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Multicenter Study
. 2023 Feb 2;141(5):481-489.
doi: 10.1182/blood.2022017442.

Effective treatment of low-risk acute GVHD with itacitinib monotherapy

Aaron Etra  1 , Alexandra Capellini  1 , Amin Alousi  2 , Monzr M Al Malki  3 , Hannah Choe  4 , Zachariah DeFilipp  5 , William J Hogan  6 , Carrie L Kitko  7 , Francis Ayuk  8 , Janna Baez  1 , Isha Gandhi  1 , Stelios Kasikis  1 , Sigrun Gleich  9 , Elizabeth Hexner  10 , Matthias Hoepting  9 , Urvi Kapoor  1 , Steven Kowalyk  1 , Deukwoo Kwon  11 , Amelia Langston  12 , Marco Mielcarek  13 , George Morales  1 , Umut Özbek  11 , Muna Qayed  14 , Ran Reshef  15 , Wolf Rösler  16 , Nikolaos Spyrou  1 , Rachel Young  1 , Yi-Bin Chen  5 , James L M Ferrara  1 , John E Levine  1
Affiliations
Multicenter Study

Effective treatment of low-risk acute GVHD with itacitinib monotherapy

Aaron Etra et al. Blood. .

Abstract

The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) 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/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .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 = .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 nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.

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Conflict of interest statement

Conflict-of-interest disclosure: A.E. received consulting fees from Kadmon. A.A. received research funding from Incyte. M.M.A.M. received consulting fees and research funding from Incyte. Z.D. received research support from Incyte, Regimmune, and Taiho Oncology and consulting fees from Syndax Pharmaceuticals, Kadmon, Omeros, Incyte, and MorphoSys. C.L.K. received consulting fees from Horizon Therapeutics. F.A. received research funding from Mallinckrodt/Therakos and consulting fees from Celgene/BMS, Gilead, Janssen, Mallinckrodt/Therakos, Medac, Miltenyi Biomedicine, Novartis, and Takeda. U.Ö. is now employed by Eli Lilly and Company. M.Q. received consulting fees from Jazz Pharmaceuticals, Novartis, and Vertex. R.R. received research funding from Atara Biotherapeutics, Gilead Science, J&J, Immatics, Incyte, Pharmacyclics, Precision Biosciences, Shire, and Takeda; consulting fees from Atara Biotherapeutics, Bristol-Myers Squibb, Gilead Sciences, Jasper, Novartis, Regeneron, Synthekine and Tscan; and has an expert witness role with Bayer. Y.-B.C. received consulting fees from Actimium, Celularity, Equillium, Gamida Cell, Incyte, Jasper, and Novartis. J.L.M.F. received research support from Equillium, Genentech, Incyte, and Mesoblast and consulting fees from Alexion, Bo Fu Rui, Equillium, Eurofins Viracor, Nimbus Discovery, Physicians Education Resource, and Xenikos. J.E.L. received research support from Biogen, Equillium, Incyte, MaaT Pharma, and Mesoblast and consulting fees from Bluebird Bio, Equillium, Jazz, Mallinckrodt/Therakos, Mesoblast, and X4 Pharmaceuticals. U.Ö., J.L.M.F., and J.E.L. are coinventors on a GVHD patent and receive royalties. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
ORR after 4 weeks of systemic therapy for GVHD. ORR was defined as CR and PR within 28 days of treatment with either itacitinib (Ita) or systemic corticosteroids (SCS) without additional therapy. (A) All GVHD patients. (B) Patients with lower GI (LGI) symptoms.
Figure 2.
Figure 2.
Long-term outcomes following systemic treatment of acute GVHD.P values express the difference between the itacitinib (Ita) and the systemic corticosteroid (SCS) groups. The Gray test was used to compare cumulative incidences, and the log-rank test was used to compare survival between groups. (A) Relapse: P = .64. (B) cGVHD: P = .33. (C) NRM: P = .21. (D) Overall survival (OS): P = .11.
Figure 3.
Figure 3.
Serious infections within 90 days following systemic treatment of acute GVHD.P values express the difference between the itacitinib (Ita) and systemic corticosteroid (SCS) groups. The Gray test was used to compare cumulative incidences, and the Fisher exact test was used to compare categories of serious infections. (A) Cumulative incidence. (B) Categories of serious infections. Any patient with a fungal infection is included in fungal ± other. One control patient included in the viral + bacterial category also had a parasitic infection.
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