Hypomethylating Agents for Relapse After Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

Background:

Allogeneic hematopoietic cell transplantation (HCT) can be curative in patients with acute myeloid leukemia (AML), but relapse after HCT continues to be a leading cause of mortality.  Treatment options for these patients are limited.  Hypomethylating (HM) agents such as 5-azacytidine and 5-aza-2'-deoxycytidine (gemcitabine) have immunomodulatory properties including augmenting tumor antigen presentation that may enhance graft-versus-leukemia (GVL) effect.  Moreover, inhibitory effects of these agents on T-cell activation and cytokine production may lead to low incidence of graft-versus-host-disease (GVHD).  Our aim was to describe the outcomes, including response, survival, and incidence of GVHD, in patients treated with HM agents for relapsed AML or loss of donor chimerism (LDC) after HCT.

Methods:

Subjects were patients with relapsed AML or LDC after allogeneic HCT for AML or high-risk myelodysplastic syndrome (MDS) who were treated with either 5-azacytidine or decitabine at the University of Pittsburgh Cancer Institute.  Relapse was defined as a period of complete remission (CR) after HCT followed by re-occurrence of >5% myeloid blasts or cytogenetic abnormalities on bone marrow biopsy.  LDC was defined as <100% donor chimerism without relapse.  Retrospective analysis was performed to determine response to HM agents, overall survival from time of relapse or LDC, and incidence of GVHD.

Results:

Thirteen patients were identified, whose median age was 57 years (22-62), and median time to relapse after HCT was 124 days (30 to 847).  Seven patients received myeloablative conditioning regimens, and 6 patients received reduced-intensity conditioning.  Nine patients had relapsed AML, and 4 patients had LDC.  Ten patients were treated with decitabine and 3 patients were treated with 5-azacytidine, with median cycles received of 4 (1-9).  After hypomethylating agents, 9 of 12 (75%) evaluable patients had a CR, and 3 patients had progressive disease.  Eight of 10 (80%) evaluable bone marrow biopsies revealed 100% donor chimerism after treatment with a HM agent.  Grade I-IV acute GVHD of the liver occurred in 6 patients, 3 of whom had isolated liver involvement.  Median survival was 308 days (44-857) from time of relapse or LDC, and 7 patients are alive at time of analysis and remain in CR.

Conclusions:

HM agents in patients with relapsed AML can be effective in reversing loss of donor chimerism and inducing CR.  This may be due to epigenetic changes and subsequent immunomodulatory effects that enhance GVL effect.  There may be a relationship between use of these agents with development of acute liver GVHD, and further exploration into pathophysiology and predisposing factors are warranted.  The use of HM agents as a maintenance strategy in patients at high risk of relapse after HCT should be further explored.