JAK2/mTOR Inhibition Fails to Prevent Acute Gvhd Despite Reduced Th1/Th17 Cells: Final Phase II Trial Results

Introduction: Our phase I graft-versus-host disease (GVHD) prevention trial of pacritinib (recommended phase II dose: 100mg po BID day 0 to +70, dose level 2) plus sirolimus (8-14ng/ml) and tacrolimus (3-7ng/ml) (PAC/SIR/TAC) demonstrated the regimen was safe and free of pan-JAK myelosuppression after allogeneic hematopoietic cell transplantation (alloHCT). PAC inhibits JAK2 with no activity against JAK1, avoiding off-target suppression of IL-2 required by Tregs. JAK2/STAT3 activity mediates IL-6, IL-12, and IL-23 receptor signaling and subsequent pathogenic Th1 and Th17 differentiation. JAK2/mTOR blockade supports Treg potency, providing further rationale for the PAC/SIR/TAC combination. Herein we report on our completed phase II trial of PAC/SIR/TAC after 8/8-HLA matched alloHCT. Methods: This single-arm phase II trial (NCT02891603) was powered to determine if PAC/SIR/TAC suppressed %pSTAT3 + CD4 + T cells at day +21 (primary endpoint: %pSTAT3 + CD4 + T cells ≤ 35%) and determine the cumulative incidence of grade II-IV acute GVHD by day +100. We also evaluated the impact of PAC/SIR/TAC on CD4 T cell differentiation (Treg, Th1, Th17) and related CD28 (pS6 and pH3ser10) and IL-2 receptor (pSTAT5) signal transduction after alloHCT. Eligible patients (n=28) received alloHCT for AML, MDS, ALL, and MF. Reduced (n=21) or myeloablative (n=7) intensity conditioning was permitted. HLA-A, -B, -C, and -DRB1 matched-related (n=7) or unrelated donors (n=21) were allowed. Adequate vital organ function and Karnofsky performance status (KPS ≥ 80%) were required. Results: PAC/SIR/TAC (PAC 100mg BID) met the primary endpoint of the phase II study, reducing %pSTAT3 + CD4 + T cells to 9.62% at day +21 ( Figure 1A). PAC/SIR/TAC significantly improved CD4 + T cell STAT5 phosphorylation at day +21, increasing the ratio of pSTAT5 + to pSTAT3 + CD4 + T cells (ratio 80.7 v 1.71 P