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Allogeneic stem cell transplantation (SCT) is a curative therapy for patients with hematological malignancies related largely to an immunological graft-versus-leukemia (GVL) effect mediated by donor T cells and natural killer cells. Relapse of disease after SCT represents failure of GVL and is now the major cause of treatment failure. We sought to augment GVL effects in patients (n = 29) relapsing after SCT in a prospective phase I/II clinical trial of dose-escalated pegylated interferon-2α (peg-IFNα). The administration of peg-IFNα after reinduction chemotherapy, with or without subsequent donor lymphocyte infusion (DLI), resulted in a 2-year overall survival (OS) of 31% (95% confidence interval, 17.3%-49.2%), which rejects the null hypothesis of 7% generated by observations in an institutional historical cohort. As expected, peg-IFNα was associated with graft-versus-host disease (GVHD) and hematological toxicity, which was manageable with scheduled dose modifications. Progression-free survival (PFS) was greatest in patients who experienced GVHD, although the majority of those patients still eventually progressed. Higher PFS and OS were associated with pretreatment proportions of immune cell populations with regulatory function, including mucosal invariant T cells, regulatory T cells, and plasmacytoid dendritic cells, independent of any association with GVHD. Peg-IFNα administration after relapse thus constitutes a logical strategy to invoke GVL effects and should be studied in a larger, multicenter cohort. This trial was registered at www.anzctr.org.au as #ACTRN12612000728831., (© 2019 by The American Society of Hematology.)