Itacitinib for Prevention of Graft-Versus-Host Disease and Cytokine Release Syndrome with T-Cell Replete Peripheral Blood Haploidentical Transplantation

Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are higher with PB grafts compared with bone marrow, affecting 35-45% of patients and outcomes are poor in steroid refractory cases. Severe CRS occurs in 10-15% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and one-year overall survival between 25-30%. As interferon-γ and IL-6 are important mediators in both acute GVHD and CRS, we hypothesized that JAK1 inhibition with itacitinib could prevent these toxicities without impairing engraftment. Here we report outcomes from our study of itacitinib with haplo-HCT (NCT03755414). Methods: Patients with AML, MDS, ALL, or NHL in remission undergoing PB haplo-HCT were treated with itacitinib 200 mg/day on days -3 through +100 (first 20 patients) or 180 (second 22 patients), followed by a taper. Myeloablative and reduced intensity conditioning were allowed. GVHD prophylaxis was tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. Primary outcomes were incidence of primary graft failure and incidence of grade III-IV acute GVHD. Secondary outcomes included incidence and severity of CRS, relapse, GRFS, and overall survival. Results: Forty-two patients were enrolled and underwent transplantation on study between November 2019 and December 2022, median days of follow up was 453 days (range 142-1259). The patient population had a median age of 60 years (20 - 73 years) with the majority of patients having AML (AML 60%, ALL 21%), MDS 10%, MF 5%, NHL 4%). All patients with AML, MDS, or ALL were in a complete morphologic remission, although 45% had disease by either cytogenetics, next generation sequencing, or measurable residual disease assay (flow cytometry for AML/MDS, NGS for ALL). There were no cases of grade III-IV acute GVHD. The cumulative incidence of grade II acute GVHD on day 100 was 17.3% (95% CI, 7% - 31%), day 180 was 20.5% and day 365 was 20.5%. There were no cases of severe CRS with 90% of patients having grade 1 CRS and 10% having no CRS. No anti-IL6R or steroid therapy was used. There were no cases of primary graft failure. The cumulative incidence of relapse at 1 year was 10% (95% CI, 3% to 22%) and at 2 years was 14% (95% CI, 5% to 29%). In patients who survived without relapse to day 100, the 1-year cumulative incidence of moderate or severe chronic GVHD was 5% (95% CI 1% - 17%). The refined GRFS at day +180 was 85% (95% CI 69% - 93%) and at day +365 was 79% (95% CI 62% - 89%). Overall survival at 180 days 87% (95% CI 72% - 94%) and at 1 year was 80% (95% CI 63% - 90%). Analysis of peripheral blood mononuclear cells at day +28, +60, and +100, revealed that patients on itacitinib, compared with control haplo-HCT patients, had lower numbers of CD4 and CD8 central memory T cells, lower numbers of CD4 and CD8 naïve T cells, and higher numbers of classical monocytes, nonclassical monocytes, and both myeloid and plasmacytoid dendritic cells. In itacitinib treated patients, T-cell subsets expressed lower LAG3 and PD-1 and higher TIGIT, while monocytes expressed higher HLA-DR, CD80, and CD86. Conclusions: Itacitinib with PB haplo-HCT was safe with low rates of acute and chronic GVHD, without increased risk of relapse or transplant related mortality. Severe CRS was not seen in this trial, and no anti-IL6 or steroid therapy was used. The addition of Jak inhibition to standard PtCy based GVHD prophylaxis was associated with encouraging rates of GRFS and OS on this pilot and expansion study. Patients on itacitinib have unique immune reconstitution characteristics both in terms of PBMC counts and signaling markers within subsets.