Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia

Jeff P. Sharman, MD; Steven E. Coutre, MD; Richard R. Furman, MD; Bruce D. Cheson, MD; John M. Pagel, MD, PhD; Peter Hillmen, MBChB, PhD; Jacqueline C. Barrientos, MS, MD; Andrew D. Zelenetz, MD, PhD; Thomas J. Kipps, MD, PhD; Ian W. Flinn, MD, PhD; Paolo Ghia, MD, PhD; Herbert Eradat, MD; Thomas Ervin, MD; Nicole Lamanna, MD; Bertrand Coiffier, MD, PhD; Andrew R. Pettitt, MA, Mb, BChir, PhD; ShuoMa, MD, PhD; Eugen Tausch, MD; Paula Cramer, MD; Julie Huang, PhD; Siddhartha Mitra, MD, PhD; Michael Hallek, MD; Susan M. O'Brien, MD; Stephan Stilgenbauer, MD


J Clin Oncol. 2019;37(16):1391-1402. 

In This Article

Abstract and Introduction


Purpose: A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies.

Patients and Methods: Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety.

Results: The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases.

Conclusion: IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.


Chronic lymphocytic leukemia (CLL) is most prevalent in patients age 65 years or older, who often have comorbidities that include decreased renal or bone marrow function.[1–4] Treating such patients with chemotherapy is challenging because of an increased risk of toxicity that may complicate disease management.[2–4]

Idelalisib (IDELA) is a small molecule that targets the delta isoform of phosphoinositol 3-kinase (PI3Kδ) and inhibits PI3Kδ-dependent signaling, which leads to decreased activity of the AKT and mammalian target of rapamycin pathways and reduced survival of malignant B cells.[5,6] A randomized, double-blind, placebo-controlled phase III study evaluated the efficacy and safety of rituximab in combination with IDELA or placebo in patients with relapsed and refractory CLL who had notable comorbidities (cumulative illness rating scale score > 6, renal insufficiency, and/or poor bone marrow reserve) that precluded use of standard chemoimmunotherapy.[7] In August 2013, at the first prespecified interim analysis, the study was terminated because of the superior efficacy of IDELA plus rituximab (IDELA/R).[7] These results led to approval of IDELA in combination with rituximab for the treatment of patients with relapsed CLL.[8,9]

Upon primary study termination and unblinding, patients could transition to the extension study to receive open-label IDELA monotherapy. The focus of this report is the long-term efficacy and safety of IDELA in patients who received IDELA/R in the primary study and continued IDELA treatment in the extension study (IDELA/R-to-IDELA arm). In addition, we provide the final results from the primary, double-blinded study as an update to the previously published article.[7]