PracticeUpdate Conference Series ASH 2018

experienced a thrombotic event after discontinuing rivaroxaban therapy. “Pending confirmation by a second, similarly designed trial, these findings could lead to a change in guidelines regarding primary prevention of VTE in cancer patients initiating systemic ther- apy,” Dr. Khorana concluded. Risk of major bleeding, the primary safety endpoint, was not significantly different between treatment groups; major bleed- ing occurred in 8 of 405 patients (1.98%) in the rivaroxaban group and in 4 of 404 patients (0.99%) in the placebo group

standard-of-care FCR therapy (HR 0.352; 95% CI 0.223–0.558, P < .0001). The hazard ratio for OS, a prespecified secondary endpoint, also significantly favored therapy with ibrutinib plus ritux- imab (HR 0.168; 95% CI 0.053–0.538, P = .0003). A further subgroup analysis revealed that, in terms of PFS, ibrutinib plus ritux- imab offered superior outcomes to FCR therapy independent of patient age, sex, performance status, disease stage, or the presence or absence of the del11q23 mutation. However, patients with the IGHV mutation did not experience significantly better PFS outcomes when treated ibruti- nib plus rituximab therapy (HR 0.435; 95% CI 0.140–0.1350, P = .07). “These findings have immediate prac- tice-changing implications,” study presenter Tait D. Shanafelt, MD, of the Stanford University School of Medicine in Stanford said during a press briefing. “They establish the combination of ibru- tinib plus rituximab as the most effective The primary efficacy endpoint occurred within the 180-day observation period in 25 of 420 patients who received rivar- oxaban (5.95%) and in 37 of 421 patients receiving placebo (8.79%), resulting in a number needed to treat of 35 (HR 0.66; 95% CI 0.40–1.09, P = .101). According to Dr. Khorana, the primary endpoint lacked statistical power in the intention-to-treat group because many patients discontinued therapy prior to the prespecified 180 days. Indeed, as many as half of those given placebo and nearly 44% of those assigned to receive rivaroxaban discontinued therapy before completing the 180-day regimen. A prespecified analysis that sought to detect the primary composite endpoint during the on-treatment period detected significant differences between the rivar- oxaban and control groups; whereas 11 of 420 patients receiving rivaroxaban (2.62%) experienced the primary endpoint within the on-treatment period, 27 of 421 patients receiving placebo (6.41%) did (HR 0.40; 95% CI 0.20–0.80, P = .007). This translated to a number needed to treat of 26. Taken together, Dr. Khorana said these results suggest rivaroxaban is likely to remain effective so long as patients continue to remain adherent to therapy. As many as 38.7% of patients with VTE

(HR 1.96; 95% CI 0.59–6.49, P = .265). The number needed to harm was 101. Incidence of clinically relevant non-major bleeding also did not significantly differ between treatment groups (HR 1.34; 95% CI 0.54–3.32, P = .53). In this context, the number needed to harm was 135. “With any blood thinner, safety is an issue,” Dr. Khorana told Elsevier’s PracticeUpdate . “We only saw a low incidence of major and non-major bleeding events, and no substantial concern for additional adverse events.”

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first-line treatment for CLL patients age 70 and younger.” Treatment-related adverse events of grades 3 and 4 occurred in 58% of patients receiving ibrutinib plus rituximab therapy and 72% of patients receiving FCR therapy (P = .0042). In particular, both neutropenia (23% vs 44%, P < .0001) and infectious complications (7.1% vs 17.7%, P < .0001) were significantly less common in patients receiving ibrutinib plus rituximab therapy, compared with those receiving FCR standard-of-care therapy. “With respect to side effects, I would emphasize that the new therapy was also less toxic than our historical cancer therapy,” said Dr. Shanafelt. “So, obviously, in cancer trials, as physicians we want to improve the effectiveness of treatment or

reduce its side effects. This trial is one of the rare circumstances where we’ve done both with a single therapy.” Despite the promise offered by a shift to ibrutinib-based therapy, a possible limita- tion to putting these results into practice is the high cost of ibrutinib: Dr. Shanafelt questioned whether the lack of afforda- bility of ibrutinib at nearly USD $10,000 in the United States for a 1-month sup- ply would make it difficult for patients to remain adherent to therapy over the long term. He said that two upcoming clinical trials, EA9161 and A041702, will be “evaluating combination strategies to determine if the need for indefinite therapy can be eliminated” for patients taking ibrutinib.

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ASH 2018 • PRACTICEUPDATE CONFERENCE SERIES 17