Enhancement Of High-Dose Chemotherapy and Autologous SCT with the PARP Inhibitor Olaparib for Refractory Lymphoma.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Yago Nieto, Jeremy Ramdial, Benigno Valdez, Peter F Thall, Roland Bassett, Melissa Barnett, Samer Srour, Chitra Hosing, Amin Alousi, Muzaffar Qazilbash, Uday Popat, Alison Gulbis, Terri Lynn Shigle, Sairah Ahmed, Maria Guillermo Pacheco, Richard Champlin, Elizabeth J Shpall, Borje S Andersson

TLDR

  • This phase I study combined olaparib with HDC and ASCT in patients with refractory lymphoma, achieving a 90% CR rate and promising EFS and OS rates.
  • The combination was safe and effective, with mucositis being the main extramedullary toxicity.
  • This study paves the way for further research into the role of PARP inhibitors in lymphoma treatment.

Abstract

More active high-dose chemotherapy (HDC) regimens are needed for autologous stem-cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a poly(ADP-ribose) polymerase (PARP) inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT. Patients ages 15-65 with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dose was escalated from 25 mg PO BID on days (d)-11 to -3, plus vorinostat (1,000 mg PO/d, d-10 to -3), gemcitabine (2,475 mg/m2/d IV, d-8 and -3), busulfan (target AUC 4,000 μM.min-1/d IV, d-8 to -5), melphalan (60 mg/m2/d IV, d-3 and -2), and rituximab (CD20+ tumors) (375 mg/m2, d-10), with ASCT. Fifty patients were enrolled (23 Hodgkin, 18 DLBCL, 9 T-NHL); median age 35 (range, 20-61); median 3 prior lines of therapy (range, 2-7); 17 patients had previously relapsed after CAR-T or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dose of 150 mg PO BID was identified as the recommended phase 2 dose. The main extramedullary toxicity was mucositis. The ORR/CR rates were 100%/90%. At median follow-up of 30 months (range, 12-56) months, the EFS/OS rates were 72%/82%, and 71%/88% in patients with prior CAR-T cell failure. In this first trial combining a PARP inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and showed promising activity in refractory lymphomas, including post-CAR-T relapses.

Overview

  • This study explored the combination of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, with high-dose chemotherapy (HDC) and autologous stem-cell transplantation (ASCT) for treatment-refractory lymphomas.
  • The study included 50 patients with refractory lymphoma, including 23 with Hodgkin lymphoma, 18 with diffuse large B-cell lymphoma (DLBCL), and 9 with T-cell lymphoma.
  • The primary objective of the study was to determine the recommended phase 2 dose of olaparib in combination with HDC and ASCT, and to assess its safety and efficacy in patients with refractory lymphoma.

Comparative Analysis & Findings

  • The combination of olaparib, vorinostat, gemcitabine, busulfan, and melphalan (GemBuMel) with ASCT showed promising activity in refractory lymphomas, with an overall response rate (ORR) of 100% and a complete response rate (CR) of 90%.
  • The recommended phase 2 dose of olaparib was 150 mg PO BID, and the main extramedullary toxicity reported was mucositis.
  • The event-free survival (EFS) and overall survival (OS) at median follow-up of 30 months were 72%/82% and 71%/88%, respectively, in patients with prior CAR-T cell failure.

Implications and Future Directions

  • This study demonstrates the potential for combining PARP inhibitors with HDC and ASCT as a promising treatment strategy for refractory lymphomas.
  • Future studies will assess the combination of olaparib with HDC and ASCT in larger cohorts of patients with refractory lymphoma, as well as explore its use in combination with other molecularly targeted agents.
  • This study highlights the importance of further research into the role of PARP inhibitors in lymphoma treatment, particularly in cases where patients have relapsed after CAR-T cell therapy.
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