FIXED DURATION TREATMENT OF BENDAMUSTINE-RITUXIMAB AND ACALABRUTINIB IN FRONTLINE WALDENSTROM’S MACROGLOBULINEMIA: DEEP MOLECULAR RESPONSES IN HIGH-RISK PATIENT SUBSETS

Background: An optimal first-line therapy for Waldenstrom’s Macroglobulinemia (WM) has not been defined. We postulated that combining bendamustine and rituximab (BR) with acalabrutinib will result in deep and durable responses, particularly in high-risk patient subsets.

Methods: The BRAWM clinical trial (NCT04624906) combined BR and acalabrutinib in a one-year, fixed duration treatment course of six 28-day cycles of BR and 365 days of concurrent acalabrutinib. This phase II trial took place at 9 clinical sites across Canada. The primary outcome was combined complete response + very good partial response (CR+VGPR) rate, and secondary outcomes included PFS, OS and Measurable Residual Disease (MRD). Outcomes were assessed for all participants, and for high-risk subsets (MYD88^WT, CXCR4^MUT and TP53^MUT). MRD analyses uses bone marrow (BM) and peripheral blood (PB) samples collected at trial specific time points, assessments being performed by Adaptive Biotechnologies (Seattle, USA) using the clonoSEQ assay. Outcomes were compared between high-risk and non-high risk subsets.

Results: This trial enrolled 63 participants. The median age was 69 years (range 39–85), and 49 (78%) were male, 38% intermediate-risk and 51% high-risk IPSS-WM score. Mutational analysis in 57 participants showed 50 (88%) were MYD88^MUT and 16 (30%) were CXCR4^MUT, 1 was TP53 ^MUT. CR+VGPR occurred in 37/59 participants (62.7%) at cycle 7, 28/45 (62.2%) at cycle 12, and 21/39 (53.8%) at month 18 (Figure 1A). The median follow-up was 18 months (1.4–42.4). Both 24-month OS and PFS were 97.6% (95% CI: 93%–100%), 1 participant died at 15 months unrelated to treatment. On univariate analysis, CXCR4^MUT was not associated with inferior CR+VGPR rate at 1 year (p = 0.10). Grade 3/4 treatment-related adverse events (TRAE) occurred in 31/63 participants during combination therapy, most common being neutropenia (n = 23) and thrombocytopenia (n = 3). During monotherapy, 13/59 participants had a grade 3/4 TRAE, 6 of whom had neutropenia. MRD negativity (threshold of 10⁻⁶) in PB was 82% at cycle 7, 91% at cycle 12 and 71% at month 18. MRD negativity in BM was not as frequent but increased in BM over time (9% at cycle 7, 12% at cycle 12 and 23% at month 18). MRD negativity rates at cycles 7 and 12 were similar in those with and without CXCR4^MUT and MYD88^WT (Figure 1B). Log reductions of MRD in PB and BM in high-risk subsets were also comparable to corresponding non-high risk subsets.

Conclusions: Fixed duration BR and acalabrutinib was effective and well-tolerated. This regimen achieves amongst the highest CR+VGPR rates seen in frontline WM trials. Acknowledging sample size limitations, high-risk subsets appear to achieve CR+VGPR and MRD negativity rates similar to corresponding non-high risk subsets. We hypothesize that the deep responses and high rates of MRD negativity seen in this trial may translate into durable responses and prolonged survival in high-risk and non-high risk WM patient subsets.

Research funding declaration: AstraZeneca provides acalabrutinib at no cost and trial funding

Keywords: minimal residual disease; combination therapies; indolent non-Hodgkin lymphoma

Potential sources of conflict of interest:

D. Villa

Consultant or advisory role: Roche, Abbvie, Janssen, Beigene, AstraZeneca, BMS/Celgene, Kite/Gilead, Kyowa Kirin, Incyte, Merck

Honoraria: Roche, Abbvie, Janssen, Beigene, AstraZeneca, BMS/Celgene, Kite/Gilead, Kyowa Kirin, Incyte, Merck

D. MacDonald

Consultant or advisory role: Abbvie, AstraZeneca, Beigene, Gilead, Roche, SeaGen

Honoraria: Abbvie, AstraZeneca, Beigene, Gilead, Roche, SeaGen

M. Aljama

Consultant or advisory role: Pfizer, Janssen, Beigene, Sanofi

Honoraria: Janssen, Pfizer, Sanofi

M. Shafey

Consultant or advisory role: AstraZeneca, Beigene, Jansen, Roche

Honoraria: AstraZeneca, Beigene, Jansen, Roche

N. Forward

Consultant or advisory role: Abbvie, AstraZeneca, Beigene, Celgene/BMS, Janssen, Kite/Gilead, Pfizer, Roche, SeaGen, Servier

Honoraria: Beigene, AstraZeneca, Roche, SeaGen

J. Larouche

Consultant or advisory role: AstraZeneca

A. Nikonova

Consultant or advisory role: Janssen, AstraZeneca, Abbvie, Gilead, Karyopharm

Honoraria: Janssen, Apotex, Gilead

I. Sandhu

Honoraria: Janssen, Celgene/BMS, Pfizer, Sanofi, Gilead/Kite, Vertex, GSK

M. Gallucci

Employment or leadership position: Adaptive Biotechnologies Inc.

H. Simmons

Employment or leadership position: Adaptive Biotechnologies Inc.

N. L. Berinstein

Consultant or advisory role: AstraZeneca and Beigene