A Phase I Study Of Azacitidine After Donor Lymphocyte Infusion For Relapsed Acute Myeloid Leukemia Post Allogeneic Stem Cell Transplantation

Disease relapse remains a significant cause of morbidity and mortality for patients with acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT). In the event of relapse, remissions may be re-established with salvage chemotherapy, but are rarely durable. Reinfusion of additional donor lymphocytes (DLI) from the same donor without prophylactic immunosuppression has been used to potentially augment the graft vs leukemia (GVL) effect, and shown to prolong survival in the post alloSCT relapse setting (Schmid et al, JCO 2007). However, DLI is also associated with an increased incidence of acute graft versus host disease (aGVHD). Regulatory T cells (Tregs) are characterized by increased FoxP3 gene expression and have been correlated with a reduced incidence and severity of GVHD. Using a mouse model, Choi et al (Blood, 2010) observed that administration of azacitidine post stem cell infusion resulted in increases in both FoxP3 expression and Treg numbers, and reduced the incidence and severity of GVHD without hindering neutrophil engraftment. Based on these findings, we conducted a study of azacitidine following salvage chemotherapy and subsequent DLI for AML patients with post alloSCT relapse, with the goal of reducing the incidence and severity of aGVHD.

(i) To establish the MTD of azacitidine administered after salvage chemotherapy and DLI in patients with relapsed AML after alloSCT and (ii) to determine the response rate, the rate of aGVHD, and overall survival of this regimen.

Patients with relapsed AML after allogeneic stem cell transplant undergoing salvage chemotherapy followed by DLI were eligible for enrollment. Patients with prior exposure to azacitidine were not excluded. Salvage chemotherapy was determined by the treating physician. Six to twenty-one days following the completion of chemotherapy, a DLI was administered consisting of > 1x10⁶ CD3+ cells/kg. Azacitidine was administered on Days 4, 6, 8 and 10 post-DLI. G-CSF was administered daily beginning Day +11 post-DLI until neutrophil recovery. Dose escalation was done using a 3+3 design with two azacitidine dose levels, 45mg/m² and 75mg/m². Dose-limiting toxicity (DLT) was defined as treatment-related grade 3-5 non-hematologic toxicities or bone marrow suppression lasting past Day +32 in the absence of persistent AML.

Eight patients were enrolled from June 2012-July 2013. The median age was 54.5 years (range 31-68) and five were female. Four of eight patients received stem cells from sibling donors. The median time post alloSCT until salvage chemotherapy was 109 days (range 56-1102). Pre-DLI chemotherapy consisted of: FLAG-Ida (3), FLAG (1), MEC (1), 7+3 (1), CLAM (1), or Azacitidine (1). Three patients were treated in the 45mg/m² dose level and 5 patients were treated in the 75mg/m²dose level; no DLTs or grade 3-5 treatment related toxicities were observed. Five patients experienced aGVHD, all of which was grade I or II and easily controlled. The median duration of time to neutrophil recovery was 17 days post DLI (range 6-34) and 24 days from last day of salvage chemotherapy (range 16-41), similar to historical controls. Six patients achieved responses, including two cytogenetic complete remissions, one hematologic complete remission, and three complete remissions with incomplete blood count recovery; two patients failed to achieve remission. At the time of abstract submission, the median follow-up for all patients was 102 days (range 31-308). Four responders have subsequently relapsed and three patients have expired from refractory disease.

Administration of azacitidine post salvage chemotherapy and DLI is well tolerated and does not hinder neutrophil recovery. The recommended dose for further studies is 75mg/m².

Off Label Use: vidaza for GVHD prophylaxis. Abboud:Novartis: Honoraria; Ariad: Honoraria; Alexion: Honoraria; Teva: Speakers Bureau. Schroeder:sanofi-aventis: Research Funding; celgene: Research Funding. Stockerl-Goldstein:Celgene : Speakers Bureau; Millennium: Speakers Bureau. Vij:celgene: Honoraria, Research Funding. Westervelt:celgene: Honoraria, Research Funding.