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489 High Efficacy of the PARP Inhibitor Olaparib Combined with High-Dose Chemotherapy and Autologous Stem-Cell Transplant for Refractory Lymphomas

Program: Oral and Poster Abstracts
Type: Oral
Session: 731. Autologous Transplantation: Clinical and Epidemiological: Lymphoma, AML, and Multiple Sclerosis
Hematology Disease Topics & Pathways:
Research, clinical trials, Hodgkin lymphoma, Lymphomas, non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Combination therapy, T Cell lymphoma, Diseases, Therapies, Lymphoid Malignancies
Sunday, December 11, 2022: 10:00 AM

Yago Nieto, MD1, Benigno C Valdez, PhD1, Peter F Thall, PhD2*, Jeremy L. Ramdial, MD1, Samer A Srour, MD, MS1, Chitra Hosing, MD1, Neeraj Saini, MD1, Amin M Alousi, MD1, Muzaffar H Qazilbash, MD1, Uday R Popat, MD1, Alison Gulbis, PharmD3*, Terri Lynn Shigle, PharmD3*, Roland Bassett, MS2*, Maria Guillermo-Pacheco1*, Celina Ledesma1*, Paolo Strati, MD4, Sairah Ahmed, MD4, Raphael Steiner, MD4*, Jason Westin, MD4, Ranjit Nair, MD4*, Swaminathan P. Iyer, MD4, Richard E Champlin, MD1, Elizabeth J Shpall, MD1 and Borje S Andersson, MD, PhD1

1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
3Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX

More active HDC are needed for ASCT for refractory/poor-risk relapsed lymphomas. Enhancement of the activity of HDC through combination with DNA damage repair (DDR) inhibitors is a promising but unexplored avenue. The enzyme poly(ADP-ribose) polymerase (PARP) catalyzes PARylation at the DNA damage site, which initiates DDR. Olaparib, the first FDA-approved PARP inhibitor for use in selected solid tumors, has shown synergy with conventional-dose chemotherapy, albeit with increased myelotoxicity. We studied in vitro the interaction of olaparib, epigenetically potentiated with the histone deacetylase (HDAC) inhibitor vorinostat, with a combination of gemcitabine/busulfan/melphalan (GemBuMel), which we had developed previously. We observed a markedly increased cytotoxicity of vorinostat/GemBuMel when combined with olaparib in refractory B- and T-cell lymphoma lines (Valdez et al., Leuk Lymphoma 2017;58:2705-16). Our preclinical work led us to design and clinically study olaparib plus vorinostat/GemBuMel with ASCT in refractory lymphomas.


Patients ages 15-65 with refractory lymphomas and adequate end-organ function were eligible for this phase I trial (NCT03259503). Olaparib was given from day -11 to -3, at 7 dose levels (DL1-DL7), ranging from 25 to 300 mg PO twice daily. Vorinostat was given at 1,000 mg PO daily (days -10 to -3). Gemcitabine was administered at 2,475 mg/m2/day IV (days -8 and -3), infused as a loading dose of 75 mg/m2 followed by continuous infusion at 10 mg/m2/min over 4 hours. Busulfan dosing targeted 4,000 μM.min-1/day IV (days -8 to -5). Melphalan was infused at 60 mg/m2/day IV (days -3 and -2). Patients with CD20+ tumors received rituximab (375 mg/m2) IV on day -10. ASCT was on day 0. The trial goals were to identify the recommended phase 2 dose (RP2D) of olaparib, and estimate the overall (ORR), and complete response (CR) rates, event-free (EFS) and overall survival (OS) rates of the regimen.


Between 10/19 and 06/22 we enrolled 30 patients: 18 Hodgkin, 6 DLBCL and 6 T-NHL, median age 34 (20-61), median prior lines of therapy 3 (range, 2-7), 8 prior CAR-T or other cellular immunotherapies. Eleven patients had PET+ tumors at HDC (3 of them in PD). An olaparib dose of 150 mg PO BID (DL4) was identified as the RP2D. There was 1 TRM (sepsis) at DL5. The toxicity profile was similar to that of vorinostat/GemBuMel without olaparib and included mucositis (17 grade 3, 11 grade 2), asymptomatic elevation of transaminases (10 grade 3, 7 grade 2), hyperbilirubinemia (7 grade 3, 2 grade 2, with no cases of VOD/SOS), colitis (2 grade 3, 3 grade 2), diarrhea (3 grade 3, 3 grade 2), and asymptomatic bradycardia during the HDC regimen (6 grade 1). Neutrophils and platelets engrafted promptly. The ORR and CR rates were both 100%. At median follow-up of 16 (range, 2-34) months, the EFS and OS rates are both 90%. There were only two relapses at 4 and 7 months, respectively, both in patients treated at DL1. Olaparib markedly inhibited PAR levels (measured by ELISA in PBMNC), which decreased significantly from baseline to day -5 (and became undetectable in those patients treated at the RP2D), with rapid PARylation recovery on day -2 (around 12 hours after the last dose of olaparib).

In this first trial combining a PARP inhibitor and an HDAC inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and highly active in refractory relapsed lymphomas, including post-CAR-T relapses. Olaparib, in combination with HDAC inhibition, strongly potentiates HDC through inhibition of PARylation and DDR during treatment. The clinical data are encouraging and this approach warrants further evaluation.

Disclosures: Nieto: Affimed: Other: Scientific advisory Board, Research Funding; Secura Bio: Research Funding; Astra Zeneca: Research Funding. Srour: Orca Bio: Research Funding. Alousi: Sanofi / Kadmon: Honoraria; Genetech: Consultancy; Mallinkrodt: Honoraria; Incyte: Honoraria, Research Funding; Prolacta: Consultancy. Popat: Novartis: Research Funding; Iovance: Consultancy; Incyte: Research Funding; Bayer: Research Funding; Abbvie: Research Funding. Gulbis: EUSA Pharma: Honoraria. Shigle: Takeda: Membership on an entity's Board of Directors or advisory committees. Strati: Roche Genentech: Consultancy; Sobi: Research Funding; ALX Oncology: Research Funding; Astrazeneca Acerta: Research Funding; Kite Gilead: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Hutchinson MediPharma: Consultancy. Ahmed: Seagen: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Tessa Therapeutics: Consultancy, Research Funding; Xencor: Research Funding; Chimagen: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy. Steiner: Seagen: Research Funding; BMS: Research Funding; GSK: Research Funding; Rafael Pharmaceuticals: Research Funding. Westin: Abbvie/GenMab: Consultancy; Iksuda: Consultancy; Merck: Consultancy; Calithera: Consultancy, Research Funding; MonteRosa: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; MorphoSys/Incyte Corporation: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SeaGen: Consultancy. Iyer: Salarius Pharmaceuticals, Inc.: Consultancy. Champlin: Kadmon: Consultancy; Omeros: Consultancy; Actinium: Consultancy; Johnson &Johnson: Consultancy; General Oncology: Other: Data Safety Monitoring Board; Bluebird: Other: Data Safety Monitoring Board; Cell Source Inc.: Research Funding. Shpall: Fibroblasts and FibroBiologics: Consultancy; adaptimmune: Consultancy; NY blood center: Consultancy; Navan: Consultancy; axio: Consultancy; Affimed: Other: License agreement; Takeda: Patents & Royalties; Bayer: Honoraria.

OffLabel Disclosure: Olaparib is a PARP inhibitor approved for ovarian cancer, breast cancer and prostate cancer. We use it in this trial to inhibit DNA damage repair after high-dose chemotherapy for lymphomas.

*signifies non-member of ASH