Abstract
BACKGROUND The graft-versus-leukemia (GVL) effect contributes to the efficacy of allogeneic stem cell transplantation (alloSCT). However, relapse, indicative of GVL failure, is the greatest single cause of treatment failure. Based on preclinical data showing that IFN-γ is important to sensitize myeloblasts to alloreactive T cells, we performed a phase I trial of IFN-γ combined with donor leukocyte infusions (DLIs) in myeloblastic malignancies that relapsed after HLA-matched alloSCT.METHODS Patients with relapsed acute myeloid leukemia or myelodysplastic syndrome after alloSCT were eligible. Patients self-administered IFN-γ for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-γ for a total of 12 weeks. Bone marrow samples were analyzed by single-cell RNA sequencing (scRNA-Seq) to assess in vivo responses to IFN-γ by malignant myeloblasts.RESULTS IFN-γ monotherapy was well tolerated by all participants (n = 7). Treatment-related toxicities after DLI included grade I–II graft-versus-host disease (n = 5), immune effector cell–associated neurotoxicity syndrome (n = 2), and idiopathic pulmonary syndrome (n = 1), all of which resolved with corticosteroids. Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97–906) in responders. scRNA-Seq validated in vivo activation of the IFN-γ response pathway in hematopoietic stem cell–like or myeloid progenitor cells after IFN-γ in analyzed samples.CONCLUSION IFN-γ was safe and well tolerated in this phase I study of IFN-γ for relapsed acute myeloid leukemia and myelodysplastic syndrome after alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach.TRIAL REGISTRATION ClinicalTrials.gov NCT04628338.FUNDING UPMC Hillman Cancer Center Cancer Immunology and Immunotherapy Program Pilot Award and Cure Within Reach: Drug Repurposing Clinical Trials to Impact Blood Cancers.
Authors
Sawa Ito, Emily Geramita, Kedwin Ventura, Biswas Neupane, Shruti Bhise, Erika M. Moore, Scott Furlan, Warren D. Shlomchik
Figure 2
Clinical course of responders after initiation of IFN-γ.
