Next Generation BTK Inhibitor Acalabrutinib with Bendamustine-Rituximab in First Line Waldenstrom's Macroglobulinemia: The Brawm Study

Background: Waldenström's macroglobulinaemia is an uncommon lymphoproliferative disorder. Although the life expectancy is relatively long there are no curative therapies for this disease. Several different first line treatment options are available and include chemotherapy immunotherapies such as bendamustine and rituximab (BR) or BTK inhibitor therapy. Neither of these therapies generate a high frequency of complete responses (CR) or very good partial responses (VGPR). We postulated that combining bendamustine and rituximab with a next generation BTK inhibitor would result in deeper responses as measured by the CR and VGPR rates, and provide a longer duration of response.

Objectives: The primary objective of this trial is to document the Complete and Very good partial response rate.

Methods: The BRAWM clinical trial combines standard of care first line treatment of bendamustine and rituximab with Acalabrutinib in a fixed duration treatment course including six cycles of bendamustine and rituximab and 12 months of Acalabrutinib. This trial is taking place at nine clinical sites across Canada and 19 patients have been enrolled, with a recruitment goal of 59.

Results: An interim analysis of the first 10 patients showed that the median age of patients at screening was 66, and 6 of the subjects were males. Based on the IPSS-WM scoring system, one patient was low risk, one was intermediate risk and 8 were high risk. Eight patients required treatment due to already symptomatic disease with cytopenia or neuropathy. The remaining two started treatment due to hematological and biochemical compromise related to their lymphoma. The median screening IgM was 28.5 and all but two normalized their IgM by cycle 6 cycle of treatment (one patient had not finished cycle 6 assessment). Although adverse events occurred in all patients, grade 3 or 4 AEs only occurred in 9.2% and 1.7% of all AEs, respectively. The most common grade 3 and grade 4 toxicities were cytopenias, which represented 61.5% of grade 3 or 4 events, all of which were neutropenias. Other important grade 3/4 toxicities included 1 event each of transaminitis, atrial fibrillation, and infection. No events of anemias, secondary malignancies, hepatotoxicity events, or deaths were reported. There were 7 study drug interruptions related to AEs, of those, six patients restarted Acalabrutinib, five at full dose, and one required a dose reduction. The single drug discontinuation event was due to a combination of grade 3 atrial fibrillation, and grade 2 pericardial effusion and pericarditis that were all possibly related to Acalabrutinib. With a median follow up of 5 months for the 8 patients who have completed BR cycles, all achieved a very good partial response at cycle 7. There have been no patients yet with recurrent or progressive disease. All 10 patients have MyD88 mutations, and one has a CXCR4 mutation. Minimal residual disease analysis will be performed at cycle 7, 12, and month 18 in all patients.

Conclusions: Bendamustine, Rituximab and Acalabrutinib front-line therapy for Waldenström's macroglobulinaemia is safe and well tolerated and initial clinical results show all 8 patients who completed 6 cycles of BR and Acalabrutinib to date have achieved a VGPR.

Berinstein:AstraZeneca: Research Funding. Shafey:Kite/Gilead: Honoraria; BMS: Honoraria; Novartis: Honoraria; Astrazeneca: Honoraria; Janssen: Honoraria; BeiGene: Honoraria; Incyte: Honoraria. Villa:Roche, AstraZeneca, Abbvie, Janssen, Kite/Gilead, BMS/Celgene, BeiGene, Kyowa Kirin: Consultancy, Honoraria; AstraZeneca, Roche: Research Funding. Aljama:Jansen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Larouche:Kite-Gilead: Research Funding; German: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Astrazeneca: Research Funding.