Final Analysis of Phase 2a Study of Adding Itacitinib to Tacrolimus/Sirolimus Gvhd Prophylaxis after Fludarabine/Melphalan-Based Conditioning Hematopoietic Cell Transplantation for Acute Leukemias, Myelodysplastic Syndrome (MDS), or Myelofibrosis (MF)

Introduction: In a phase 2a clinical trial (NCT04339101), we hypothesized that adding Itacitinib, a potent and selective Janus kinases-1 inhibitor, to the standard tacrolimus/sirolimus (Tac/Siro) graft-vs-host-disease (GVHD) prophylaxis is safe and can potentially improve GVHD-free, relapse-free survival (GRFS). We previously reported the early results of our trial including the safety, tolerability, pharmacokinetics (PK), GVHD, and incomplete survival estimates due to short follow up period [Blood (2022) 140 (Supplement 1): 1872–1874]. Here, we present our final results focused on the primary endpoint of 1-year GRFS, survival outcomes, and immunologic correlates.

Methods: Patients with acute leukemias, MDS, or MF who underwent peripheral blood stem cell allogeneic hematopoietic cell transplant (HCT) from a matched donor. Patients received fludarabine (125 mg/m²) and melphalan (140 mg/m² or 100 mg/m² for patients ≥70 years) as reduced intensity conditioning with Tac/Siro (target levels: 5-10ng/ml for both) and itacitinib (200 mg/day) starting from day -3 pre-HCT and continued until day +100 as GVHD prophylaxis. The primary objective was to investigate the safety of itacitinib (Safety lead-in segment; n=6) and estimate 1-year GRFS (expansion segment). Ultimately a total of 59 patients were enrolled to estimate 1-year GRFS rate with a half width of 95% confidential limits as 0.13 for the promising target 1-year GRFS rate of 45%.

Results: The Median age at the time of HCT was 63 years (range: 23-75), with 14 patients being ≥70 years old. Patients received HCT from a matched related (n=23) or unrelated (n=36) donor for acute leukemias (n=37; 63%), MDS (n=17; 29%), or MF (n=5; 8%). HCT-CI was 0 in 37 (63%) and 1 in 14 (24%) patients. There was no case of protocol-defined unacceptable toxicity in the safety lead-in phase. All patients completed at least 12 months of observation with the median of 725 days for surviving patients (range: 358-771). At 1 and 2 years post-HCT, GRFS was 54% (95% CI: 41-66%) and 40% (95% CI: 28-52%), respectively. 1-year GRFS rate of 54% was significantly higher than the historical rate of 30% using one-sided 0.05 level test. At 180 days post-HCT, acute GVHD (aGVHD) grades 2-4 and 3-4 were diagnosed in 9% (95% CI: 3-18%) and 7% (95% CI:2-15%) of patients, respectively. The cumulative incidence of overall and moderate/severe chronic GVHD at 2 years were 38% (95% CI: 25-50%) and 20% (95% CI: 11-32%), respectively. Of the 6 patients who experience grade 2-4 GVHD, 3 were diagnosed after day 100 post-HCT. The non-relapse mortality (NRM) was very low at 2% at 100 days and 21% (95% CI: 11-32%) at 2 years. The cumulative incidence of relapse was 17% at 2 years (95% CI: 9-28%).

Results of serum cytokine analysis showed that elevated levels (≥median) of HGF, IL17, and TNFaR on day 14 post-HCT were significantly associated with higher incidence of aGVHD (grade 2-4 and 3-4), while higher levels (≥median) of GCSF, TNFaR and IL10 on day 14 were associated with inferior GRFS. Flow cytometry analyses of peripheral blood mononuclear cells on days 35 and 100 demonstrated cellular immune reconstitution in this cohort and showed a trend towards improved 1-year GRFS associated with a greater Treg:Tcon ratio on day 35 (≥ median) (67% vs. 48%, p=0.10). Itacitinib PK results showed that higher average trough levels (≥median, measured on days -3 to +5) was associated with 1-year GRFS of 59% compared with 50% in patients with lower levels (<median) without reaching statistical significance (p=0.16). Itacitinib AUC on Day +5 was positively correlated with day 14 HGF (p=0.01) and IL17 (p=0.04) levels.

Conclusion: Addition of itacitinib to Tac/Siro GVHD prophylaxis was safe and associated with 100% engraftment and low rate of acute/chronic GVHD. The study met the primary endpoint of 1-year GRFS at 54%, which is compared favorably to Tac/Siro or Tac/methotrexate as GVHD prophylaxis, similar to the results observed in PTCy/tacrolimus/MMF (BMT CTN 1703). The observed aGVHD rate was lower than our previously published historic data in patients receiving Tac/Siro alone (31% vs. 9%), half of the cases with grade 2-4 aGVHD were diagnosed after day +100 when itacitinib administration stopped per protocol therapy, indicating the need for further refinement in tapering strategy of Tac/Siro/itacitinib, potentially guided by the cytokine/cellular biomarkers identified in our study.