Ramdial Jeremy, Lin Ruitao, Thall Peter F, Valdez Benigno C, Hosing Chitra, Srour Samer, Popat Uday, Qazilbash Muzaffar, Alousi Amin, Barnett Melissa, Gulbis Alison, Shigle Terri Lynn, Shpall Elizabeth J, Andersson Borje S, Nieto Yago
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Bone Marrow Transplant. 2024 Dec;59(12):1754-1762. doi: 10.1038/s41409-024-02394-0. Epub 2024 Sep 28.
Refractory aggressive lymphomas can be treated with allo-SCT, pursuing a graft-vs-lymphoma effect. While reduced intensity conditioning is safe, tumors often progress rapidly, indicating the need for more active conditioning regimens. The preclinical synergy we saw between gemcitabine (Gem), clofarabine (Clo) and busulfan (Bu) against lymphoma cell lines led us to study Gem/Clo/Bu clinically. Eligibility: age 12-65, refractory aggressive B-NHL, T-NHL or Hodgkin, with a matched donor. Infusional Gem was dose-escalated on days (d) -6 and -4 (475-975 mg/m/day), followed by Clo (40 mg/m/day) and Bu (target AUC, 4000 μMol min/day) (d -6 to -3). CD20 tumors received rituximab. GVHD prophylaxis included ATG (MUD), tacrolimus and MMF. We compared their outcomes to matched-pair concurrent controls receiving Flu/Mel + matched allo-SCT. We enrolled 64 patients, median age 46 (17-63), 31 B-NHL/22 T-NHL/11 Hodgkin, 36 MSD/28 MUD (all PBPC), median 4 (2-10) prior therapies; 18 prior auto-SCT, 42 active diseases at allo-SCT (12 PD). Toxicities (mucositis and transaminitis) were manageable. Gem/Clo/Bu was myeloablative yielding early full donor chimerism. Grades II-IV/III-IV acute GVHD rates of 37% and 18%; chronic GVHD of 33% (13% severe); NRM at D100/1 year was 7% and 18%. ORR/CR rates: 78%/71% (B-NHL), 93%/93% (T-NHL), 67%/67% (Hodgkin). At a median follow-up of 60 (12-110) months, EFS/OS rates: 36%/47%. Gem/Clo/Bu patients had better median EFS (12 vs. 3 months, P = 0.001) and OS (25 vs. 7 months, P = 0.003) than 113 Flu/Mel matched-pair controls. The new myeloablative regimen Gem/Clo/Bu has limited toxicity and high activity in allo-SCT for aggressive lymphomas, yielding better outcomes than concurrent matched-pair controls receiving Flu/Mel.
难治性侵袭性淋巴瘤可通过异基因造血干细胞移植（allo-SCT）进行治疗，以发挥移植物抗淋巴瘤效应。虽然减低强度预处理是安全的，但肿瘤往往进展迅速，这表明需要更积极的预处理方案。我们在吉西他滨（Gem）、氯法拉滨（Clo）和白消安（Bu）对淋巴瘤细胞系的临床前协同作用促使我们开展Gem/Clo/Bu的临床研究。入选标准：年龄12 - 65岁，难治性侵袭性B细胞非霍奇金淋巴瘤（B-NHL）、T细胞非霍奇金淋巴瘤（T-NHL）或霍奇金淋巴瘤，且有匹配供者。在第 - 6天和 - 4天对静脉输注的Gem进行剂量递增（475 - 975mg/m²/天），随后给予Clo（40mg/m²/天）和Bu（目标曲线下面积，4000μMol·min/天）（第 - 6天至 - 3天）。CD20阳性肿瘤患者接受利妥昔单抗治疗。移植物抗宿主病（GVHD）预防措施包括抗胸腺细胞球蛋白（ATG，用于非血缘供者）、他克莫司和霉酚酸酯。我们将他们的结果与接受氟达拉滨/美法仑（Flu/Mel）+匹配异基因造血干细胞移植的配对同期对照进行比较。我们纳入了64例患者，中位年龄46岁（17 - 63岁），其中31例为B-NHL/22例为T-NHL/11例为霍奇金淋巴瘤，36例为同胞全相合供者/28例为非血缘供者（均为外周血造血干细胞），既往中位治疗次数为4次（2 - 10次）；18例曾接受过自体造血干细胞移植，42例在异基因造血干细胞移植时疾病处于活动期（12例为疾病进展）。毒性反应（黏膜炎和转氨酶升高）可控。Gem/Clo/Bu具有清髓性，可产生早期完全供者嵌合。Ⅱ - Ⅳ级/Ⅲ - Ⅳ级急性移植物抗宿主病发生率分别为37%和18%；慢性移植物抗宿主病发生率为33%（13%为重度）；100天/1年时的非复发死亡率分别为7%和18%。总缓解率/完全缓解率：B-NHL为78%/71%，T-NHL为93%/93%，霍奇金淋巴瘤为67%/67%。在中位随访60个月（12 - 110个月）时，无事件生存期/总生存期率分别为36%/47%。与113例Flu/Mel配对对照相比，接受Gem/Clo/Bu治疗的患者中位无事件生存期（12个月对3个月，P = 0.001）和总生存期（25个月对7个月，P = 0.003）更好。新的清髓性方案Gem/Clo/Bu在侵袭性淋巴瘤异基因造血干细胞移植中毒性有限且活性高，比接受Flu/Mel的配对同期对照产生更好的疗效。
