Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

By R. Furman, J. Sharman, S. Coutre, B. Cheson, J. Pagel, P. Hillmen, J. Barrientos, A. Zelenetz, T. Kipps, I. Flinn and 17 more. New England Journal of Medicine, 2014

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BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemo-therapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta iso-form of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemo-therapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.)

Subfields: Cell Biology, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1113638ddc3ae5b863d29598f7216b601560a81b

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The PI3K pathway in human disease (2017, positive): “…rather, p110 d inhibition suppresses host responses that nurture the survival and expansion of transformed B cell clones in CLL. Adverse events associated with idelalisib treatment included elevation of liver enzymes, diarrhea, pneumonitis, and pneumonia (Furman et al., 2014; Gopal et al., 2014).”
Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. (2016, neutral): “CML 1/24 (4) 1 (,1) 0/11 (0) 0 (0) 1/13 (8) 1 (,1)”
The PI3K/AKT Pathway as a Target for Cancer Treatment. (2016, methodology): “F or p er so na l u se o nl y. Table 1 Select PI3K inhibitors in clinical development Drug target Drug Source Phase of development Tumor types Pan-PI3K Buparlisib (BKM120) Novartis Phase 3 Advanced solid cancers, NSCLC, endometrial, prostate, breast, colorectal, pancreatic, renal cell, GIST, melanom”
Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2015, neutral): “– BCL2 antagonists alone or in combination within a clinical study – Bruton’s tyrosine kinase inhibitor ibrutinib [23] – PI3K inhibitor idelalisib in combination with rituximab [24] – Other chemoimmunotherapy combinations should only be administered if TP53 deletion/mutation was excluded (Figure 2).”