Idelalisib for Treatment of Relapsed Follicular Lymphoma and Chronic Lymphocytic Leukemia

Abstract

IMPORTANCE Idelalisib (IDEL) is approved as monotherapy in relapsed follicular lymphoma (FL) and with rituximab (IDEL+R) for relapsed chronic lymphocytic leukemia (CLL). Toxic effects can be severe and treatment-limiting. Outcomes in a real-world population are not yet characterized. OBJECTIVE We compared IDEL treatment outcomes in the clinical setting with outcomes in clinical trial data. DESIGN, SETTING, AND PARTICIPANTS This cohort study compared clinical trial participants treated with IDEL, aged 65 years or older, in studies 101-09 and 312-0116 with Medicare beneficiaries treated with IDEL of the same disease state and treatment regimen. Study 101-09 was a phase 2, single-group, open-label trial supporting accelerated approval of IDEL for relapsed or refractory FL. Study 312-0116 was a phase 3, multicenter, randomized, double-blind trial supporting approval of IDEL+R for relapsed CLL. Analyses were conducted between February and December 2018. MAIN OUTCOMES AND MEASURES Treatment duration, on-treatment and overall mortality, and serious and fatal infections were compared between trial participants and Medicare beneficiaries. Cox proportional hazards models quantified differences by cohort. RESULTS We identified 26 trial participants (mean [SD] age, 73 [4.9] years; 12 [46.2%] women) and 305 Medicare beneficiaries (mean [SD] age, 76 [6.9] years; 103 [54.8%] women) receiving IDEL for FL and 89 trial participants (mean [SD] age, 74 [6.0] years; 30 [33.7%] women) and 294 Medicare beneficiaries (mean age, 76 [6.3] years; 111 [37.8%] women) receiving IDEL+R for CLL. Medicare beneficiaries were older with higher comorbidity; had a shorter median treatment duration for CLL (173 days vs 473 days, P < .001) but not FL (114, days vs 160 days, P = .38); a numerically higher mortality rate (CLL: HR, 1.40; 95% CI, 0.93-2.11; FL: HR, 1.39; 95% CI, 0.69-2.78); and a significantly higher fatal infection rate per 100 person-years for CLL (18.4 vs 9.8, P = .04) and a numerically higher rate for FL (27.6 vs 18.6, P = .54), compared with trial participants. Trial participants had approximately twice as many dose reductions (CLL: 32.6% vs 18.0%; P = .003; FL: 38.5% vs 16.1%; P = .02). Among Medicare beneficiaries, a hospitalized infection within 6 months prior to IDEL initiation was associated with a 2.11-fold increased risk for on-treatment fatal infections (95% CI, 1.44-3.10). Despite a March 2016 recommendation for Pneumocystis jirovecii pneumonia prophylaxis in patients treated with IDEL, prophylaxis rates were low after March 2016 (FL: 25%, CLL: 37%). CONCLUSIONS AND RELEVANCE We observed substantial imbalances in baseline comorbidities and treatment outcomes between Medicare beneficiaries and trial participants aged 65 years or older. Immunosuppression-related toxic effects, including infections, may have been somewhat reduced in trials by more frequent dose reductions and exclusion of patients with ongoing infections. Selective eligibility criteria and closer monitoring of trial patients may be responsible for limited gener...

Copanlisib in the Treatment of Relapsed Follicular Lymphoma: Utility and Experience from the Clinic

“…infections, have been noted to be higher in real-world outcomes study of idelalisib, as compared to those observed in trials, likely due to frequent dose reductions and exclusion of patients with ongoing infections in the trial setting. 20 This toxicity profile counterweighs the feasibility of oral agents. Dual PI3K α and δ inhibition is also an astute strategy for overcoming PI3K resistance.…”

“…1 , 19 Unfortunately, the initial enthusiasm concerning these agents was dampened by a high incidence of gastrointestinal and immune-mediated toxicities. 20 , 21 …”

“…1,19 Unfortunately, the initial enthusiasm concerning these agents was dampened by a high incidence of gastrointestinal and immune-mediated toxicities. 20,21 Copanlisib (BAY 80-6946; Bayer Pharma AG, Berlin, Germany) is an intravenous, potent, highly selective, panclass I PI3K inhibitor with preferential activity against the p110α and p110δ isoforms, compared with the p110β and p110γ isoforms. 22 Copanlisib is indicated in the US for the treatment of patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.…”

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma

“…Serious toxicities were even more frequent in a real-world sample of older Medicare beneficiaries receiving idelalisib. 99 Longer use has amplified the safety concerns about colitis, hepatitis, pneumonitis, neutropenia, and opportunistic infections (CMV, Pneumocystis jirovecii pneumonia) and ultimately dissuaded many clinicians from routine use of idelalisib. 100 Duvelisib was also studied in a phase 2 study of iBCL patients after median 3 lines of therapy.…”

Phase 1 clinical trial of the PI3Kδ inhibitor YY-20394 in patients with B-cell hematological malignancies

“…The selective PIP2 3-kinase δ (PI3Kδ) inhibitor idelalisib in combination with rituximab [ 1 – 3 ] and the PI3K-δ/γ inhibitor duvelisib (IPI-145) [ 4 ] have been approved to treat B-cell malignancies. In addition, a selective PI3Kδ inhibitor parsaclisib (INCB050465) is undergoing phase 2 trials [ 5 , 6 ].…”