Efficacy and tolerability of bendamustine, rituximab and acalabutinib in elderly treatment naïve Waldenström's macroglobulinemia

Abstract Background: The optimal treatment of treatment naïve (TN) Waldenström's macroglobulinaemia (WM) has not yet been defined. Recently we have shown high complete and very good partial responses (CR+VGPR) with a tolerable toxicity profile in participants with treatment-naïve WM treated in the BRAWM trial (NCT04624906). We have also reported that age was not a predictive variable for the primary endpoint of combined CR+VGPR rates or for negative peripheral blood (PB) Minimal Residual Disease (MRD) responses. Objectives: In this current analysis, we evaluate the efficacy, tolerability and dose intensity of this combination in participants with WM in the BRAWM trial who were less than age 70 and those greater than or equal to age 70. Methods: The BRAWM clinical trial is an investigator-initiated multicentre clinical trial that evaluated the combination of bendamustine, rituximab and acalabrutinib (100mg twice daily) in 63 participants with TN WM. CR+VGPR rates were 59% in this trial. In addition, the tolerability was acceptable. Here, we analyze the efficacy, dose intensity and toxicity profile of this treatment in participants entered in the trial who were <70 years old (y/o) and those who are ≥70 y/o. Results: Of the 63 participants entered in the BRAWM clinical trial, 31 were ≥70 y/o. Participants up to age 85 were treated in the trial. The baseline demographic factors, including B2 microglobulin, LDH, baseline haemoglobin or platelets, total IgM, IWWM-IPS, bone marrow involvement and MYD88MUT and CXCR4MUT status were similar in participants under between the two cohorts. At cycle 7, the combined CR+VGPR rate was very similar between the two groups at 59.4% in those <70 y/o and 58.1% in those ≥70 y/o. The PB MRD rate was 78.6% and 77.8% in those <70 y/o and in those ≥70 y/o, respectively. With respect to dose intensity, 24/31 participants ≥70 y/o received 81-100% of the planned acalabrutinib dose and 26/32 of participants <70 y/o received 81 to 100% of planned acalabrutinib dose. Two participants ≥70 y/o received less than 60% of acalabrutinib, whereas four participants <70 y/o received less than 60% of acalabrutinib. The response rates in participants <70 y/o and those ≥70 y/o in these different dose intensity groups for acalabrutinib were similar. Of the planned bendamustine administration, twenty-five participants ≥70 y/o received greater than 75%, and twenty-nine participants <70 y/o did. Of the five participants who received 50% or less of the expected bendamustine, three withdrew during combination therapy. Patients <70 y/o received a mean of 5.9 cycles of bendamustine (range 2-6 cycles), whereas patients >70 y/o received a mean of 5.5 cycles of bendamustine (range 1-6 cycles). Grade 3/4 neutropenia or febrile neutropenia occurred in 9 participants (29%) ≥70 y/o, and 12 participants (37.5%) <70 y/o during combination therapy. There were no major differences in frequency of grade 3/4 adverse events between the two age groups during monotherapy. Bendamustine was discontinued in 8 participants (26%) ≥70 y/o and 3 participants (9%) <70 y/o. There were no major differences between the two age groups in VGPR+CR rates or major responses in any of the different dose intensity groups. Conclusions: the BRAWM clinical trial for TN WM produces amongst the highest CR and VGPR rates for this patient population. This combination treatment was equally effective in participants ≥70 y/o or <70 y/o. In addition, both age cohorts were able to tolerate similar dose intensities of bendamustine and acalabrutinib. Older patients received a slightly lower mean number of cycles of bendamustine. Although more patients ≥70 y/o discontinued bendamustine due to toxicities, this did not appear to compromise efficacy. The toxicity profile also was very similar. We conclude that this regimen can be administered effectively to patients with TN WN, as age does not appear to be a limitation for administration with no impact on efficacy, tolerability or dose intensity of this regimen.