Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
, 18 (3), 297-311

Idelalisib or Placebo in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukaemia: Interim Results From a Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial

Affiliations
Clinical Trial

Idelalisib or Placebo in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukaemia: Interim Results From a Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial

Andrew D Zelenetz et al. Lancet Oncol.

Abstract

Background: Bendamustine plus rituximab is a standard of care for the management of patients with relapsed or refractory chronic lymphocytic leukaemia. New therapies are needed to improve clinically relevant outcomes in these patients. We assessed the efficacy and safety of adding idelalisib, a first-in-class targeted phosphoinositide-3-kinase δ inhibitor, to bendamustine plus rituximab in this population.

Methods: For this international, multicentre, double-blind, placebo-controlled trial, adult patients (≥18 years) with relapsed or refractory chronic lymphocytic leukaemia requiring treatment who had measurable lymphadenopathy by CT or MRI and disease progression within 36 months since their last previous therapy were enrolled. Patients were randomly assigned (1:1) by a central interactive web response system to receive bendamustine plus rituximab for a maximum of six cycles (bendamustine: 70 mg/m2 intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2-6) in addition to either twice-daily oral idelalisib (150 mg) or placebo until disease progression or intolerable study drug-related toxicity. Randomisation was stratified by high-risk features (IGHV, del[17p], or TP53 mutation) and refractory versus relapsed disease. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01569295.

Findings: Between June 26, 2012, and Aug 21, 2014, 416 patients were enrolled and randomly assigned to the idelalisib (n=207) and placebo (n=209) groups. At a median follow-up of 14 months (IQR 7-18), median progression-free survival was 20·8 months (95% CI 16·6-26·4) in the idelalisib group and 11·1 months (8·9-11·1) in the placebo group (hazard ratio [HR] 0·33, 95% CI 0·25-0·44; p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib group were neutropenia (124 [60%] of 207 patients) and febrile neutropenia (48 [23%]), whereas in the placebo group they were neutropenia (99 [47%] of 209) and thrombocytopenia (27 [13%]). An increased risk of infection was reported in the idelalisib group compared with the placebo group (grade ≥3 infections and infestations: 80 [39%] of 207 vs 52 [25%] of 209). Serious adverse events, including febrile neutropenia, pneumonia, and pyrexia, were more common in the idelalisib group (140 [68%] of 207 patients) than in the placebo group (92 [44%] of 209). Treatment-emergent adverse events leading to death occurred in 23 (11%) patients in the idelalisib group and 15 (7%) in the placebo group, including six deaths from infections in the idelalisib group and three from infections in the placebo group.

Interpretation: Idelalisib in combination with bendamustine plus rituximab improved progression-free survival compared with bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukaemia. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection.

Funding: Gilead Sciences Inc.

Figures

Figure 1
Figure 1
Study disposition. AE, adverse event; BR, bendamustine and rituximab.
Figure 2
Figure 2
Progression-free and overall survival. (A) PFS at a median follow-up of 12 months. (B) Forest plot of hazard ratios for PFS by prespecified subgroups. (C) OS. (D) Forest plot of hazard ratios for OS by prespecified subgroups. An Independent Review Committee adjudicated disease progression. BR, bendamustine and rituximab; CI, confidence interval; NR, not reached; OS, overall survival; PFS, progression-free survival.
Figure 2
Figure 2
Progression-free and overall survival. (A) PFS at a median follow-up of 12 months. (B) Forest plot of hazard ratios for PFS by prespecified subgroups. (C) OS. (D) Forest plot of hazard ratios for OS by prespecified subgroups. An Independent Review Committee adjudicated disease progression. BR, bendamustine and rituximab; CI, confidence interval; NR, not reached; OS, overall survival; PFS, progression-free survival.
Figure 3
Figure 3
Kaplan-Meier curves of PFS for patients with (A) neither del(17p) or TP53 (B) either del(17p) nor TP53 mutations BR, bendamustine and rituximab; CI, confidence interval; PFS, progression-free survival.
Figure 3
Figure 3
Kaplan-Meier curves of PFS for patients with (A) neither del(17p) or TP53 (B) either del(17p) nor TP53 mutations BR, bendamustine and rituximab; CI, confidence interval; PFS, progression-free survival.
Figure 4
Figure 4
Nodal response to treatment by patient. Response assessed by computed tomography scan according to standard criteria and adjudicated by an Independent Review Committee. BR, bendamustine and rituximab; SPD, sum of the products of the perpendicular diameters of measured lymph nodes.

Comment in

Similar articles

See all similar articles

Cited by 47 articles

See all "Cited by" articles

References

    1. National Comprehensive Cancer Network. [Accessed 2016 Jan 20];NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Lymphomas. Version 1. 2016 Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.
    1. Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007;25:799–804. - PubMed
    1. Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010;28:4473–9. - PubMed
    1. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–6. - PubMed
    1. Hallek M. Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. Am J Hematol. 2015;90:446–60. - PubMed

Publication types

MeSH terms

Associated data

Feedback