Oncology

Chronic Lymphocytic Leukemia

Optimal Sequencing of Novel Agents for Chronic Lymphocytic Leukemia

clinical study insights by Anthony R. Mato, MD, MSCE

Overview

Clinical Study Title: Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in Chronic Lymphocytic Leukemia: Results From a Multicenter Study of 683 Patients

Clinical Study Abstract: BACKGROUND: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.

PATIENTS AND METHODS: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).

RESULTS: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1–60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3–6.3, P =0.01], relapsed-refractory (HR 2.8, CI 1.9–4.1, P<0.001), del17p (HR 2.0, CI 1.2–3.4, P=0.008), and complex karyotype (HR 2.5, CI 1.2–5.2, P=0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3–1.0, P=0.06).

CONCLUSIONS: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Reference: Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050-1056.

Expert Commentary

Anthony R. Mato, MD, MSCE

Director, Chronic Lymphocytic Leukemia Program Associate Attending, Memorial Sloan Kettering Cancer Center New York, NY

We are fortunate to have novel therapies for chronic lymphocytic leukemia (CLL), which include ibrutinib, idelalisib, and venetoclax, and we are now focused on learning more about the optimal sequencing of these agents. We have some prospective data for venetoclax, in the post-KI setting, demonstrating high response rates in patients who progressed on ibrutinib or idelalisib, with approximately 70% to 80% PFS at 1 year. The sequencing of therapies is a challenging topic for us at this juncture, however, because much of the data that might speak to the most effective sequencing strategies come from retrospective comparisons. There are currently 2 KIs that are US Food and Drug Administration–approved for use in the treatment of adults with CLL: idelalisib for relapsed/refractory disease and ibrutinib in various treatment settings. Acalabrutinib is a newer KI that has been approved for patients with mantle cell lymphoma who have had at least 1 prior therapy. We have done some work with retrospective data sets, as reflected in the above-mentioned multicenter study of 683 patients that attempted to compare ibrutinib- versus idelalisib-based therapies. We found that the outcomes seem to favor ibrutinib in first-line settings, relapsed/refractory settings, and high-risk patients, despite a higher ORR observed with idelalisib-rituximab.

“We have done some work with retrospective data sets, as reflected in the above-mentioned multicenter study of 683 patients that attempted to compare ibrutinib- versus idelalisib-based therapies. We found that the outcomes seem to favor ibrutinib in first-line settings, relapsed/refractory settings, and high-risk patients, despite a higher ORR observed with idelalisib-rituximab.”

Anthony Mato, MD, MSCE

Sorensen and colleagues have reported the results of their retrospective analysis of ibrutinib versus idelalisib plus ofatumumab in patients with relapsed or refractory CLL, and these data also seem to favor ibrutinib. However, the findings should be taken with caution in that these are not randomized comparisons, and this underscores the need for trials that test sequencing strategies to optimize treatment algorithms.

In summary, data to guide the selection of a first KI for patients in the relapsed/refractory setting are limited. In the front-line setting, it is an easier question to answer because ibrutinib is indicated for first-line use in adults with CLL while idelalisib is not.

“In summary, data to guide the selection of a first KI for patients in the relapsed/refractory setting are limited. In the front-line setting, it is an easier question to answer because ibrutinib is indicated for first-line use in adults with CLL while idelalisib is not.”

Anthony Mato, MD, MSCE

References

Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131(15):1704-1711.

Hallek M, Cheson BD, Catovsky D, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018 Mar 14. pii: blood-2017-09-806398. doi: 10.1182/blood-2017-09-806398. [Epub ahead of print]

Hallek M, Shanafelt TD, Eichhorst B. Chronic lymphocytic leukaemia. Lancet. 2018;391(10129):1524-1537.

O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910-1919.

Sorensen S, Wildgust M, Sengupta N, et al. Indirect treatment comparisons of ibrutinib versus physician’s choice and idelalisib plus ofatumumab in patients with previously treated chronic lymphocytic leukemia. Clin Ther. 2017;39(1):178-189.e5.

Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768-778.