Background: Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) that has demonstrated activity in relapsed Waldenström’s macroglobulinemia (WM). Single-agent ibrutinib is approved in the United States and Europe for WM.
Objectives: To evaluate the efficacy and safety of ibrutinib/rituximab versus placebo/rituximab in WM; to educate nurses on the role of BTK inhibitors in WM and provide guidance on adverse event (AE) management during ibrutinib treatment.
Methods: Patients had confirmed, symptomatic WM, and patients who had received prior rituximab therapy were required to have had a minor response (MR) or better to their last rituximab therapy. Patients were randomized to receive daily ibrutinib (420 mg orally) or placebo. All patients received rituximab (375 mg/m2/week IV at weeks 1-4 and 17-20). The primary end point was progression-free survival (PFS) by independent review committee assessment. Additional end points included response rates, hemoglobin improvement, time to next treatment (TTnT), overall survival (OS), and safety.
Results: Among the 150 patients treated, the median age was 69 years; 45% of patients were treatment-naive, and 38% had a high score on the International Prognostic Scoring System for WM. Of the 136 patients with genetic data, 85% and 36% had MYD88 L265P and CXCR4 WHIM mutations, respectively. PFS was longer with ibrutinib/rituximab versus placebo/rituximab at a median follow-up of 26.5 months (median PFS, not reached [NR] vs 20 months; hazard ratio [HR] 0.20; CI, 0.11-0.38, P <.0001). Estimated 30-month PFS rates were 82% with ibrutinib/rituximab and 28% with placeob/rituximab. PFS was prolonged across patient subgroups, including treatment-naive (HR 0.34; CI, 0.12-0.95) and relapsed (HR 0.17; CI, 0.08-0.36) patients, and across different MYD88/CXCR4 genotypes. More patients achieved a MR or better with ibrutinib/rituximab versus placebo/rituximab (92% vs 47%; P <.0001), and more patients had a partial response or better with ibrutinib/rituximab (72% vs 32%; P <.0001). Improved hemoglobin was observed in more patients treated with ibrutinib/rituximab (73%) than placebo/rituximab (41%; P <.0001). Among patients who received ibrutinib/rituximab, 75% continued on treatment. Median TTnT was NR and 18 months with ibrutinib/rituximab and placebo/rituximab, respectively (HR 0.096; P <.0001); 30-month OS rates were 94% and 92%. The rate of grade ≥3 treatment-emergent AEs was similar between treatment arms (60% vs 61%) at a median time on treatment of 25.8 months for ibrutinib/rituximab patients. Serious AEs occurred in 43% of patients on ibrutinib/rituximab and 33% of patients on placebo/rituximab. No fatal AEs occurred with ibrutinib/rituximab versus 3 with placebo/rituximab. Among patients receiving ibrutinib/rituximab, meaningful reductions in grade ≥3 infusion reactions (1% vs 16%) and in any grade IgM flare (8% vs 47%) were observed versus placebo/rituximab. Additional guidance and strategies on managing AEs with ibrutinib will be presented.
Conclusions: Ibrutinib/rituximab showed improved efficacy compared with placebo/rituximab, including significant benefits to PFS, regardless of prognostic/genotypic factors. The combination had a predictable toxicity profile. Nurse navigators are key to providing guidance on managing ibrutinib-related AEs to patients and establishing a follow-up care plan. They also play a role in educating patients on the benefits of oral, once-daily ibrutinib.
Supported by Pharmacyclics LLC, an AbbVie Company.
