Indolent Lymphoma: Well Tolerated, Fixed Duration Treatment Involving Bendamustine, Rituximab and Acalabrutinib for Front-Line Waldenström's Macroglobulinaemia That Induce Deep Clinical Responses

Background: Waldenström's macroglobulinaemia (WM) is an uncommon lymphoproliferative disorder. An optimal first-line therapy for WM has not been defined. We postulated that combining bendamustine and rituximab (BR) with the second generation covalent BTK inhibitor Acalabrutinib would result in deeper responses as measured by complete response (CR) and very good partial response (VGPR) rates, and provide a longer duration of response.

Objectives: The primary objective of this trial is to document the CR and VGPR rates.

Methods: The BRAWM clinical trial (NCT04624906) combines BR with acalabrutinib in a one-year, fixed duration treatment course of six 28-day cycles BR and 365 days of concurrent acalabrutinib. This ongoing trial is taking place at 9 clinical sites across Canada. The Intent to Treat (ITT) population includes all participants who have started treatment and were evaluable for safety. Participants who reached cycle 7 were evaluable for response. The sample size was calculated to be able to detect a CR + VGPR rate whose lower level of confidence is greater that the historically defined CR + VGPR rates of 23%. Clinical responses were defined using 6^th IWWM. Minimal residual disease (MRD) negativity, assessed with clonoSEQ assay, was a secondary endpoint.

Mutational analysis of screening biopsy samples from participants with adequate sample for assessment (n=56), showed 50 with MYD88 L265P mutation, 16 with a CXCR4 mutation of which 8 were S338fs, and 1 with a TP53 l195T mutation. Preliminary minimal residual disease (MRD) analysis of peripheral blood (PB) and bone marrow (BM), using next generation sequencing with a sensitivity of 10^-6, shows that most evaluable participants (those with MRD samples at two or more time-points) have become MRD negative in PB, with increasing rates of BM MRD negativity over time. From baseline screening levels, there was a median log reduction in the PB of 4.42 (IQR 1.32) by cycle 7, 4.11 (IQR 1.25) by cycle 12, and 4.06 (IQR 0.81) by month 18. Uni- and multi-variate analyses of clinical variables that may be associated with clinical and MRD outcomes are underway.

Conclusions: Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated in a relatively elderly population with a toxicity profile consistent with the utilized drugs and not greater than that seen with BR and Placebo in the randomized ECHO trial in untreated Mantle Cell Lymphoma. Initial clinical results show that this treatment is associated with a very high proportion of CR + VGPRs as well as MRD negativity.

Forward:AstraZeneca: Consultancy; BeiGene: Consultancy, Honoraria; BMS: Consultancy; Kite/Gilead: Consultancy; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seagen: Consultancy; Janssen: Consultancy; Servier: Consultancy; Abbvie: Consultancy. Shafey:AstraZeneca: Honoraria; BeiGene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Nikonova:Karyopharm: Consultancy; Abbvie: Consultancy; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy; Apotex: Honoraria. Sebag:Amgen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Janssen: Honoraria, Research Funding. MacDonald:AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seagen: Consultancy, Honoraria. Villa:Roche, AstraZeneca: Research Funding; Merck, Abbvie, Roche, AstraZeneca, BeiGene, Janssen, BMS/Celgene, Kite/Gilead, InCyte: Consultancy; Merck, Abbvie, Roche, AstraZeneca, BeiGene, Janssen, BMS/Celgene, Kite/Gilead, InCyte: Honoraria. Sandhu:Janssen, Celgene/BMS, Pfizer, Sanofi, GSK, Forus, Beigene: Honoraria; Janssen, Celgene/BMS, Pfizer, Sanofi, GSK, Forus, Beigene: Consultancy. Aljama:Beigene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Simmons:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Gallucci:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Tomlinson:Spectral Inc: Consultancy; Editas Inc: Consultancy. Berinstein:AstraZeneca: Honoraria, Research Funding; Regeneron: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Merck Inc: Research Funding; IMV Inc: Research Funding; Pfizer: Honoraria; Roche: Honoraria; Forus: Honoraria; Beigene: Honoraria.

Acalabrutinb is approved for other lymphomas but not for WM and therefore this is off-label