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Adding Idelalisib to Bendamustine/Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia

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Key Points

  • Adding idelalisib to bendamustine/rituximab improved progression-free and overall survival in patients with relapsed or refractory CLL.
  • Febrile neutropenia and infections were more common with idelalisib.

As reported by Zelenetz et al in The Lancet Oncology, an interim analysis of a phase III trial has shown the superiority of adding the phosphoinositide-3-kinase δ inhibitor idelalisib (Zydelig) to bendamustine/rituximab (Rituxan) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Study Details

In the double-blind trial, 416 patients from 110 sites in 19 countries including the United States were randomized between June 2012 and August 2014 to receive bendamustine at 70 mg/m2 on days 1 and 2 for six 28-day cycles plus rituximab at 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2–6 with either twice-daily oral idelalisib at 150 mg (n = 207) or placebo (n = 209) until disease progression or intolerable toxicity. Patients had to be aged ≥18 years with measurable lymphadenopathy by computed tomography or magnetic resonance imaging and disease progression within 36 months since the last previous therapy.

Randomization was stratified by high-risk features (IGHV, del[17p], or TP53 mutation) and refractory vs relapsed disease. The primary endpoint was progression-free survival on independent review committee assessment in the intention-to-treat population.

For the idelalisib vs control groups: median age was 62 vs 64 years; 77% vs 75% were men; 90% vs 91% were white; median time since diagnosis was 74 vs 75 months; Rai stage was 0, I, II, III, and IV in 1% vs 2%, 19% vs 20%, 29% vs 34%, 10% vs 8%, and 40% vs 33%; the median number of previous regimens was 2 in both (range = 1–4 in both); 16% vs 18% were refractory to fludarabine; ≤ 1% had not received an anti-CD20 antibody; prior treatments included fludarabine-containing regimens in 93% vs 90%; disease status was relapsed in 66% vs 68% and refractory in 34% vs 33%; and genetic risk markers were del(17p) in 18% vs 19%, no del(17p) in 82% vs 81%, del(17p) or TP53 mutation in 33% vs 33%, and unmutated IGHV in 84% vs 83%.

Improved Progression-Free Survival and Other Outcomes

A prespecified interim efficacy analysis performed with data cutoff in June 2015, when the median duration of follow-up was 11 months and 75% of the prespecified 260 progression-free survival events had occurred, resulted in the recommendation by the independent data monitoring committee to halt and unblind the study on the basis of high efficacy of idelalisib.

At updated analysis at a median follow-up of 14 months, median progression-free survival was 20.8 months (95% confidence interval [CI] = 16.6–26.4 months) in the idelalisib group vs 11.1 months (95% CI = 8.9–11.1 months) in the placebo group (hazard ratio [HR] = 0.33, P < .0001).

Hazard ratios favored idelalisib in all prespecified subgroups and were significant for virtually all, including among patients with relapsed disease (0.34, 95% CI = 0.24–0.48) or refractory disease (0.42, 95% CI = 0.26–0.67); patients without del(17p), mutated and unmutated IGHV; patients with either (0.47, 95% CI = 0.31–0.72) or neither (0.27, 95% CI = 0.18–039) del(17p) and TP53 mutation; patients aged < 65 and ≥ 65 years; men and women; and white and nonwhite race. The hazard ratio approached significance among 78 patients with del(17p; 0.62, 95% CI = 0.37–1.04).

Median overall survival was not reached in the idelalisib group (95% CI= not reached to not reached) vs 31.6 months (95% CI = 21.3 months to not reached) in the placebo group (HR = 0.62, P = .031. Hazard ratios favored idelalisib in all prespecified subgroups, although the study was not powered to detect a significant benefit in subgroup analysis.

The overall response rates were 70% vs 45%, with median response durations of 22.8 vs 11.2 months. A ≥ 50% reduction in the sum of perpendicular diameters of lymph nodes was observed in 97% vs 61% of patients. Organomegaly response was observed in 85% vs 57% in spleen and 58% vs 43% in liver.

Adverse Events

The most common adverse events of any grade were neutropenia (64%) and pyrexia (41%) in the idelalisib group and neutropenia (55%) and nausea (34%) in the placebo group. The most common grade ≥3 adverse events were neutropenia (60%) and febrile neutropenia (23% vs 5%) in the idelalisib group and neutropenia (47%) and thrombocytopenia (13%) in the placebo group. Grade ≥ 3 adverse events occurring more frequently in the idelalisib group also included diarrhea (9% vs 2%) and alanine transaminase (21% vs 3%) and aspartate transaminase (15% vs 2%) elevation. Infection of any grade occurred in 69% vs 59% of patients, with 39% vs 25% being grade ≥ 3. Most infections were bacterial.

Serious adverse events occurred in 68% vs 44%, with the most common in the idelalisib group being febrile neutropenia (20% vs 5%) and pneumonia (14% vs 7%). Treatment was discontinued due to adverse events in 27% vs 13%.

Adverse events led to death in 11% vs 7% of patients. Causes of death occurring in more than one patient were pneumonia (three patients), sepsis (three patients), and septic shock (two patients) in the idelalisib group and pneumonia (four patients) and acute myocardial infarction (two patients) in the placebo group. Adverse events leading to death that were considered to be related to idelalisib or placebo consisted of herpes zoster, sepsis, and multiorgan failure in the idelalisib group and bacterial and cytomegaloviral pneumonia, pulmonary mycosis, and liver disorder in the placebo group.

The investigators concluded: “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.”

The study was funded by Gilead Sciences Inc.

Andrew D. Zelenetz, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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