PracticeUpdate Oncology February 2019

EDITOR’S PICKS 6

Ibrutinib Regimens vs Chemoimmunotherapy in Older Patients With Untreated CLL The New England Journal of Medicine Take-home message • This phase III trial evaluated the efficacy of ibrutinib, either alone or in combina- tion with rituximab, compared with chemoimmunotherapy in patients aged ≥65 years with untreated chronic lymphocytic leukemia (CLL). Patients were randomly assigned to receive bendamustine plus rituximab (n=183), ibrutinib (n=182), or ibru- tinib plus rituximab (n=182). • Treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival (PFS). PFS was similar in the ibrutinib group and the ibrutinib plus rituximab group.

" The benefit of receiving treatment with ibrutinib or ibrutinib plus rituximab was particularly large in patients carrying a del17p abnormality. "

COMMENT By Isabel Cunningham MD T his study reports on 547 patients over 65 years old with de novo CLL requiring treatment, enrolled over 2.5 years in 219 North American sites. Patients were randomized among three arms: one of standard bendamustine/rituximab for 6 cycles, and the other two contained ibrutinib given until progression, with or without rituximab, for 6 cycles. The supe- rior PFS of the ibrutinib arms is elucidated in the Kaplan-Meier plot that shows that a remarkable divergence of both ibrutinib arms from the benda/ritux arm began very early and grew much larger after 2 years and larger still at years 3 and 4. This no doubt reflects the different durations of therapy: 6 cycles in the benda/ ritux arm and a median of 32 months of continuous ibrutinib in By Alessandra Ferrajoli MD D efining the best treatment for older patients with CLL is very relevant. As older people are an increasing propor- tion of the population, the number of individuals affected by CLL will increase in parallel. Older patients with cancer have historically been under-represented in clinical trials. Fortunately, this is not the case for patients with CLL, who, for many years, have been enrolled in clinical trials, some of which are specifi- cally designed for older patients. Woyach and colleagues reported the result of a large phase III trial evaluating three treatment options: bendamustine and ritux- imab (BR) given for six cycles, ibrutinib as monotherapy given indefinitely, and the combination of ibrutinib and rituximab (ibru- tinib given indefinitely and rituximab given for six cycles) as initial therapy for patients with CLL age 65 and older. The results of this trial are likely to be practice-changing because of a significantly longer progression-free survival (PFS) observed in the patients treated in both ibrutinib-containing arms (2-year estimated PFS was 74% in patients treated with BR vs 87% and 88% in patients treated with ibrutinib and ibrutinib plus rituximab). The benefit of receiving treatment with ibrutinib or ibrutinib plus rituximab was particularly large in patients carrying a del17p abnormality.

its two arms that maintains response. Despite the higher rate of overall response (determined by CT and physical exam) in the ibrutinib arms (93% vs 81%), it is noteworthy that complete remis- sion was achieved in only 7%, compared with 26% in the benda/ ritux arm. Only small numbers of patients achieved undetectable MRD: 1% in benda/ritux arm and 4% to 8% in the ibrutinib arms. This trial raises questions about whether rituximab adds anything to ibrutinib in untreated CLL, and whether and how a higher inci- dence of MRD can be achieved, with the potential that patients would not require ibrutinib to be taken indefinitely. Results from comparison with younger patients in a similar ongoing trial are anticipated. This is a subgroup of patients for whom treatment with ibrutinib has already been clearly shown in phase II studies to be asso- ciated with a superior outcome compared with treatment with chemotherapy. For patients without del17p (the majority of front-line patients), the findings of this study confirm the superiority of ibrutinib as initial treatment in older patients with CLL seen in the RESO- NATE-2 study. In the RESONATE-2 study, a superiority for the ibrutinib as monotherapy arm compared with chlorambucil was seen in terms of PFS, and, most importantly, in terms of overall survival. The study of Woyach and colleagues will likely need a longer observation time before a difference in survival can be detected. More treatment-related toxicities were observed in the BR arm, particularly myelosuppression; however, treating physicians should be familiar with the increased rate of atrial fibrillation and uncontrolled hypertension observed in patients undergoing treatment with ibrutinib. Dr. Ferrajoli is Professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas.

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