Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound

Abstract

Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4-fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.

Ibrutinib Dose Adherence and Therapeutic Efficacy in Non-Hodgkin Lymphoma: A Single-Center Experience

“…The discontinuation rates reported here are similar to previous studies in both CLL and WM populations 1, 2, 4, 13 . However, our rate of discontinuation is smaller than a recently reported discontinuation rate in a community based CLL study, which also saw much lower frequency of discontinuation due to progression (10.7% vs. 35% in this study) potentially indicating a less heavily pre-treated and lower risk population 14 .…”

“…However, our rate of discontinuation is smaller than a recently reported discontinuation rate in a community based CLL study, which also saw much lower frequency of discontinuation due to progression (10.7% vs. 35% in this study) potentially indicating a less heavily pre-treated and lower risk population 14 . Similar to analyses of CLL patients and WM on clinical trials, patients who discontinued ibrutinib for progression had a worse overall survival compared to those who discontinued for other reasons 1, 4 . Among CLL patients that discontinued for progression median overall survival was 54 days.…”

“…While ibrutinib therapy is generally well tolerated across multiple indications, dose reductions are required in 6–26% of patients and treatment discontinuation rates are reported in 4–24% of patients 1, 2, 4, 5 . Further, patients need to interrupt ibrutinib therapy for invasive procedures due to bleeding risk 6 and may be non-adherent to their prescribed therapy.…”

Impact of ibrutinib dose intensity on patient outcomes in previously treated Waldenström macroglobulinemia

“…Temporary interruption of ibrutinib therapy was associated with transient increases in serum IgM level, and more than half of WM patients temporarily holding ibrutinib would experience disease progression based on current criteria [5]. However, a response is regained in virtually all cases at ibrutinib reinitiation, as previously reported [8]. The time to response after progression during a temporary hold appears longer for WM patients with the MYD88 MUT CXCR4 WHIM tumor genotype.…”

How I treat Waldenström macroglobulinemia

“…Ibrutinib is associated with a risk for atrial fibrillation (in ;10% to 12% of patients) 64 and hemorrhages (usually minor, but risk increases with anticoagulants), has several interactions with commonly used drugs (antibiotics, antiarrhythmics, etc), and requires continuous uninterrupted therapy. An ibrutinib withdrawal syndrome can occur, characterized by B symptoms and IgM rebound in ;20% of patients that interrupt ibrutinib for unrelated reasons 66,67 ; however, most patients recover on reinitiation and eventually reachieve IgM response. 67 Two new BTK inhibitors are tested in WM in phase 2 (acalabrutinib) or phase 3 (zanabrutinib compared with ibrutinib) studies.…”