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Extended Phase 3 Results From RESONATE-2
A PFS
B PFSinthepresenceorabsenceofDel(11q)
C PFS with mutated vs. unmutated IGHV
HR (95% CI) P value
cough, anemia, and nausea (Online Supplementary Table S2). Grade ≥3 AEs were generally observed more fre- quently during the first 12 months of ibrutinib therapy and generally decreased over time (Figure 4). Rates of grade ≥3 cytopenias decreased over time from 8.1%, 5.9%, and 2.2% during the first year of treatment to 0%, 1%, and 0% during the third year of treatment for neu- tropenia, anemia, and thrombocytopenia, respectively.
Several AEs of clinical interest were characterized in greater detail (Table 3). Diarrhea generally occurred early in treatment (median, 26 days) and was completely reversible in 95% of patients within a median of 6 days. Visual disturbances (blurred vision or reduced visual acu- ity) were grade 1 or 2, with 57% of these completely resolving within a median of 37.5 days after onset. Hypertension occurred at a median of 187 days, with improvements reported at a median of 14 days after onset. Arthralgia was observed at a median of 135 days and was generally reversible (78% complete, 4% partial) within a
median duration of approximately 3 weeks. Atrial fibrilla- tion was observed throughout treatment follow up, with 4% of patients experiencing a grade 3 event. Symptoms of atrial fibrillation quickly resolved in the majority of patients (57% complete, 7% partial resolution) within a median of 3 days. Nine patients (7%) experienced a major hemorrhage occurring at a median of 310 days. Of these, 3 patients were reported to have active treatment with concomitant medications that impact platelets or coagula- tion (aspirin, low molecular weight heparin, and naprox- en, respectively) including a traumatic hematoma, post- procedural hematoma, and hematuria, all of which were grade 3 in severity and did not result in study drug discon- tinuation. Grade ≥3 infection occurred in 23% of patients at a median of 138 days, including 2 that were fatal (Klebsiella infection and septic shock). Grade ≥3 infections were observed most frequently in the first year of treat- ment and decreased thereafter (Figure 4). There were no cases of pneumocystis pneumonia or multifocal leukoen-
haematologica | 2018; 103(9)
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Figure 1. PFS for the intent-to-treat population. Survival analyses from ran- domization until event or censored at last follow up using the Kaplan-Meier method. Vertical ticks indicate censored patients. PFS: progression-free sur- vival.