Chronic Lymphocytic Leukemia: Ibrutinib Monotherapy
EHA 2017. S769. Long-term Efficacy and Safety with Ibrutinib in Previously Treated CLL: Up to Four Years Follow-up of the RESONATE Study
Byrd, John C et al.
Results: A total of 391 patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). The median age was 67 years, with 40% age ≥70 years, and Rai stage III/IV in 57% of patients. At a median follow-up of 44 months (maximum 53 months) for the ibrutinib arm, PFS was significantly longer for ibrutinib vs ofatumumab (median NR vs 8 months, [HR 0.133; P<0.0001]). The 3-year PFS was 59% for ibrutinib vs 3% for ofatumumab. A significant PFS benefit was observed across baseline subgroups. In the ibrutinib arm, PFS for the del11q subgroup trended to have the most favorable outcome; however, PFS outcomes were not statistically different for patients with del17p or del11q or patients without these FISH abnormalities. At time of analysis, with the majority of patients randomized to ofatumumab (68%) crossing over to receive ibrutinib therapy, OS was longer for ibrutinib vs ofatumumab (median OS NR for either arm). The 3-year OS rate for ibrutinib was 74%. The ORR for ibrutinib was 91% with a CR/CRi rate that increased over time (currently 9%). Baseline cytopenias improved with extended ibrutinib therapy for hemoglobin (85% of patients), platelet (95% of patients), and absolute neutrophil counts (95% of patients). The adverse event (AE) profile of ibrutinib was consistent with previous reports. During a follow-up of up to 4 years, major hemorrhage occurred in 6%, grade ≥3 atrial fibrillation occurred in 6%, and grade ≥3 hypertension occurred in 8% of patients. The incidence of most grade ≥3 AEs decreased from year 1 vs year 2-3: neutropenia: 18% vs 8%; pneumonia: 11% vs 4%; atrial fibrillation: 4% vs 2%, respectively. The most frequent reasons for treatment discontinuation were progressive disease (27%) and AEs (12%). At analysis, 90 patients randomized to ibrutinib (46%) continue to receive ibrutinib.
Conclusion: In this international phase 3 RESONATE study with median follow-up of up to 4 years, long-term treatment with ibrutinib showed a favorable tolerability profile with sustained PFS and OS benefit regardless of high-risk cytogenetics. The results in relapsed del17p and del11q patients compared favorably to those previously reported in phase 2 studies.
Clinical trial information: NCT01578707
CARE Faculty Perspective: Ibrutinib improves long-term survival outcomes, especially in patients with relapsed/refractory CLL who are not eligible for chemotherapy approaches.
This phase 3 RESONATE trial confirmed these positive survival effects in terms of PFS and OS, while maintaining a favourable tolerability profile. Furthermore, at the recent International Workshop on Chronic Lymphocytic Leukemia, pooled data from the RESONATE, RESONATE-2, and HELIOS trials were presented. Ibrutinib achieved higher CR rates, ORR rates, PFS, and OS when compared with other agents. This pooled analysis confirms the data from the original studies and highlights the efficacy of ibrutinib as monotherapy or as part of a combination.
Access & Innovation Considerations - The main concerns with ibrutinib use relate to toxicities that may limit its use or lead to the introduction of alternative therapies. Ibrutinib resistance is another clinical challenge. A better understanding of the mechanisms of resistance to monotherapy and combination strategies as well more in depth understanding of the effects of ibrutinib on immune effectors will be of benefit for practicing clinicians.