Although allogeneic hematopoietic cell transplantation (alloHCT) is currently the only curative option for many patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), relapse remains the most common cause of morbidity and mortality. In a prospective, open-label, phase II clinical trial, researchers evaluated whether a post-transplant strategy combining prophylactic or preemptive donor lymphocyte infusion (DLI) and the hypomethylating agent azacitidine could reduce the risk of post-transplant relapse.
At the European Society for Blood and Marrow Transplantation, lead author Thierry Guillaume, MD, PhD, from the Centre Hospitalier Universitaire in Nantes, France, and colleagues reported that this combination led to a 3-year survival rate of 66 percent and a lower rate of relapse than historical controls.
The trial evaluated relapse rate and disease-free survival in 30 patients (median age = 58 years; range = 22-70 years) with high-risk AML (n=20) or MDS (n=10) who received azacitidine and DLI post-alloHCT as prophylactic treatment. The patient’s disease status at the time of alloHCT was in first complete remission (CR; n=16; 53%), second CR (n=6; 20%), refractory (n=5; 16%), and upfront transplantation for MDS (n=3; 10%). Cytogenetics were normal or intermediate for 15 patients and unfavorable for 15 patients – eight of whom had complex karyotype.
Azacitidine treatment began between 56 and 112 days post-transplant, at doses of 32 mg/m² per day administered subcutaneously for 5 days every 28 days for up to 12 cycles; 10 patients (33%) completing all 12 cycles. However, 20 patients discontinued treatment because of graft-versus-host disease (GVHD; n=11), relapse (n=5), infection (n=1), sudden death resulting from heart failure (n=1), or withdrawal of consent (n=2).
The first DLI was started following three cycles of azacitidine and discontinuation of immunosuppressive prophylaxis as long as the patient had no clinical signs of GVHD, uncontrolled infection, or a recent history of grade >2 acute GVHD (aGVHD). Two additional DLIs were administered after the fifth and seventh cycles of azacitidine (8 and 16 weeks after the first DLI).
DLIs were administered in the following doses: 5×106, 1×107, 5×107 CD3+cells/kg for related donor alloHCTs and 1×106, 5×106, 1×107 CD3+cells/kg for unrelated donor alloHCTs. Forty-one DLIs were injected in 17 patients: Five patients received one DLI, two patients received two DLIs, and eight patients received all three planned DLIs. Two patients received additional DLIs because of persistent mixed chimerism.
Four months following transplantation, 24 patients (80%) demonstrated full donor chimerism (>95%) in CD3+ cells. Nine patients developed grade 1-3 aGVHD (CI 29.8±9), six of whom did not receive DLI and three following DLI. No grade 4 aGVHD was observed. Nine patients developed chronic GVHD, three of whom did not receive DLI and six following DLI.
The median follow-up from alloHCT of 36 months (range = 12-46 months). The median time to relapse was 5 months (range = 2.5-9 months), and the cumulative incidence of relapse at 3 years was approximately 28 percent.
These results suggest that azacitidine and DLI may have utility as a prophylactic treatment to reduce the risk of post-transplant relapse. The incidence of GVHD following azacitidine plus DLI was not “overwhelming,” the authors concluded.
This study is limited by its small patient population and lack of a control group.
Guillaume T, Yakoub-Agha I, Tabrizi R, et al. Prospective phase II study of prophylactic azacitidine and donor lymphocyte infusions following allogeneic hematopoietic stem cell transplantation for high risk acute myeloid leukemia and myelodysplastic syndrome. Oral abstract presented at the 43rd Annual Meeting of the European Society for Blood and Marrow Transplantation, March 28, 2017; Marseilles, France.