Type 1 interferon to prevent leukemia relapse after allogeneic transplantation

A potent graft-versus-leukemia (GVL) response is crucial in preventing relapse, the major impediment to successful allogeneic hematopoietic cell transplantation (HCT). In preclinical studies, type 1 interferon (IFN-a) enhanced cross-presentation of leukemiaspecific antigens by CD8a dendritic cells (DCs) and amplified GVL. This observation was translated into a proof-of-concept phase 1/2 clinical trial with long-acting IFN-a (pegylated IFN-a [pegIFNa]) in patients undergoing HCT for high-risk acute myeloid leukemia (AML). Patients with treatment-resistant AML not in remission or those with poor-risk leukemia were administered 4 dosages of pegIFNa every 14 days beginning at day 21 before HCT. Dose selection was established by adaptive design that continuously assessed the probability of dose-limiting toxicities throughout the trial. Efficacy was evaluated by determining the 6-month incidence of relapse at the maximum tolerated dose (MTD). Thirty-six patients (median age, 60 years) received pegIFNa treatment. Grade 3 or greater severe adverse events occurred in 25% of patients, establishing 180 mg as the MTD. In phase 2, the incidence of relapse was 39% at 6 months, which was sustained through 1-year post-HCT. The incidence of transplant-related mortality was 13%, and severe grade III-IV acute graft-versus-host disease (GVHD) occurred in 11%. Paired blood samples from donors and recipients after HCT revealed elevated levels of type 1 IFN with cellular response, the persistence of cross-presenting DCs, and circulating leukemia antigenspecific T cells. These data suggest that prophylactic administration of pegIFNa is feasible in the peri-HCT period. In high-risk AML, increased toxicity was not observed with preliminary evidence for reduction in leukemia relapse after HCT. This trial was registered at www.clinicaltrials.gov as #NCT02328755.

Automated summary

A strong graft-versus-leukemia (GVL) response is essential in preventing relapse after allogeneic hematopoietic cell transplantation (HCT). Preclinical studies showed that type 1 interferon (IFN-a) enhances cross-presentation of leukemia-specific antigens, leading to amplified GVL. Clinical trials with pegylated IFN-a (pegIFNa) in high-risk AML patients undergoing HCT demonstrated feasibility of prophylactic pegIFNa administration without increased toxicity and potential reduction in leukemia relapse post-transplantation.