IFN-γ and donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation
Sawa Ito, … , Scott Furlan, Warren D. Shlomchik
Sawa Ito, … , Scott Furlan, Warren D. Shlomchik
Published March 25, 2025
Citation Information: JCI Insight. 2025;10(9):e190655. https://doi.org/10.1172/jci.insight.190655.
View: Text | PDF
Clinical Research and Public Health Hematology Transplantation

IFN-γ and donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation

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 5

scRNA-Seq of BM samples collected before and after in vivo treatment with IFN-γ.

Options: View larger image (or click on image) Download as PowerPoint
scRNA-Seq of BM samples collected before and after in vivo treatment wit...
(A) Two-dimensional uniform manifold approximation and projection (UMAP) with cell lineage annotations for the combined pre–IFN-γ and post–IFN-γ samples. For patient 1, transcriptomes from the unfractionated and CD34-selected samples are also combined. (B) Donor and recipient origin of cells by SNP differences between donor and recipient in transcribed genes mapped onto the same UMAP as in A. Most early myeloid and erythroid cells were recipient in origin (consistent with relapsed MDS) whereas lymphoid cells and maturing monocytes were dominantly donor derived. (C) Pre– and post–IFN-γ samples are separately annotated. The overall distributions of major lineage clusters of the pre– and post–IFN-γ samples were similar. (D) SCPA. Shown are q values for changes in the listed pathways (higher values = greater changes in the pathway activity in the post–IFN-γ treatment sample). (E) Volcano plots of the expression of selected genes included in key gene sets in D for HSCs (patients 1 and 7) and myeloid progenitors (patient 5). Shown are Hallmark sets for “IFN-γ response” and Kyoto Encyclopedia of Genes and Genomes (KEGG) for genes involved in antigen processing and presentation. X axis shows average log2 fold-change in the post–IFN-γ treatment samples. Y axis shows –log10 of adjusted P values. (F) The dominant malignant lineage clusters shown in A were separately re-embedded. HSC-like cells were re-embedded for patients 1 and 7, and myeloid progenitor cells were re-embedded for patient 5. The cells in the clustering are depicted as UMAPs with the pre– and post–IFN-γ samples in separate plots. The representative expression levels of STAT1, HLA-A, CIITA, and HLA-DRA are shown in each patient. Ovals surround regions of differences in the re-embedded pre– and post–IFN-γ transcriptomes.