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Idelalisib improves PFS for relapsed, refractory CLL
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The addition of idelalisib to bendamustine plus rituximab prolonged PFS in patients with relapsed or refractory chronic lymphocytic leukemia, according to results of a phase 3 clinical trial.
However, high incidence for infections persisted among patients who received idelalisib (Zydelig, Gilead).
“The results of this study add to the body of evidence that idelalisib produces clinically meaningful outcomes in patients with relapsed or refractory chronic lymphocytic leukemia, either as a monotherapy or in combination with other agents,” Andrew D. Zelenetz, MD, PhD, medical oncologist in the lymphoma service of the department of medicine at Memorial Sloan Kettering Cancer Center, and colleagues wrote.
Phase 1 studies of idelalisib — a potent inhibitor of phosphoinositide-3-kinase delta inhibitor — have shown benefit as both a monotherapy and in combination with bendamustine or an anti-CD20 antibody in patients with relapsed or refractory CLL. Zelenetz and colleagues conducted this phase 3 multicenter study with 419 patients from 19 clinical sites to determine the safety and efficacy of adding idelalisib to a combination of bendamustine plus rituximab (Rituxan; Genentech, Biogen).
All patients received 70 mg/m2 bendamustine intravenously on days 1 and 2 for six 28-day cycles plus rituximab, given in a 375 mg/m2–dose on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, for a maximum of six cycles. Researchers randomly assigned patients 1:1 to receive this combination with twice-daily oral 150 mg idelalisib (n = 207) or placebo (n = 209).
At a median follow-up of 14 months (interquartile range [IQR], 7-18), 141 of the patients (34%) were still receiving treatment as part of the study — this included 95 in the idelalisib group and 46 in the placebo group.
At that time, progressive disease occurred in 20% of patients in the idelalisib arm and 51% of the placebo arm, and death occurred in 8% of patients on the idelalisib arm and 6% of patients in the placebo arm. Ninety-seven patients — 54 in the idelalisib arm and 43 in the placebo arm — discontinued for other reasons, most commonly adverse events, physician’s decision or withdrawal of consent.
The median number of cycles of treatment was six with bendamustine (IQR, 4-6) and with rituximab (IQR, 5-6); however, the median duration of exposure was longer for patients who received idelalisib (14.8 months vs. 11.1 months).
The median PFS was 20.8 months (95% CI, 16.6-26.4) among patients who received idelalisib and 11.1 months (95% CI, 8.9-11.1) among patients who received placebo (HR = 0.33; 95% CI, 0.25-0.44).
Common grade 3 or worse adverse events in the idelalisib group were neutropenia (60%) and febrile neutropenia (23%), whereas neutropenia (47%) and thrombocytopenia (13%) were the most common events in the placebo group.
More patients who received idelalisib experienced grade 3 or worse infections and infestations compared with patients who received placebo (39% vs. 25%). Treatment-emergent adverse events leading to mortality occurred in 23 patients (11%) in the idelalisib group and 15 (7%) in the placebo group. Of these, infections caused six deaths in the idelalisib group and three in the placebo group.
“The question of how best to manage and mitigate this risk while maximizing the therapeutic benefit of idelalisib needs to be addressed,” the researchers wrote.
Although treatment for CLL has evolved rapidly, these data show additional studies are needed to clearly define the benefits of combining chemoimmunotherapy with kinase inhibitors, Francesca R. Mauro, MD, PhD, from the department of cellular biotechnologies and hematology of Sapienza University in Italy, wrote in a related editorial.
“Careful selection of patients, better knowledge, management of treatment-related adverse events and enforcement measures to mitigate the risk for infections might have relevant effects in maximizing the therapeutic benefit of idelalisib,” Mauro wrote. – by Melinda Stevens
Disclosure: Zelenetz reports institutional research grants from Gilead Sciences. Please see the full study for a list of all other researchers’ relevant financial disclosures. Mauro reports consulting fees from advisory board roles with AbbVie, Gilead Sciences, Janssen and Roche.
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