Purpose: 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.
Methods: 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.
Findings: 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.
Conclusions: 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.