CHOP/R-DHAP arm of the MCL Younger trial who were included in the primary analysis from July 2004 to March 2010. These patients received 3 cycles of R-CHOP alternating with 3 cycles of R-DHAP for a total of 6 cycles, followed by high-dose cytarabine chemotherapy, total body irradiation conditioning, and ASCT. Patients in the MCL Younger trial were not recommended to receive maintenance rituximab after ASCT, as it had not yet been established as the standard of care.

The primary end point of this trial was PFS with an adjusted HR. PFS was defined as the time from the initiation of first-line therapy to the date of first progression or relapse.

Secondary end points included event-free survival (EFS), response rates, ASCT rates, time to next treatment (TTNT), and OS. EFS was defined as the time from the initiation of first-line therapy to the date of first progression or relapse, date of next lymphoma therapy, or date of death from any cause. TTNT was defined as the time from the initiation of first-line therapy to the initiation of the next line of therapy. OS was defined as the time from the initiation of first-line therapy to the date of death from any cause.

Additional findings demonstrated that the 5-year PFS rate was 76% in the BR cohort vs 68% in the R-CHOP/R-DHAP cohort.

Notably, the cohorts had similar HRs across secondary end points in both adjusted and unadjusted analyses. The 5-year EFS rates were 70% in the BR cohort vs 65% in the R-CHOP/R-DHAP cohort, with an unadjusted HR of 0.88 (95% CI, 0.56-1.37) and an adjusted HR of 0.75 (95% CI, 0.45-1.25). The 5-year OS rates were 79% in the BR cohort vs 77% in the R-CHOP/R-DHAP cohort, with an unadjusted HR of 0.81 (95% CI, 0.46-1.40; P = .44) and an adjusted HR of 0.65 (95% CI, 0.24-1.24; P = .19).

There were 16 (15%) deaths in the BR cohort from lymphoma progression (n = 12), secondary neoplasia (n = 3), and unrelated causes (n = 1), with no treatment-related deaths. There were 93 (40%) deaths in the R-CHOP/R-DHAP cohort from lymphoma progression (n = 38), salvage treatment (n = 15), ASCT (n = 9), cardiac issues (n = 2), secondary neoplasia (n = 11), unclear causes (n = 11), and unrelated causes (n = 7).

This study found no differences in either unadjusted or adjusted outcomes between the two independent cohorts. These findings demonstrate treatment with BR, followed by ASCT, and maintenance rituximab is comparable to R-CHOP/R-DHAP with ASCT and observation in terms of efficacy and feasibility for young, transplant-eligible patients with MCL.

Going forward, additional randomized studies in MCL, such as the phase 3 TRIANGLE study (NCT02858258) and the phase 2 ECOG/ACRIN 4181 study (NCT04115631) will evaluate the addition of novel agents, such as BTK inhibitors to frontline chemoimmunotherapy.

References

1. Villa D, Hoster E, Hermine O, et al. Bendamustine or high-dose cytarabine-based induction with rituximab in transplant-eligible mantle cell lymphoma. Blood Adv. Published online April 19, 2022. doi:10.1182/bloodadvances.2022007371
2. Efficacy of R-CHOP vs R-CHOP/R-DHAP in untreated MCL. ClinicalTrials.gov. Updated September 10, 2012. Accessed April 29, 2022. https://clinicaltrials.gov/ct2/show/NCT00209222.