Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia

Abstract

PURPOSE We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM). PATIENTS AND METHODS Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity. RESULTS The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL ( P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88Mut, wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88Mut CXCR4Mut. Conversely, four patients who had MYD88WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with MYD88Mut CXCR4WT and MYD88Mut CXCR4Mut WM, respectively ( P = .02). In patients with MYD88WT, the median PFS was 0.4 years ( P < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management. CONCLUSION Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.

Cell‐free DNA analysis for detection of MYD88L265P and CXCR4S338X mutations in Waldenström macroglobulinemia

“…1,2 The presence of mutated MYD88 is associated with a decreased risk of histological transformation, longer overall survival, and sensitivity to ibrutinib. 3,4 Over 40 nonsense and frameshift CXCR4 variants have been identified in WM patients. 5,6 Nonsense CXCR4 S338X variants are the most common, occurring in 50% of WM patients due to C > A or C > G nucleotide transversions.…”

First Report of Eltrombopag Induced Severe Autoimmune Hemolytic Anemia in the Management of Waldenström Macroglobulinemia-associated Autoimmune Thrombocytopenia

“…However, no clear drug was found after searching published literatures and from our experience. According to the patient's preference, ibrutinib single treatment was initiated, which may be bene cial for the primary disease as well as secondary ITP and AIHA [14][15][16] . As expected, the thrombocytopenia was quickly resolved, and became transfusion independent, but the AIHA did not resolved and even worsen, which further indicated that the AIHA was not WM-related.…”

Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy

“…10 Ibrutinib monotherapy was highly active with an overall response rate (ORR) of 91%, major response rate (MRR) of 79%, and very good partial response rate (VGPR) of 30% with prolonged follow-up. 10,11 Responses to ibrutinib were durable with an estimated 5-year progression-free survival (PFS) and overall survival (OS) of 54% and 87%, respectively. A notable finding was the impact of MYD88 and CXCR4 mutations on ibrutinib outcomes.…”

“…Patients wildtype (WT) for both MYD88 and CXCR4 had no major responses and a median PFS of 5 months to ibrutinib. [10][11][12] Among patients with mutated MYD88, the concurrent presence of a CXCR4 mutation adversely impacted response rates, response kinetics, and 5-year PFS (38% vs. 70%). 10,11 Similar outcomes to ibrutinib monotherapy have been reported in phase 2 trials of treatment-naïve (n=30) and rituximab-refractory WM patients (n=31), as well as in the recent phase 3 ASPEN trial (n=199) comparing ibrutinib to zanubrutinib.…”

“…[10][11][12] Among patients with mutated MYD88, the concurrent presence of a CXCR4 mutation adversely impacted response rates, response kinetics, and 5-year PFS (38% vs. 70%). 10,11 Similar outcomes to ibrutinib monotherapy have been reported in phase 2 trials of treatment-naïve (n=30) and rituximab-refractory WM patients (n=31), as well as in the recent phase 3 ASPEN trial (n=199) comparing ibrutinib to zanubrutinib. [13][14][15][16] Despite the high response rates and durable remissions, acquired ibrutinib resistance is increasingly being observed in WM patients.…”