AE leading to idelalisib discontinuation were lower when used in the relapsed setting vs front-line setting. Nine patients (8%) discontinued treatment in the relapsed CLL trial due to gastrointestinal and skin side effects, while 25 patients (20.8%) discontinued idelalisib in the relapsed iNHL trial due to hepatotoxicity, colitis, and pneumonia.24,27 However, 29 patients (45.3%) discontinued idelalisib in treatment-naïve CLL patients. The most reported AE in the front-line setting included diarrhea/colitis (18.8%), dyspnea (4.7%), and rash (4.7%).25
Given the activity of idelalisib in the relapsed setting, a Phase II clinical trial of idelalisib plus ofatumumab for treatment-naïve CLL patients was launched. Preliminary results presented at the 2015 Annual Society of Hematology Meeting revealed a high rate of hepatic toxicity, suggesting that patients without exposure to prior immunosuppressive chemotherapy may be insufficiently immunocompromised to tolerate idelalisib therapy as front-line treatment.29
A recent retrospective analysis examined the incidence of colitis in 50 patients treated with idelalisib continuously for 3 months. Of the 23 patients who developed diarrhea, eight patients had severe symptoms. Twelve of 14 patients who underwent a colonoscopy with biopsies had histological evidence of colitis with intraepithelial lymphocytosis and crypt apoptosis. Eleven of 50 patients had to discontinue treatment due to severity of symptoms, while nine patients were successfully treated with steroids.30 It has been noted that idelalisib-induced diarrhea may be poorly responsive to antimotility agents, lasting up to 1 month after treatment discontinuation.28
There are many factors influencing patient adherence; the ease of administration, a tolerable side effect profile, and acceptable drug–drug interactions make idelalisib an encouraging medication for patient adherence. However, the average wholesale price of a 28-day supply is estimated at $8,862 at the recommended full dose.31
Idelalisib is an active agent in indolent B-cell leukemia/lymphoma. We foresee further investigation in combination with other chemo- and immunotherapies, as well as studies trying to replace chemoimmunotherapy in various indications. The utility of this agent in other settings such as aggressive B-cell lymphoma needs investigation. Given the cumulative burden of cost, immune toxicities, and unknown long-term AE, studies comparing stopping treatment, perhaps in a minimal residual disease state, vs continuous therapy would be worthwhile. Enthusiasm of moving this effective therapy to the front-line setting may be tempered by the preliminary data for front-line treatment, which is concerning for a high incidence of autoimmune complications.
Concurrent inhibition of multiple isoforms of the PI3K enzyme demonstrated theoretical benefit in vitro studies.32 Duvelisib (IPI-145) is a novel oral inhibitor of both PI3K delta and gamma isoforms that is in clinical development.33
Recent data demonstrated that PI3K pathway inhibition by idelalisib sensitized malignant B-cells to overcome resistance to the Bcl-2 inhibitor venetoclax (formerly ABT-199) through downregulation of myeloid cell leukemia 1 and Bcl-2-associated X protein activation, paving the way for rational combination therapies.34