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After allogeneic-hematopoietic stem cell transplantation (allo-HSCT), 50–70% of patients develop acute graft-versus-host disease (aGvHD), which accounts for approximately 10% of non-relapse mortality (NRM). First-line treatment for aGvHD often involves corticosteroids; however, corticosteroid-refractory aGvHD (SR-aGvHD) can develop. Preclinical studies have demonstrated that the Janus kinase (JAK) pathway is involved in the pathogenesis of aGvHD as JAK1/2 inhibition prevents the production of various cytokines, and consequently, the differentiation, proliferation, and trafficking of T cells.1
Ruxolitinib, an oral selective JAK1/2 inhibitor, is already approved by the U.S. Food and Drug Administration (FDA) for the treatment of SR-aGvHD. However, newer preclinical studies have shown that specific targeting of JAK1 may abrogate the cytokine signaling involved in GvHD pathogenesis, without inducing cytopenias that are caused by the co-inhibition of JAK2 signaling. As such, itacitinib, a selective JAK1 inhibitor that has shown preclinical activity in aGvHD models, was investigated in an open-label, phase I trial.1
Mark A. Schroeder from the Washington University School of Medicine, St. Louis, US, and colleagues evaluated the safety, efficacy, and pharmacokinetics (PK) of itacitinib in combination with corticosteroids in patients with treatment-naïve or SR-aGvHD. The results were recently published in Blood Advances.1
Table 1. Patients characteristics1
CIBMTR, Center for International Blood and Marrow Transplant Research; ECOG PS, Eastern Cooperative Oncology Group performance status; GI, gastrointestinal; GvHD, graft-versus-host disease |
|
Characteristic |
Patients (N = 29) |
---|---|
Age, median (range), years |
51 (18–71) |
Sex, male/female, % |
69/31 |
Race, % |
|
White |
82.8 |
African American |
6.9 |
Asian |
6.9 |
Other |
3.4 |
ECOG PS, % |
|
0 |
6.9 |
1 |
44.8 |
2 |
44.8 |
3 |
3.4 |
GvHD organ involvement, % |
|
Lower GI tract |
58.6 |
Upper GI tract |
31.0 |
Skin |
44.8 |
Liver |
17.2 |
Isolated skin |
20.7 |
Skin + upper GI |
6.9 |
> 1 organ involved |
89.7 |
≥ 2 organs involved |
48.3 |
GvHD Minnesota grade, % |
|
II–IV |
96.6 |
III/IV |
62.1 |
GvHD CIBMTR grade, % |
|
B–D |
96.6 |
C/D |
58.6 |
Table 2. Hematological and non-hematological TEAEs1
TEAE, treatment-emergent adverse event *Occurring in > five patients †Including patients with GI GvHD ‡Thrombocytopenia and decreased platelet count were mutually exclusive in this data set. Decreased platelet count was chosen in cases of laboratory decreases; thrombocytopenia was chosen as a clinical diagnosis. |
||||
Itacitinib dose |
200 mg (n = 14) |
300 mg (n = 15) |
||
---|---|---|---|---|
TEAE* |
Grade 3/4 |
All grades |
Grade 3/4 |
All grades |
Non-hematological, % |
|
|
|
|
Diarrhea† |
28.6 |
57.1 |
13.3 |
40.0 |
Peripheral edema |
0.0 |
28.6 |
6.7 |
60.0 |
Abdominal pain |
14.3 |
42.9 |
6.7 |
33.3 |
Hypokalemia |
28.6 |
42.9 |
20.0 |
33.3 |
Hyperglycemia |
21.4 |
42.9 |
26.7 |
26.7 |
Fatigue |
28.6 |
28.6 |
0.0 |
33.3 |
Decreased appetite |
14.3 |
21.4 |
6.7 |
33.3 |
Tachycardia |
14.3 |
42.9 |
0.0 |
13.3 |
Headache |
0.0 |
35.7 |
0.0 |
13.3 |
Hypoalbuminemia |
21.4 |
28.6 |
6.7 |
20.0 |
Hypophosphatemia |
21.4 |
28.6 |
13.3 |
20.0 |
Nausea |
0.0 |
35.7 |
6.7 |
13.3 |
Vomiting |
0.0 |
35.7 |
6.7 |
13.3 |
Arthralgia |
0.0 |
0.0 |
0.0 |
40.0 |
Fall |
0.0 |
28.6 |
0.0 |
13.3 |
Hypertension |
0.0 |
7.1 |
26.7 |
33.3 |
Hypogammaglobulinemia |
0.0 |
28.6 |
0.0 |
13.3 |
Edema |
7.1 |
21.4 |
0.0 |
20.0 |
Pyrexia |
0.0 |
28.6 |
0.0 |
13.3 |
Hematological‡, % |
|
|
|
|
Anemia |
35.7 |
35.7 |
33.3 |
40.0 |
Decreased platelet count |
14.3 |
14.3 |
40.0 |
40.0 |
Thrombocytopenia |
14.3 |
21.4 |
20.0 |
26.7 |
Schroeder MA, Khoury HJ, Jagasia M, et al. A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease. Blood Adv. 2020;4(8):1656-1669. DOI: 1182/bloodadvances.2019001043
Clinicaltrials.gov. Study of itacitinib in combination with corticosteroids for the treatment of acute GVHD. https://clinicaltrials.gov/ct2/show/study/NCT02614612. Updated Mar 8, 2019. Accessed May 19, 2020
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