Impact of Ibrutinib Dose Intensity on Patient Outcomes in Previously Treated Waldenström Macroglobulinemia

Introduction: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib recently became the first approved therapy for patients with symptomatic Waldenstrom macroglobulinemia (WM). Temporary interruption of therapy is recommended to manage treatment-related toxicities and when patients undergo invasive procedures. However, the impact of interrupted therapy with ibrutinib has not been evaluated in patients with WM. We therefore examined the clinical implications of dose intensity in previously treated WM patients treated with ibrutinib in the multicenter phase 2 trial supporting regulatory approval. Methods: Patient charts were retrospectively analyzed and pertinent clinical data were collected surrounding ibrutinib drug holds. Treatment adherence to ibrutinib was documented during the clinical trial, and was measured by overall dose intensity (DIoverall). DI was defined as the proportion of administered versus planned doses from initiation of therapy until last dose received. Response was assessed based on current criteria. Time to events was estimated using the Kaplan-Meier method and comparisons between groups were made using the log-rank test. Results: Sixty-three patients with WM were enrolled and began therapy with ibrutinib 420 mg once daily. Fifty patients (79%) held ibrutinib at least once, and there were 102 drug-hold events in total. The median drug hold length was 6 days (range, 2-50 days). An increase in serum IgM level was observed on 63 occasions at the next response assessment after a drug hold. The median increase in serum IgM level was 50% (range, 4-555%), and 37 increases (59%) met criteria for progressive disease (PD). Following the reinitiation of ibrutinib, the median time to a response of stable disease (SD) or better was 125 days (95% CI 109-186 days) for patients who met PD criteria, and was significantly longer for patients with the MYD88MUTCXCR4WHIM versus MYD88MUTCXCR4WT tumor genotype (207 vs. 101 days; p 0.05 for all comparisons). Overall PFS was significantly shorter in patients with low DIoverall versus high DIoverall (median, 22 months vs. not reached [NR]; p=0.008). The mean DIoverall for patients with MYD88MUTCXCR4WT (n=37), MYD88MUTCXCR4WHIM (n=21), and MYD88WTCXCR4WT (n=5) tumor genotype was 99%, 95%, and 99%, respectively. A subgroup analysis demonstrated a significant difference in PFS for MYD88MUTCXCR4WHIM patients with low DIoverall versus high DIoverall (median, 9.4 months vs. NR; p=0.0003), whereas no difference was observed in MYD88MUTCXCR4WT and MYD88WTCXCR4WT patients (p>0.05 for both comparisons). Twenty-five patients missed ³8 consecutive days of ibrutinib therapy. Among patients who held ibrutinib, those who missed doses for ³8 consecutive days experienced a shorter PFS compared to patients who missed Conclusion: Temporary interruption of ibrutinib therapy is associated with transient increases in serum IgM level which appear to persist longer for patients with the MYD88MUTCXCR4WHIM tumor genotype. Patients with DI higher than 97% had longer PFS, and holding ibrutinib >1 week during the entire treatment duration was associated with increased PFS events. These findings suggest ibrutinib holds should be minimized and ibrutinib restarted as soon as clinically indicated to achieve optimal patient outcomes. Disclosures Treon: Pharmacyclics: Consultancy, Research Funding. Castillo: Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding.