Idelalisib Combination Improves PFS But Increases Infection Risk in Relapsed/Refractory CLL

According to a randomized, placebo-controlled, phase III study published in the Lancet Oncology, adding idelalisib to the combination of bendamustine and rituximab (BR) nearly doubled the length of progression-free survival (PFS), compared with placebo and BR: 20.8 months versus 11.1 months (hazard ratio [HR] = 0.33; 95% CI 0.25-0.44; p<0.0001).

BR is the standard of care for the management of relapsed/refractory chronic lymphocytic leukemia (CLL), but relapse remains high in this patient population, particularly among those with high-risk features, including unmutated IGHV, TP53 mutation, or del17p. “The results of our study are clear that both PFS and overall survival (OS) are significantly enhanced when idelalisib is added to BR,” lead author Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York, told ASH Clinical News.

Dr. Zelenetz and co-authors evaluated the efficacy and safety of idelalisib plus BR in 416 adult patients who were enrolled from 110 sites in 19 countries in North America, Europe, and Asia between June 26, 2012, and August 21, 2014.

Patients were included if they had:

  • a diagnosis of B-cell CLL requiring treatment (per International Workshop on CLL criteria)
  • measurable lymphadenopathy (≥1 nodal lesion that measured ≥2.0 cm in the longest diameter and ≥1.0 cm in the longest perpendicular diameter)
  • prior therapy, including a purine analogue or bendamustine and an anti-CD20 monoclonal antibody
  • documented disease progression of <36 months since completion of previous therapy
  • discontinuation of all therapy at least 3 weeks prior to randomization

Patients were excluded if they had known histologic transformation to an aggressive lymphoma, the presence of intermediate- or high-grade myelodysplastic syndromes, or disease that was refractory to bendamustine, or if they had received previous therapy with inhibitors of AKT, BTK, JAK, mTOR, PI3K, or SYK.

All patients received bendamustine 70 mg/m2 administered intravenously on days 1 and 2 of six 28-day cycles, plus rituximab 375 mg/m2 administered on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2-6. Patients were randomized 1:1 to receive placebo (n=209) or idelalisib 150 mg administered orally twice daily (n=207). Treatment was continued until unacceptable toxicity, death, disease progression, pregnancy, substantial non-compliance with study procedures, study discontinuation, or withdrawal of consent.

At data cutoff (October 7, 2015), 34 percent of patients (n=141) remained in the study: 46 percent in the idelalisib cohort (n=95) and 22 percent in the placebo cohort (n=46). At a median of 14 months of follow-up (range = 7-18 months), 20 percent of idelalisib-treated patients (n=42) and 51 percent of placebo-treated patients (n=107) experienced progressive disease.

The PFS benefit with idelalisib treatment was consistent across most risk subgroups, the authors noted. For patients with neither del17p nor TP53 mutation, median PFS was longer in the idelalisib group than in the placebo group (24.5 months [95% CI 19.5-30.3] vs. 11.2 months [95% CI 11.1-13.6]; HR=0.27; p<0.0001). The same was true for patients with either del17p or TP53 mutation (11.3 months [95% CI 8.8-16.6] vs. 8.3 months [95% CI 5.9-8.5]; HR=0.47; p<0.0001).

Median OS was also longer in the idelalisib group (not reached [NR] vs. 31.6 months [range = 21.3 to NR]; HR=0.62; p=0.031), and there was a trend toward improvement in OS across risk subgroups, but the association was not significant.

The proportion of patients achieving an overall response was significantly higher in the idelalisib group (p<0.0001; see TABLE). A greater proportion of patients with del17p mutations had progressive disease as best overall response in the placebo cohort than in the idelalisib group (HR=0.62; 95% CI 0.37-1.04).

The most common grade ≥3 adverse events (AEs) were neutropenia (60%; n=124) and febrile neutropenia (n=48; 33%) in the idelalisib group and neutropenia (n=99; 47%) and thrombocytopenia (n=27; 13%) in the placebo group.

A total of 97 patients (54 in the idelalisib group and 43 in the placebo group) discontinued treatment. At data cutoff, more patients continued to receive idelalisib (n=90; 43%) than placebo (n=45; 22%). However, AEs leading to treatment discontinuation occurred more frequently in the idelalisib group (n=120; 58%) than in the placebo group (n=50; 24%). The most common of these AEs were pneumonia (4% in the idelalisib group vs. 2% in the placebo group), diarrhea (2% vs. 0%), and pyrexia (2% vs. <1%).

Patients receiving idelalisib had a greater frequency of infections (69%; n=143) than the placebo cohort (59%; n=124; p values not reported), most of which were bacterial. These infections led to six deaths in the idelalisib cohort and three in the placebo cohort. “The increased infectious risk requires careful monitoring of the patients,” Dr. Zelenetz told ASH Clinical News.

Forty-three patients in the idelalisib group (21%) and 59 patients in the placebo group (28%) died during study follow-up. Treatment-emergent AEs leading to death occurred in 11 percent of the idelalisib cohort (n=23) and 7 percent of the placebo cohort (n=15).

Patients who received BR plus idelalisib had a median duration of exposure of 14.8 months (range = 5.9-18.9) while patients who received BR plus placebo had a median duration of exposure of 11.1 months (range = 5.8-15.3). “The higher number of deaths in the idelalisib group was possibly a result of a longer median exposure to study treatment,” the authors noted.

“The major limitation of this study is that it did not include a third arm in which bendamustine was eliminated,” Dr. Zelenetz said. “Thus, it does not address the question of whether there was additional benefit of having both bendamustine and idelalisib.” The study’s results were also limited by the short duration of follow-up. The study was designed and sponsored by Gilead Sciences, the manufacturer of idelalisib.

Zelenetz AD, Barrientos JC, Brown JR, et al. 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. Lancet Oncol. 2017;18:297-311.

TABLE. Treatment Responses for Idelalisib Versus Placebo
  Idelalisib + BR


Placebo + BR


Overall response 70% (n=145)

(95% CI 63-76)

45% (n=94)

(95% CI 38-52)

   CR 1% (n=3) 0%
   CRi 0% <1% (n=1)
   PR 69% (n=142) 44% (n=93)
≥50% reduction in lymph nodes 97% (n=186/192)

(95% CI 93-99)

61% (n=120/197)

(95% CI 54-68)

Duration of response 22.8 months

(95% CI 19.1-27.2)

11.2 months

(95% CI 8.5-13.7)

Organomegaly response
   Spleen 85% (n=125/148)

(95% CI 78-90)

57% (n=80/141)

(95% CI 48-65)

   Liver 58% (n=57/99)

(95% CI 47-68)

43% (n=47/109)

(95% CI 34-53)

Hematologic response
   Hemoglobin 88% (n=58/66)

(95% CI 78-95)

70% (n=50/71)

(95% CI 58-81)

   Neutrophils 86% (n=24/28)

(95% CI 67-96)

81% (n=26/32)

(95% CI 64-93)

   Platelets 89% (n=71/80)

(95% CI 80-95)

78% (n=49/63)

(95% CI 66-87)

BR = brentuximab plus rituximab; CR = complete response; CRi = complete response with incomplete marrow recovery; PR = partial response