Nieto Yago, Ramdial Jeremy, Valdez Benigno, Thall Peter F, Bassett Roland, Barnett Melissa, Srour Samer, Hosing Chitra, Alousi Amin, Qazilbash Muzaffar, Popat Uday, Gulbis Alison, Shigle Terri Lynn, Ahmed Sairah, Guillermo Pacheco Maria, Champlin Richard, Shpall Elizabeth J, Andersson Borje S
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2025 Mar 17;31(6):975-982. doi: 10.1158/1078-0432.CCR-24-3544.
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.
难治性淋巴瘤的自体干细胞移植（ASCT）需要更有效的大剂量化疗（HDC）方案。为了通过聚（ADP-核糖）聚合酶（PARP）抑制剂增强HDC效果，我们观察到奥拉帕利与伏立诺他/吉西他滨/白消安/美法仑（GemBuMel）联合使用对淋巴瘤细胞系具有显著的协同作用，这种作用是由DNA损伤修复抑制介导的。我们的临床前研究促使我们对奥拉帕利/伏立诺他/GemBuMel联合ASCT进行临床研究。
年龄在15至65岁之间、患有难治性淋巴瘤且终末器官功能良好的患者符合本I期试验的条件。奥拉帕利剂量从第-11天至第-3天每日口服2次、每次25mg开始递增，同时联合伏立诺他（每日口服1000mg，第-10天至第-3天）、吉西他滨（每日静脉注射2475mg/m²，第-8天和第-3天）、白消安（目标曲线下面积4000µmol/L·分钟⁻¹/天，静脉注射，第-8天至第-5天）、美法仑（每日静脉注射60mg/m²，第-3天和第-2天）以及利妥昔单抗（CD20⁺肿瘤；375mg/m²，第-10天），并进行ASCT。
共纳入50例患者（23例霍奇金淋巴瘤、18例弥漫性大B细胞淋巴瘤和9例T细胞非霍奇金淋巴瘤）；中位年龄为35岁（范围20 - 61岁）；患者接受的中位治疗线数为3线（范围2 - 7线）；17例患者先前在嵌合抗原受体T细胞疗法或其他细胞免疫疗法后复发；23例患者在大剂量化疗时PET呈阳性肿瘤（9例处于进展期）。确定每日口服2次、每次150mg的奥拉帕利剂量为推荐的II期剂量。主要的髓外毒性是粘膜炎。总缓解率和完全缓解率分别为100%和90%。在中位随访30个月（范围12 - 56个月）时，所有患者的无事件生存率和总生存率分别为72%和82%，先前接受过CAR T细胞治疗失败的患者分别为71%和88%。
在这项将PARP抑制剂与大剂量化疗联合应用的首次试验中，奥拉帕利/伏立诺他/GemBuMel是安全的，并且在难治性淋巴瘤（包括CAR-T治疗后复发的患者）中显示出有前景的活性。
