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

Sawa Ito; Emily Geramita; Kedwin Ventura; Biswas Neupane; Shruti Bhise; Erika M. Moore; Scott Furlan; Warren D. Shlomchik

doi:10.1172/jci.insight.190655

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

Sawa Ito,¹ Emily Geramita,¹ Kedwin Ventura,¹ Biswas Neupane,¹ Shruti Bhise,² Erika M. Moore,³ Scott Furlan,² and Warren D. Shlomchik¹

Published March 25, 2025 - More info

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Abstract

BACKGROUND. The graft-vs-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 (DLI) in myeloblastic malignancies that relapsed post-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 (scRNAseq) to assess in vivo responses to IFN-γ by malignant myeloblasts.

RESULTS. IFN-γ monotherapy was well tolerated by all subjects (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. ScRNAseq confirmed in vivo activation of IFN-γ response pathway in hematopoietic stem cell-like or myeloid progenitor cells after IFN-γ in analyzed samples.

CONCLUSIONS. IFN-γ was safe and well tolerated in this phase I study of IFN-γ for relapsed AML/MDS post-alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach.

TRIAL RESGISTRATION. ClinicalTrials.gov NCT04628338.

FUNDING. The research was supported by The UPMC Hillman Cancer Center Cancer Immunology and Immunotherapy Program (CIIP) Pilot Award and Cure Within Reach: Drug Repurposing Clinical Trials to Impact Blood Cancers. Recombinant IFN-gamma (Actimmune®) was donated by Horizon Therapeutics.

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

Sawa Ito,¹ Emily Geramita,¹ Kedwin Ventura,¹ Biswas Neupane,¹ Shruti Bhise,² Erika M. Moore,³ Scott Furlan,² and Warren D. Shlomchik¹

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

Sawa Ito,1 Emily Geramita,1 Kedwin Ventura,1 Biswas Neupane,1 Shruti Bhise,2 Erika M. Moore,3 Scott Furlan,2 and Warren D. Shlomchik1

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

Sawa Ito,¹ Emily Geramita,¹ Kedwin Ventura,¹ Biswas Neupane,¹ Shruti Bhise,² Erika M. Moore,³ Scott Furlan,² and Warren D. Shlomchik¹