Ghobadi Armin, Choi Jaebok, Fiala Mark A, Fletcher Theresa, Liu Jingxia, Eissenberg Linda G, Abboud Camille, Cashen Amanda, Vij Ravi, Schroeder Mark A, Pusic Iskra, Stockerl-Goldstein Keith, Jacoby Meagan, Uy Geoffrey, DiPersio John, Westervelt Peter
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis MO, United States.
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis MO, United States.
Leuk Res. 2016 Oct;49:1-6. doi: 10.1016/j.leukres.2016.07.010. Epub 2016 Jul 22.
Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD). In mice, administration of azacitidine (AzaC) on days 4, 6, 8, and 10 post DLI increases regulatory T cell (Treg) numbers and prevents GVHD without hindering Graft vs. Leukemia (GVL). Based on these findings, we conducted a phase 1 study of AzaC post DLI for AML relapse post allo-SCT. AzaC was administered on days 4, 6, 8 and 10 post-DLI. Dose escalation was done using a 3+3 design with three AzaC dose levels: 30mg/m(2) (level -1), 45mg/m(2) (level 1) and 75mg/m(2) (level 2). Three patients were treated in the 45mg/m(2) dose level and 5 patients were treated in the 75mg/m(2) dose level; no DLTs or grade 3-5 treatment related toxicities were observed. After a median follow-up of 5.2 months, no patients developed grade III-IV aGVHD and no patients died of aGVHD. Six out of 8 patients in the treatment group responded to treatment including two cytogenetic complete remissions, one hematologic complete remission, and three complete remissions with incomplete count recovery. In conclusion, administration of AzaC early post DLI is well tolerated and can potentially prevent GVHD after DLI. Further studies are required to evaluate the effect of azacitidine early post DLI on GVHD and GVL.
在异基因干细胞移植（allo-SCT）后复发的急性髓系白血病（AML）患者中，已采用不进行预防性免疫抑制的供体淋巴细胞输注（DLI）。然而，DLI与急性移植物抗宿主病（aGVHD）的发生率增加相关。在小鼠中，于DLI后第4、6、8和10天给予阿扎胞苷（AzaC）可增加调节性T细胞（Treg）数量，并预防移植物抗宿主病，同时不影响移植物抗白血病（GVL）效应。基于这些发现，我们开展了一项关于DLI后使用AzaC治疗allo-SCT后AML复发的1期研究。在DLI后第4、6、8和10天给予AzaC。采用3+3设计进行剂量递增，设置三个AzaC剂量水平：30mg/m²（-1级）、45mg/m²（1级）和75mg/m²（2级）。45mg/m²剂量水平治疗了3例患者，75mg/m²剂量水平治疗了5例患者；未观察到剂量限制性毒性（DLT）或3-5级治疗相关毒性。中位随访5.2个月后，无患者发生III-IV级aGVHD，也无患者死于aGVHD。治疗组8例患者中有6例对治疗有反应，包括2例细胞遗传学完全缓解、1例血液学完全缓解和3例计数未完全恢复的完全缓解。总之，DLI后早期给予AzaC耐受性良好，可能预防DLI后的移植物抗宿主病。需要进一步研究来评估DLI后早期使用阿扎胞苷对移植物抗宿主病和移植物抗白血病效应的影响。
