Effective treatment of low-risk acute GVHD with itacitinib monotherapy

Abstract

The standard primary treatment for acute graft vs host disease (GVHD) requires prolonged, high dose systemic corticosteroids (SCS) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/day (responders could receive a second 28-day cycle) and compared their outcomes to 140 contemporaneous, matched control patients treated with SCS. More patients responded to itacitinib within 7 days (81% vs 66%, p=0.02) and response rates at day 28 were very high for both groups (89% vs 86%, p=0.67) with few symptomatic flares (11% vs 12%, p=0.88). Fewer itacitinib treated patients developed a serious infection within 90 days (27% vs 42%, p=0.04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, p=0.02). No other grade ≥3 adverse events occurred in >10% of itacitinib treated patients. There were no significant differences between groups at 1-year for non-relapse mortality (4% vs 11%, p=0.21), relapse (18% vs 21%, p=0.64), chronic GVHD (28% vs 33%, p=0.33) or survival (88% vs 80%, p=0.11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD that deserves further investigation.

Gastrointestinal Involvement Refines Prognosis in Minnesota Standard Risk Acute Graft-vs-Host Disease

“…It is an appealing risk classi cation as it is immediately available to clinicians, requires only bedside measures, and is calculated at GVHD onset. It is informative both in reference to AGVHD response rate and NRM and is a necessary step in re ning AGVHD therapy; HR patients may be candidates for investigational approaches to AGVHD management whereas those with more favorable outcomes may bene t from steroid-free or steroid-sparing therapies (9,10). As such, it has been incorporated into eligibility criteria for clinical trials targeting both standard and high-risk patients with AGVHD, for example the recently published BMT CTN 1501(9) (NCI02806947) trial and the currently enrolling BMT CTN 1705 (NCI04167514) trial.…”

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

“…Flares of acute GVHD are often observed during tapering or after discontinuation of immunosuppressive therapy, however their significance with respect to overall outcomes is not well understood. Although flares are recognized as important in clinical GVHD trials either as an end point (ie, duration of response) 36 , 37 or as an eligibility criterion for steroid-refractory/dependent GVHD, 9 , 38 , 39 , 40 there is no established definition. Relying on expert consensus in our consortium, in this study, we define a flare of acute GVHD as worsening of symptoms by at least 1 stage in at least 1 organ after an initial CR/VGPR that prompted an increase or restart of immunosuppressive treatment.…”

Children's Oncology Group's 2023 blueprint for research: Cellular therapy and stem cell transplantation

“…MAGIC also studied steroid‐free treatment of GVHD using the JAK1 inhibitor itacitinib in adolescent and adult patients with biomarker‐confirmed low‐risk GVHD. Itacitinib monotherapy was as effective as systemic steroid treatment in a matched control group (response rate 89% vs 86%, p = 0.67) and resulted in significantly fewer severe infections (27% vs 42%, p = 0.04) 50 . Similar trials in younger pediatric cohorts could be facilitated through the COG CT committee.…”

“…Itacitinib monotherapy was as effective as systemic steroid treatment in a matched control group (response rate 89% vs 86%, p = 0.67) and resulted in significantly fewer severe infections (27% vs 42%, p = 0.04). 50…”