Idelalisib, an oral inhibitor of PI3Kδ, was evaluated in a 48-week phase I study (50-350 mg qd or bid) enrolling 40 patients with relapsed/refractory mantle cell lymphoma (MCL). Primary outcome was safety and dose-limiting toxicity (DLT). Secondary outcomes were pharmacokinetic parameters, pharmacodynamic effects, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Patients without DLT and no evidence of disease progression after 48 weeks enrolled in the extension study. Patients had median age of 69 years (52-83) and received median of 4 prior therapies (1-14); 17/40 (43%) were refractory to their most recent treatment. Median duration of idelalisib treatment was 3.5 months (range, 0.7-30.7), with 6 (15%) continuing extension treatment. Common grade ≥3 adverse events (AEs) included (total%/grade ≥3%) diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (23/3), decreased appetite (20/15), upper respiratory infection (20/0), pneumonia (13/10), and ALT or AST elevations (60/20). Nine (25%) patients discontinued therapy due to AEs. ORR was 16/40 (40%), with CR in 2/40 (5%) patients. Median DOR was 2.7 months, median PFS was 3.7 months, and 1-year PFS was 22%. These data provide proof of concept that targeting PI3Kδ is a viable strategy and worthy of additional study in MCL. This study is registered at Clinicaltrials.gov, identifier: NCT00710528.
[Show abstract][Hide abstract] ABSTRACT: Mantle cell lymphoma is a heterogeneous subtype of non-Hodgkin lymphoma. Conventional treatment with immunochemotherapy followed by autologous stem cell transplantation or intensive immunochemotherapy alone has improved outcomes, but the disease remains incurable. Recent advances in basic and translational research have significantly enhanced our understanding of disease pathogenesis and have sparked the development of novel therapies. Novel agents include the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the phosphatidylinositol-4,5-bisphosphate 3-kinase pathway inhibitor idelalisib and the Bruton tyrosine kinase inhibitor ibrutinib. Preliminary results from clinical trials, especially from studies of ibrutinib, have proven these agents to be effective. In ongoing studies, these agents are being integrated into conventional immunochemotherapy regimens to hopefully improve patient outcomes.
British Journal of Haematology 06/2014; 167(1). DOI:10.1111/bjh.13000 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: VcR-CVAD (rituximab, bortezomib, modified hyper-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) was evaluated for efficacy and safety in ECOG protocol E1405. Patients with previously untreated mantle cell lymphoma (MCL) received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n=44) versus ASCT (n=22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in MCL. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials (RCTs) comparing MR against ASCT should be considered and RCTs evaluating bortezomib's contribution to conventional therapy are underway. This study was registered with clinicaltrials.gov (identifier NCT00433537).
[Show abstract][Hide abstract] ABSTRACT: In this issue of Blood, Flinn et al, Kahl et al, and Brown et al provide further encouragement that the possibility of a chemotherapy-free world is, indeed, a rapidly approaching reality in indolent non-Hodgkin lymphomas (NHLs), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL)
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