Uppal, Encarl

Abstract Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in patients treated with chemoimmunotherapy remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early end point, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At a median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each; P = .4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median 3.3 vs 8.8 years; hazard ratio [HR], 2.8; P = .0036) and OS (HR, 2.6; P = .036) compared with CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS, 71% vs 86%; HR, 3.1; P = .005) and higher mortality (standardized mortality ratio [SMR], 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR, 1.1). In conclusion, BR is effective irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Patients without POD24 represent a cohort with distinctly favorable outcome.

7566 Background: Parenteral limited-duration BR chemoimmunotherapy and continuous orally administered Ibr, a Bruton tyrosine kinase inhibitor, dominate the treatment landscape of WM, a rare B cell lymphoma. No trials have assessed the comparative effectiveness of these 2 vastly different approaches. We conducted a multiinstitutional, international, collaborative study to compare BR and single-agent Ibr in patients (pts) with treatment naïve (TN) WM. Methods: Data from 347 pts with active TN WM, seen between 2011 and 2021 in the US and Europe, were analyzed. The pts on rituximab maintenance were excluded. The modified IWWM-6 criteria (based on IgM alone) were used for response assessment. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Results: The median age of the pts treated with BR (n=208) and Ibr (n=139) was 66 (range 40-86) years (y) and 69 (39-97) y, respectively, (p=0.005). With a median follow up of 4.2 y (95% CI 3.8-4.5), the 4-y progression free survival (PFS) was 73% in each group, p=0.6, and 4-y overall survival (OS) was 94% (95% CI 91-98) in the BR group versus ( v) 82% (95% CI 75-90) in the Ibr group, p=0.01. In a bivariate analysis adjusting for age and the treatment type, only age emerged as a predictor for OS (HR 7.2, p=0.0001). Therefore, a 1:1 age-matched analysis of 246 pts who received Ibr (n=123) or BR (n=123) was performed. Pts with a known MYD88WT status who had received Ibr and their age matched controls on BR were excluded. The international prognostic scoring system (IPSS) WM was comparable between the 2 groups (Table). A higher proportion of pts on BR attained very good partial or deeper response (≥VGPR) as the best response in comparison to the pts on Ibr (Table). The 4-y PFS for the BR and Ibr groups was similar [72% (95% CI 63-82) v 78% (95% CI 70-87), p=0.14] and 4-y OS was 95% (95% CI 91-99) with BR v 86% (95% CI 80-93) with Ibr (p=0.3). Premature discontinuation, during active treatment, due to adverse effects (AEs) or lack of response was noted in 13% and 33% of pts on BR and Ibr, respectively. A detailed assessment of the AEs will be presented at the meeting. Conclusions: Both BR and Ibr lead to comparable outcomes in pts with TN WM, although deeper responses are attained with BR. These findings require confirmation in prospective studies. For pts who harbor MYD 88L265P mutation, selection between the 2 approaches should be dictated by their potential toxicities, pt comorbidities, pt/clinician preference (parenteral fixed-duration v continuous oral) and access to therapies. [Table: see text]