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

Abstract

Summary Background Bendamustine and rituximab (BR) has been a standard of care for the management of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We evaluated the efficacy and safety of adding idelalisib, a first-in-class targeted PI3Kδ inhibitor, to BR in patients with R/R CLL Methods This trial was a global, multicenter, double-blind, placebo -controlled trial in adult patients (≥18 years) with R/R CLL requiring treatment for their disease. Patients had to have measurable lymphadenopathy (≥1 nodal lesion ≥2.0 cm in the longest diameter and ≥1.0 cm in the longest perpendicular diameter) by computer tomography or magnetic resonance imaging, disease progression within <36 months since last prior therapy, a Karnofsky Performance Status score ≥60 and adequate bone marrow, liver and kidney function. Key exclusion criteria included histological transformation to an aggressive lymphoma (eg, Richter transformation) or disease refractory to bendamustine. Patients were randomised 1:1 using a central interactive web response system that assigned a unique treatment code for each patient, to receive intravenous BR infusions for a maximum of 6 cycles in addition to blinded study drug matching the assigned treatment of either twice-daily oral idelalisib 150 mg or placebo administered continuously until disease progression or intolerable study drug-related toxicity. Randomisation was stratified based on high-risk features (IGHV, del(17p)/TP53 mutation) and refractory vs relapsed disease. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee in the intent-to-treat population. Overall survival was a key secondary endpoint. Crossover was not permitted to the idelalisib arm at progression. The trial is ongoing (ClinicalTrials.gov # NCT01569295). Findings Between 26 June 2012 and 21 August 2014, 416 patients with R/R CLL were enrolled; 207 patients were randomised to the idelalisib and 209 to the placebo arm. After the prespecified interim analysis, the Independent Data Monitoring Committee (IDMC) recommended discontinuation and unblinding of the trial due to efficacy. Updated data are presented in this manuscript with a cutoff date of 07 October 2015. Median (95% CI) PFS was 20·8 (16·6, 26·4) and 11·1 (8·9, 11·1) months in the idelalisib and placebo arms, respectively (hazard ratio [HR], 0·33; 95% CI, 0·25, 0·44; P<0·0001) at a median (Q1, Q3) follow-up of 14 (7, 18) months. The most frequent grade 3 or greater AEs were neutropenia (124/207 [60%]) and febrile neutropenia (48/207 [23%]) in the idelalisib arm and neutropenia (99/209 [47%]) and thrombocytopenia (27/209 [13%]) in the placebo arm. Serious AEs included febrile neutropenia, pneumonia and pyrexia and were common in both treatment arms. An increased risk of infection was observed in the idelalisib vs placebo arm. Interpretation Idelalisib plus BR is superior to BR alone, improving PFS and OS. This regimen represents an important new treatment option for patients with R/R CLL.

The PI3K Pathway in Human Disease

“…Additional concerns arose following regulatory approval of idelalisib, when some patients developed fatal infections. A phase 3 study of idelalisib with bendamustine and rituximab also reported an increased risk of infection including some deaths (Zelenetz et al, 2017). It is reasonable to propose that the infection risk is due to impaired CD4 + and CD8 + effector T cell differentiation.…”

Idelalisib for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

“…Improvements in lymphadenopathy were observed with idelalisib + B ± R in individual patients with these high-risk genetic abnormalities (Figure 2). Idelalisib also demonstrated clinical activity in patients with del(17p) in the Phase III registrational trial [27,53] and in a variety of highrisk patient subgroups in the Phase III trial of idelalisib + BR [51]. These findings suggest that idelalisib would be a reasonable consideration in patients with del(17p) unable to tolerate ibrutinib or venetoclax therapy, or after failure or progression of disease.…”

“…+ BR versus placebo + BR in 416 patients with relapsed/refractory CLL [51]. The study was unblinded when a prespecified interim analysis showed compelling evidence of effectiveness.…”

Idelalisib at the Crossroads of B-Cell Lymphoproliferative Disorders.

“…5,6,[8][9][10][11][12][13][14][15][16][17] Recently published mature results of the initial treatment of CLL with idelalisib plus rituximab demonstrated that the combination is extremely effective with manageable toxicity in older CLL patients. 15,18 O'Brien et al presented the first clinical trial of idelalisib with rituximab for the initial therapy of CLL in patients with a median age of 71 years, 42% of whom had advanced-stage disease.…”