Idelalisib in Combination With Rituximab or Bendamustine or Both in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

Abstract

Phosphatidylinositol 3-kinase-delta (PI3Kδ) signaling is critical for proliferation, survival, homing, and tissue retention of malignant B cells. Idelalisib, a selective oral inhibitor of PI3Kδ, has shown considerable single-agent activity in patients with heavily pretreated chronic lymphocytic leukemia (CLL). This study evaluated the safety and clinical activity of idelalisib in combination with bendamustine (IB) or rituximab (IR) or both (IBR) in patients with relapsed or refractory (R/R) CLL. Idelalisib was given continuously at 100 or 150 mg twice daily in combination with rituximab (375 mg/m2 weekly × 8 doses), bendamustine (70 or 90 mg/m2, days 1 and 2 every 4 weeks × 6 cycles) or BR (rituximab, 375 mg/m2 every 4 weeks and bendamustine, 70 mg/m2, days 1 and 2 every 4 weeks × 6 cycles). The primary endpoint was safety; secondary endpoints included overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Fifty-two patients (median age 64 years) with a median of 3 prior therapies were enrolled. ORR was 84.6% (89.5% IR group, 77.8% IB group, and 86.7% IBR group). The overall median PFS was 25.6 months, and median DOR was 26.6 months. The most common grade ≥3 adverse events (≥10% of patients) were pneumonia (19.2%), diarrhea (13.5%), and febrile neutropenia (17.3%). Idelalisib-based combination therapy with bendamustine and/or rituximab was highly active, resulting in durable tumor control in patients with heavily pretreated R/R CLL. However, its tolerability profile suggests that these regimens should be used cautiously in this patient population. ClinicalTrials.gov ID: NCT01088048.

Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.

Figures

Figure 1

The design of the primary and extension studies examining the efficacy and safety of idelalisib in combination with rituximab and/or bendamustine in patients with R/R CLL. B = bendamustine, BID = twice daily, C = cycles, CLL = chronic lymphocytic leukemia, D = day, R = rituximab.

Figure 2

Best on-treatment change in lymph-node area by patient for combined primary and extension studies. The overall mean lymph-node response compared with baseline was −73.2%. aCriterion for lymphadenopathy response according to Hallek et al. Shaded bars represent the presence of del(17p) or TP53 mutation; black bars represent patients without a follow-up tumor assessment (unevaluable). IB = idelalisib plus bendamustine, IBR = idelalisib plus bendamustine plus rituximab, IR = idelalisib plus rituximab, SPD = sum of the product of the greatest perpendicular diameters of measured lymph nodes.

Figure 3

Overall response rates (intent-to-treat analysis) for combined primary and extension studies. Response according to International Workshop on Chronic Lymphocytic Leukemia criteria. CI = confidence interval, IB = idelalisib plus bendamustine, IBR = idelalisib plus bendamustine plus rituximab, IR = idelalisib plus rituximab, mut = mutation.

Figure 4

(A) Overall DOR for combined primary and extension studies. Median DOR was 26.6 months (N = 44). Extension study assessments based on standard of care. (B) DOR in patients with (thick line) or without (thin line) del(17p)/TP53 mutations. Median DOR was 18.5 months for patients with del(17p) and/or TP53 mutations (n = 8) and 40.6 months for patients without del(17p)/TP53 mutations (n = 33). DOR = duration of response.

Figure 5

(A) Overall PFS for combined primary and extension studies. Median PFS was 25.6 months (N = 52). Extension study assessments based on standard of care. (B) PFS in patients with (thick line) or without (thin line) del(17p)/TP53 mutations. Median PFS was 19.9 months for patients with either del(17) or TP53 mutations (n = 11) and 36.8 months for patients without del(17p)/TP53 mutations (n = 38). PFS = progression-free survival.