Primary Analysis and Results of Bendamustine, Rituximab, and Venetoclax (BR-VEN) for Initial Treatment of Mantle Cell Lymphoma in Subjects over 60 Years of Age (PrE0405)

Background

Mantle cell lymphoma (MCL) is an incurable form of aggressive non-Hodgkin lymphoma. Treatment choice at diagnosis is based on tolerability of cytarabine and high-dose chemotherapy. With a median age of 60-70 years, many patients are ineligible for aggressive treatment. Bendamustine and rituximab (BR) is a reasonable treatment option (E1411, Smith MR et al. ASH 2022) for this patient population and venetoclax (VEN) has shown pre-clinical evidence of synergy with chemoimmunotherapy. PrECOG 0405 was designed to evaluate the addition of VEN to BR in previously untreated patients with MCL aged over 60 years.

Methods

Eligible patients included those that were previously untreated and diagnosed with MCL as defined as the presence of t(11;14) by FISH or cyclin D1 expression by IHC. Patients must have been at least 60 years of age or older on D1C1 of therapy with a good performance status (ECOG 0-2). Adequate marrow and organ function was required, specifically a creatinine clearance of ≥ 40 mL/min.

Treatment administration is summarized in Figure 1. Dose of bendamustine was either 90mg/m² D1&2; or, for subjects over the age of 75 years, 70mg/m² was allowed per investigator discretion. VEN was dose escalated during Cycle 1 to 200mg. At the time of C2, BR was repeated and VEN was also escalated to 400mg. With C2-6, VEN 400mg PO daily was given D1-10 only. Primary endpoint was PET-negative complete response (CR) rate at end of treatment (EOT) by Lugano Criteria. A negative bone marrow biopsy was required to confirm CR if involved at screening. Minimal residual disease (MRD) by next-generation sequencing was performed at the EOT. Maintenance rituximab was encouraged per investigator discretion.

This was a single arm study with an original accrual goal of 53 subjects to detect a 15% improvement in CR rate compared to historical data. However, due to slow study accrual during COVID pandemic and preliminary efficacy data from E1411 study, the statistical parameters were updated after 25 subjects had been accrued. The revised accrual goal was 33 patients to obtain 32 eligible and treated patients, which provided 81.8% statistical power to detect a 17% difference in CR rate (from 60% [E1411 data] to 77%) using an exact binomial test with a 1-sided alpha of 11.6%. This combination regimen will be considered promising if 23 or more (out of 32) patients attain CR.

Results

From January 2020 to March 2022, 33 subjects enrolled and were treated on study. Subject characteristics are listed in Table 1. Seven (21%) unique subjects were treated with 70mg/m² of bendamustine during induction cycles. Laboratory tumor lysis syndrome (TLS) was seen in 2/33 during C1 only; clinical TLS was not seen. Treatment was generally well tolerated with treatment-related adverse events (TRAE) of Grade ≥3 and occurring in >10% of subjects being neutropenia (n=5, 15%), thrombocytopenia (n=5, 15%) and lymphopenia (n=9, 27%). Other common non-hematologic TRAE of all grades were nausea/vomiting (n=26, 79%), diarrhea (n=10, 30%), and fatigue (n=17, 52%). There were 4 (12%) instances of COVID-19/COVID-19 pneumonia considered treatment related. Dose adjustments and delays for any drug occurred in 36% and 67% of subjects respectively. 22/33 (66.7%) subjects completed 6 cycles of BR-VEN. Maintenance rituximab was administered in 19/33 (57.6%) of subjects.

Overall response rate was 97% (32/33) and PET-negative bone marrow biopsy confirmed CR Rate at EOT was 85% (28/33), achieving the primary endpoint (≥23 CRs). MRD at EOT is under analysis. With a median survival follow up of 21.5 months (mo), Median PFS and OS were not reached; estimated 2-year PFS and OS was 69.7% and 81.1% respectively. During follow up, there have been 6 deaths, 4 from COVID-19 (all in remission), one from influenza A (in remission), and one from disease progression (non-responding pt). There have been 2 other progression events who are alive.

Conclusions

BR-VEN was generally well-tolerated in this older patient population though GI toxicities were common. With a PET-negative CR rate of 85%, the combination is promising but longer follow-up is needed. There was a competing risk of death related to upper respiratory viruses identified, mostly COVID-19, as has been seen in other BR-based protocols during the COVID-19 pandemic. MRD analysis and survival data will be updated.