Bendamustine, Obinutuzumab and Venetoclax Results in High Complete Response Rates in Untreated Mantle Cell Lymphoma

Bendamustine and Rituximab (BR) is a common induction therapy for untreated mantle cell lymphoma (MCL) with high efficacy in both transplant eligible (SWOG 1106 trial) and ineligible (StIL/BRIGHT trials) populations. However, patients will invariably relapse after BR and there is interest in incorporating novel agents into the frontline setting (SHINE trial). The efficacy of venetoclax has been described in the relapsed setting as both a single agent and in combination (AIM trial) in relapsed MCL. We developed a phase 2 study of bendamustine, obinutuzumab, and venetoclax (BOV) for untreated patients with MCL to determine the efficacy and toxicity of this combination (NCT03872180).

Patients ≥ 18 years old with untreated MCL received up to six 28-day cycles of the regimen, consisting of bendamustine (90mg/m2 on days 1 and 2) and obinutuzumab (1000mg, C1: D 1,8,15 and C2-6: D1). Venetoclax was ramped up from 20mg to 200mg during cycle 1, and subsequently dosed at 400mg on days 1-10 of cycles 2-6. Post-induction therapy was determined by the treating physician and was not dictated by the study. The primary endpoint was CR rate by the end of induction, per Lugano criteria. Growth factor support was mandatory along with viral and PJP prophylaxis as well as CMV and tumor lysis syndrome monitoring. We targeted a sample size of 23 evaluable patients, with a target CR rate of 85%, based on the previously reported CR rate of 60% with B-R. Patients completed an interim PET/CT after 4 cycles and then again at the conclusion of cycle 6.

23 patients have enrolled, 16 patients have completed treatment per protocol and 1 patient has completed therapy, with upcoming end of treatment response assessment. 6 patients discontinued treatment prior to completion of therapy due to: disease progression (n=2), recurrent grade 3 thrombocytopenia (n=1), recurrent grade 3 neutropenia (n=2), and CMV viremia without CMV disease (n=1). Median age was 62 years old (range 41 - 80) with 9 patients 65 years and older. 6 (26%) patients were female.

Of the 16 patients who completed protocol defined therapy; the responses at end of induction were: CR (n=14), PR (n=1), and PD (n=1). The final patient on protocol therapy is on cycle 6 with significant clinical improvement and a PR on interim PET. All patients who came off protocol therapy early due to toxicity (n=4) achieved a CR on their interim restaging. MRD status and survival status will be shared at the meeting.

Grade 3+ hematologic toxicities include: Neutropenia (n=6), anemia (n=2), and thrombocytopenia (n=4). Two patients experienced grade 3 TLS and 1 patient experienced grade 4 TLS with hyperkalemia - all recovered and continued on therapy. Grade 3+ infectious complications included appendicitis (n=1) and CMV viremia (n=1). There were 2 patients who experienced grade 3 infusions reactions, one of whom declined further Obinutuzumab. There were no deaths attributable to therapy. One patient was unable to mobilize adequate stem cells for a planned autologous stem cell transplant.

Bendamustine, obinutuzumab and venetoclax in combination is characterized with favorable response rates in the context of previous trials (StIL, BRIGHT, SHINE), with 19 of 22 patients achieving a response (86%) and 18 of 22 patients (81%) achieving a complete response (1 additional patient is pending final response assessment per protocol). The complete response rates in the StIL and BRIGHT trials were 40% and 31% respectively, and the BR+ibrutinib arm of SHINE had a CR of 66%. Three of 22 patients had to discontinue protocol therapy for high grade cytopenias. This regimen is highly active and future studies may consider an abbreviated course of bendamustine to limit myelosuppression while maintaining a high CR rate.

Greenwell:Stemline: Consultancy; Kyowa Kirin: Consultancy. Alizadeh:Syncopation: Current equity holder in private company, Patents & Royalties; Gilead: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties; Adaptive Biotechnologies: Consultancy; Foresight Diagnostics: Consultancy, Current equity holder in private company, Patents & Royalties; Cibermed Inc: Consultancy, Current equity holder in private company, Patents & Royalties; Roche: Consultancy; BMS: Consultancy, Research Funding; Genentech: Consultancy; Karyopharm: Consultancy. Allen:Kyowa: Consultancy, Honoraria; Daiichi Sanyko: Consultancy, Honoraria. Cohen:Astrazeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genentech: Research Funding; HutchMed: Consultancy, Research Funding; Takeda: Research Funding; Kite Pharma/Gilead: Consultancy; Aptitude Health: Consultancy; Lilly Oncology/Eli Lilly: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy; BMS/Celgene: Research Funding.