Phase IIa Study of Adding Itacitinib to Tacrolimus/Sirolimus Gvhd Prophylaxis after Fludarabine/Melphalan-Based Conditioning Hematopoietic Cell Transplantation for Acute Leukemias, Myelodysplastic Syndrome, or Myelofibrosis

Abstract

Graft-versus-host disease (GVHD) is the primary cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). Itacitinib is a novel, potent, and selective Janus kinases-1 (JAK1) inhibitor that has shown activity in treatment of acute and chronic GVHD. We hypothesized that adding Itacitinib to the standard tacrolimus/sirolimus GVHD prophylaxis is safe and can potentially improve GVHD-free, relapse-free survival (GRFS). Here, we are reporting outcomes of our single arm, single center phase 2a study (NCT04339101) investigating the safety and efficacy of itacitinib administration in patients with acute leukemias, myelodysplastic syndrome (MDS), or myelofibrosis (MF) who underwent PBSC-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. GVHD prophylaxis was sirolimus/tacrolimus (target levels: 5-10ng/ml for both), with itacitinib at 200 mg/day starting from day -3 pre-HCT and continued until day +100. (Figure 1a) Our primary objective was to investigate the safety of itacitinib (Safety lead-in segment; n=6) and estimate 1-year GRFS. Ultimately a total of 59 patients were treated with itacitinib at 200 mg/day dose. Primary endpoint for the safety lead-in segment was toxicity; scored on both the Bearman and NCI CTCAEv5.0 scales. Primary endpoint for the expansion segment was 1-year GRFS. Key secondary endpoints included grade 2-4 acute GVHD, engraftment, infection, overall survival (OS), progression-free survival (PFS), NRM, relapse, chronic GVHD, and itacitinib pharmacokinetics (PK). The enrollment goal was 59 including 6 in the safety lead-in to estimate GRFS at 45% with precision of 0.13. We completed the enrollment (n=59; 36 males [61%] and 23 [39%] females) in May 2022. Median age at the time of HCT was 63 years (range: 23-75), with 14 patients being ≥70 years old at the time of HCT. Patients received HCT from a matched related (n=22) or unrelated (n=36) donor for acute leukemias (n=38; 64.4%), MDS (n=17; 28.8%), or MF (n=4; 6.8%). HCT-CI was 0 in 37 (62.7%) and 1 in 14 (23.7%) of patients. At the time of this report, 57 patients have completed the 100-day observation. The current report is focused on the early data and endpoints with a median follow up duration of 5.9 months (range: 0.6-12.4). There was no case of protocol-defined unacceptable toxicity in the safety lead-in phase. All 59 patients engrafted with a median time to neutrophil and platelet engraftment of 15 days (range: 11-23) and 16 days (range: 8-80), respectively. There were no deaths in the first 100 days except for one patient who passed due to severe sepsis and resultant multiple organ failure. Grade 3-4 adverse events (by CTCAEv5.0) within 100 days, reported as at least possibly related to itacitinib, were anemia (n=1), febrile neutropenia (n=2), abdominal pain (n=1), lymphocytopenia (n=8), neutropenia (n=1), thrombocytopenia (n=3), leukopenia (n=3), and hypertriglyceremia (n=1). There were 19 microbiologically documented infections during the first 100 days (12 bacterial, 5 viral, and 2 fungal infections). Acute GVHD grade 2-4 and 3-4 were observed in 6 (10%) and 5 (8%) patients, respectively. With the limited follow up duration (5.9 months) and observed events including all-cause mortality (n=9, NRM=6), grade 3-4 acute GVHD (n=5), moderate/severe chronic GVHD (n=2), and disease relapse (n=8), the estimated GRFS at 6-months and 1-year were 0.71 (95%CI: 0.56-0.81) and 0.51 (95%CI: 0.31-0.68), respectively. (Figure 1b) Results of our preliminary PK studies (n=18) showed average itacitinib trough levels between days -2 and +5 of 25.2.6 ± 39.1 nM. Average Cmax, AUC 0-inf, T1/2, and CL/F around the dose on Day +5 were 11362.0 ± 852.9 nM, 4905.6 ± 2422.8 nM x hr, 4.4 ± 1.7 hr, and 90.3 ± 39.6 L/hr (Figure 1c). The measured itacitinib exposure is significantly higher than previously reported results, indicating a potential drug interaction with sirolimus. In conclusion, early results of this phase 2 study indicated that itacitinib (200 mg daily) with tacrolimus/sirolimus GVHD prophylaxis was safe and tolerated with 100% engraftment and low rate of acute GVHD without excessive toxicities. Early survival data including preliminary GRFS are promising. The study follow up is ongoing, and mature clinical data and immune reconstitution analyses will be updated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal