Dose Adjustment Outcomes In Patients With Waldenström Macroglobulinemia Treated With Ibrutinib
Topic: Indolent and mantle-cell non-Hodgkin lymphoma — Clinical
Background:Ibrutinib (Ibr) has dramatically changed the treatment (tx) landscape for patients (pts) with Waldenströmmacroglobulinemia (WM) since its approval as single-agent or combination therapy with rituximab (R). Inrelapsed/refractory (R/R) WM, single-agent Ibr demonstrated sustained efficacy and safety with long-termfollow-up of >5 y and superior progression-free survival (PFS) and longer time to next tx in combination with Rvs R alone. Pts who continue Ibr-based tx have better survival outcomes than those who discontinue within thefirst few years. Real-world evidence suggests that Ibr dose adjustments do not negatively affect hematologicresponse or time to discontinuation after adverse events (AEs). Here we examine Ibr dosing patterns andoutcomes in pts with WM with and without dose reductions (DRs) after AEs.
Aims:To describe characteristics and outcomes of pts treated with Ibr for WM with and without DR due to an AE.
Methods:This post hoc analysis used data from 2 Ibr registrational trials where pts received Ibr 420 mg daily: (1) anopen-label, single-arm, phase 2 trial (PCYC-1118; NCT01614821) of pts with R/R WM who received single-agent Ibr; and (2) a randomized, double-blind, placebo-controlled, phase 3 trial (iNNOVATE; NCT02165397)including pts with previously untreated WM who received Ibr plus R (I+R) and pts who received single-agentIbr after failure of prior R-containing therapy. Median follow-up for PCYC-1118 and I+R and Ibr arms ofiNNOVATE was 15, 50, and 58 mo, respectively. Pts were categorized as with or without a DR due to an AE. DRswere conducted per study protocols and physician discretion. Key outcomes included baseline demographicsand clinical characteristics, PFS, and resolution and recurrence in the DR cohort.
Results:The analysis included* 169 pts (113 [67%] male; median age 67 y [range, 36–90]; median baseline IgM andhemoglobin 35.2 and 105 g/L, respectively); 29 pts (17%) with a DR and 140 pts (83%) without a DR. Baselinecharacteristics among pts with and without DR were similar to the pooled population. For the entire cohort(n=169), median follow-up was 45 mo. Estimated 48-mo PFS (95% CI) was 68% (59–76) for all pts in thisanalysis, and 79% (57–91) and 65% (54–74) for pts with and without DR, respectively. Most DRs occurredwithin 12 mo (62%) with a median time to first DR of 9 mo (range, 1–41). Causes of AEs leading to DRincluded hematologic (n=8), gastrointestinal and musculoskeletal (n=6 each), dermatologic and other (n=5each), and cardiac and infection (n=2 each). Initial AEs resolved in 27 of 29 pts (93%) in the DR cohort; 22 pts(76%) had no recurrence or recurrence at lower grade; 7 pts (24%) had recurrence at the same or higher grade.For pts with a DR, median time on study tx from first DR until Ibr discontinuation was 25 mo (range, 1–52). Atotal of 14 pts (8%) had recommended DR per USPI (AESI; Gr 2 cardiac failure, Gr 3 cardiac arrhythmia, Gr 3–4nonhematologic AEs, Gr 3–4 neutropenia with infection or fever, Gr 4 hematologic AEs). These AESIs resolvedafter first Ibr DR in 14 of 14 pts (100%); 12 pts (86%) had no recurrence or recurrence of initial AE at lowergrade, and 2 pts (14%) experienced recurrence at the same or higher grade. Median time on study tx after firstDR due to an AESI was 28 mo (range, 1–51).
Summary/Conclusion:In this analysis, most AEs resolved following DRs without negatively affecting efficacy outcomes in pts with WM treated with Ibr-based tx with or without R. Thus, Ibr DR can be an effective strategy to manage AEs whilemaintaining clinical efficacy for pts with WM
Keywords: Dose intensity, Outcome, ibrutinib, Waldenstrom’s macroglobulinemia