Abstract
More active high-dose chemotherapy (HDC) regimens are needed for autologous stem cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a PARP inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by the inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT.
Patients ages 15 to 65 years with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dosage was escalated from 25 mg orally twice a day on days −11 to −3, plus vorinostat (1,000 mg orally/day, days −10 to −3), gemcitabine (2,475 mg/m2/day i.v., days −8 and −3), busulfan (target AUC 4,000 µmol/L.minute−1/day i.v., days −8 to −5), melphalan (60 mg/m2/day i.v., days −3 and −2), and rituximab (CD20+ tumors; 375 mg/m2, day −10), with ASCT.
Fifty patients were enrolled (23 with Hodgkin lymphoma, 18 with diffuse large B-cell lymphoma, and 9 with T-cell non–Hodgkin lymphoma); the median age was 35 years (range, 20–61); patients received a median of three prior lines of therapy (range, 2–7); 17 patients had previously relapsed after chimeric antigen receptor T-cell therapy or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dosage of 150 mg orally twice a day was identified as the recommended phase II dosage. The main extramedullary toxicity was mucositis. The overall response rate and complete response rate were 100% and 90%, respectively. At the median follow-up of 30 (range, 12–56) months, the event-free survival and overall survival rates were 72% and 82% in all patients and 71% and 88% in patients with prior CAR T-cell failure, respectively.
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.
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