Patient-Reported Outcomes from Patients with Waldenström Macroglobulinemia Treated with Ibrutinib-Rituximab: Results from iNNOVATE Study

Purpose of the Study: For patients with Waldenström macroglobuli- nemia (WM), anemia and fatigue can impair quality of life. Ibrutinib is the only once-daily inhibitor of Brutons tyrosine kinase and is approved in the United States for the treatment of patients with WM as a single agent or in combination with rituximab. In patients with rituximab-refractory WM, treatment with single-agent ibrutinib resulted in meaningful improvements in patient-reported outcomes (PROs) (1). In the primary analysis of the iNNOVATE study (NCT02165397), patients treated with ibrutinib-rituximab had higher rates of sustained hemoglobin improvement and clinically meaningful improvements in PROs compared with patients treated with placebo-rituximab (2). Detailed data on PROs from the iNNOVATE study were prospectively collected to assess patients’ perspectives of the therapeutic benefit of ibrutinib-rituximab compared with placebo-rituximab, and the results are reported here.

Summarized Description of the Project: Patients with symptomatic WM requiring therapy were randomized into 2 arms to receive once daily 420 mg oral ibrutinib or placebo, in combination with rituximab (375 mg/m^2/week IV at weeks 14 and 1720). PRO measures included FACIT-Fatigue (FACIT-F), FACT-An total score (TS) and anemia subscale score (AS), and EQ-5D-5L (copyright EuroQol Research Foundation; EQ-5D is a trade mark of the EuroQol Research Foundation) visual analog scale (VAS) and utility score (US).

Results: A total of 150 patients (n=75/arm) were randomized to receive either ibrutinib-rituximab or placebo-rituximab. Patients had comparable baseline PRO scores across both arms. The most common reasons patients initiated therapy were fatigue (61%), constitutional symptoms (32%), and anemia (32%). A greater proportion of patients treated with ibrutinib-rituximab had clinically meaningful improvements in FACIT-F (69% vs 57%), TS (73% vs 59%), and AS (64% vs 48%) at a median follow-up of 26.5 months than patients treated with placebo-rituximab (Table). In both arms, there was a short (1-2 month) median time to PRO improvement. The Pearson correlation coefficients at  week  25 were 0.28, 0.29, and 0.26 for changes in hemoglobin levels versus changes in FACIT-F, TS, and AS, respectively, in the ibrutinib-rituximab arm; there were no meaningful correlations observed in the placebo- rituximab arm. For ibrutinib-rituximab, the correlation coefficients for changes in IgM versus changes in FACIT-F, TS, AS, and EQ-VAS were -0.32, -0.33, -0.35, and -0.26, respectively. For placebo-rituximab, the correlation coefficients for changes in IgM levels versus changes in FACIT-F and TS were 0.29 and 0.35, respectively.

Conclusion: The clinical response and improvements in anemia observed with ibrutinib-rituximab are consistent with more patients showing clinically meaningful improvements in PROs when treated with ibrutinib-rituximab compared with patients treated with placebo- rituximab. Changes in IgM were found to correlate with PRO improvements in patients treated with ibrutinib-rituximab.

References

1. Trotman, et al. EHA 2017; abstract 2766.

2. Dimopoulous, et al. NEJM. 2018; 378:2399-2410.