PracticeUpdate: Conference Series - EHA 2018

Consider Ibrutinib-Rituximab (IR) as Standard Therapeutic Option forWaldenstrom’s Macroglobulinemia Efficacy of the IR combination superior to that of rituximab alone

I brutinib-rituximab (IR) should be considered a standard therapeutic option for patients with Waldenstrom’s macroglobulinemia, according to new research findings presented at EHA 2018. Waldenstrom’s macroglobulinemia (WM) is a rare form of non-Hodgkin’s lymphoma that in Europe affects approximately 7.3 men and 4.2 women per million people. The causes of WM are unknown although it typically affects older adults and is slightly more common in men than women. Since WM is rare, it is difficult to conduct large clinical studies and determine a standard treatment for the disease. Ibrutinib, an oral, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for adults with WM and in the European Union for adults previously treated for WM or those with untreated WM who could not tolerate chemo- therapy. Single-agent ibrutinib is highly active in relapsed WM with reported progression-free survival (PFS) rates of 86% (at 18 months) and 69% (at 24 months). Rituximab, a therapy used to treat other types of blood cancer, is also effective and commonly used in treating WM by itself or in com- bination with other treatments. In this study, led by Meletios A. Dimopoulos, MD, with the National and Kapodistrian University of Athens School of Medicine in Greece, 150 patients with confirmed WM and symptomatic disease requiring treatment were randomized to daily ibrutinib (420 mg) or placebo, both with rituximab (375 mg/m 2 /week IV for infusions at weeks 1–4 and 17–20). The median age of study participants was 69 years, 45% were treatment-naive, and 38% had a high-risk score under the International Prognostic Scoring System for WM. Of the 150 patients, 136 had available mutation data. MYD88L265P and CXCR4WHIM mutations were identified by target exome sequencing assay in

85% and 36%, respectively. At a median follow-up of 26.5 months, IR significantly prolonged PFS compared with rituximab alone. The research team noted that this represented “a five-fold reduction in the risk of progression or death.” More patients had a major response rate to treat- ment with ibrutinib + rituximab (72%) than with placebo plus rituximab (32%). At 30 months after starting treatment, an estimated 82% of patients treated with IR were alive and did not have disease progression versus 28% of patients treated with placebo plus rituximab. Improvements in PFS were consistently reported in all relevant subgroups, including treatment-naive (HR 0.34; 95% CI 0.12–0.95), relapsed (HR 0.17; 95% CI 0.08–0.36), MYD88L265P/CXCR4WT (HR 0.17; 95% CI 0.06–0.49), MYD88L265P/CXCR4WHIM (HR 0.24; 95% CI 0.09–0.66), and MYD88WT/ CXCR4WT (HR 0.21; 95% CI 0.04–1.1). Overall (≥ MR) and major (≥ PR) response rates were significantly higher for IR vs R, 92% vs 47% (P < .0001) and 72% vs 32% (P < .0001), respectively. Improvements in hemoglobin were observed in 73% vs 41% of IR and R patients (P < .0001). Approximately 60% of patients in both treatment groups experienced at least one significant (grade ≥ 3) side effect; the most common grade ≥ 3 side effects with ibrutinib plus rituximab were high blood pressure and atrial fibrillation. However, ending treatment with ibrutinib or placebo because of side effects was uncommon (≤ 5% of patients in both treatment groups). The research team concluded that the efficacy of the ibrutinib plus rituximab combination was supe- rior to that of placebo plus rituximab, producing improvements in PFS for all WM patients regardless of prognostic or genotypic factors. The IR combi- nation was also determined to have a manageable toxicity profile and no new or unexpected adverse effects were observed. The findings presented at the EHA 2018 mirror find- ings from another study presented earlier this year at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously pub- lished in The New England Journal of Medicine . In that study, ibrutinib plus rituximab significantly reduced the risk of disease progression or death by 80% compared to placebo plus rituximab (HR 0.20; CI 0.11–0.38, P < .0001). In late 2017, the Independent Data Monitoring Committee (IDMC) recommended that based on these results the phase III iNNOVATE trial, which is evaluating IR in WM patients, should be unblinded.

" More patients had a major response rate to treatment with ibrutinib + rituximab (72%) than with placebo plus rituximab (32%). At 30 months after starting treatment, an estimated 82% of patients treated with IR were alive and did not have disease progression versus 28% of patients treated with placebo plus rituximab. "

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PRACTICEUPDATE CONFERENCE SERIES • EHA 2018 12