Novel Therapies for Severe Acute GVHD (Graft-versus-host Disease)

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression as first line therapy. Many patients with severe acute GVHD do not respond to primary therapy, high-dose systemic corticosteroids; therefore, survival for those patients remains particularly poor. Here we determine the efficacy and safety of combined Ruxolitinib With Corticosteroids as First Line Therapy for the Treatment of severe acute GVHD.

• Ruxolitinib and Methylprednisolone (Drug): Participants began oral administration of ruxolitinib at 5 mg QD; Methylprednisolone (1mg/kg)
• Methylprednisolone (Drug): Methylprednisolone 2mg/kg/d , iv or iv gtt for at least 1 week, then taper according to the clinical response.

Primary outcomes

• Overall response rate (ORR) at Day 28 [Day 28 after treatment]: Defined as the proportion of participants demonstrating a complete response (CR), and partial response (PR).

Secondary outcomes

• Six-month duration of response [Six-month after treatment]: Defined as the time from first response until graft-versus-host disease (GVHD) progression or death. Six-month duration of response will be assessed when all participants who are still on study complete the Day 180 visit.
• Ninety-day duration of response [Day 90 after treatment]: Defined as the time from first response until GVHD progression or death, when all participants who are still on study complete the Day 90 visit.
• Nonrelapse mortality (NRM) [1 year after treatment]: NRM was defined as death from any cause without relapse. Cumulative incidence of NRM was analyzed in a competing risk framework using Gray's method.
• Cumulative incidence of relapse [1 year after treatment]: Defined as the proportion of participants whose underlying malignancy relapsed.Relapse was defined as hematologic recurrence of malignancies after transplantation. Cumulative incidence of relapse was analyzed in a competing risk framework using Gray's method.
• Disease-free survival (DFS) [1 year after treatment]: Defined as the time from first dose of ruxolitinib to the earliest date that a participant died, had a relapse/progression of the underlying malignancy, required additional therapy for aGVHD, or demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD).DFS will be evaluated in an intent-to-treat analysis by Kaplan Meier estimate and Log Rank test. Survival will be calculated from the date of randomization.
• GVHD-free and relapse-free survival (GRFS) [1 year after treatment]: GRFS was defined as the time onset of grade 3 to 4 aGVHD, moderate to severe cGVHD, or relapse/disease progression/death. GRFS will be evaluated in an intent-to-treat analysis by Kaplan Meier estimate and Log Rank test.
• recurrence of aGVHD [1 year after treatment]: Defined as the proportion of participants whose aGVHD relapsed.Relapse was defined as recurrence of new GVHD related symptoms after complete remission of aGVHD. Cumulative incidence of recurrence of aGVHD was analyzed in a competing risk framework using Gray's method.
• Failure-free survival [1 year after treatment]: Failure-free survival (FFS) refers to the time from randomization to disease relapse or progression, non-relapse mortality, or the addition of new therapy for aGVHD.

Sex: All, ages: 14 Years to any

Inclusion Criteria:

1. diagnosed with hematological diseases.
2. Have undergone first allogeneic hematopoietic stem cell transplantation (allo-HSCT) from any donor source using bone marrow, peripheral blood stem cells, or cord blood for hematologic malignancies.
3. New onset of severe acute GVHD within 100 days post-transplantation.

Exclusion Criteria:

1. Recipients of second allogeneic stem cell transplant.
2. Acute GVHD induced by donor lymphocyte infusion, interferon.
3. Received first line aGVHD treatment before enrollment.
4. Overlap GVHD syndrome.
5. Pregnant or breast-feeding women.
6. Absolute neutrophil count (ANC) <0.5×10e9/L or platelet count (PLT) < 20×10e9/L.
7. Serum creatinine > 2.0 mg/dL or creatinine clearance < 40 mL/min measured or calculated by Cockroft-Gault equation.
8. Uncontrolled infection.
9. Human immunodeficiency virus infection.
10. Active hepatitis b virus, hepatitis C virus infection and need antivirus treatment.
11. Subjects with evidence of relapsed primary disease, or subjects who have been treated for relapse after the allo-HSCT was performed, or graft rejection.
12. Allergic history to Janus kinase inhibitors.
13. Severe organ dysfunction unrelated to underlying GVHD, including:

(1)Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to GVHD and ongoing organ dysfunction).

(2)Clinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy.

(3)Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen.

14.Received Janus kinase inhibitor therapy after allo-HSCT for any indication. 15.Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.

• Betts BC, Bastian D, Iamsawat S, Nguyen H, Heinrichs JL, Wu Y, Daenthanasanmak A, Veerapathran A, O'Mahony A, Walton K, Reff J, Horna P, Sagatys EM, Lee MC, Singer J, Chang YJ, Liu C, Pidala J, Anasetti C, Yu XZ. Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):1582-1587. doi: 10.1073/pnas.1712452115. Epub 2018 Jan 30. PMID 29382747
• Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socie G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. doi: 10.1056/NEJMoa1917635. Epub 2020 Apr 22. PMID 32320566
• Michonneau D, Devillier R, Keranen M, Rubio MT, Nicklasson M, Labussiere-Wallet H, Carre M, Huynh A, Viayna E, Roset M, Finzi J, Pfeiffer M, Thunstrom D, Lara N, Sabatelli L, Chevallier P, Itala-Remes M. Treatment Patterns and Clinical Outcomes of Patients with Moderate to Severe Acute Graft-Versus-Host Disease: A Multicenter Chart Review Study. Hematol Rep. 2024 May 6;16(2):283-294. doi: 10.3390/hematolrep16020028. PMID 38804281
• Mehta AK, Koreth J. Toward Improving Initial Therapy of Acute Graft Versus Host Disease. Am J Hematol. 2025 May;100 Suppl 3:40-54. doi: 10.1002/ajh.27593. Epub 2025 Feb 12. PMID 39936555
• Dou L, Zhao Y, Yang J, Deng L, Wang N, Zhang X, Liu Q, Yang Y, Wei Z, Wang F, Jiao Y, Li F, Luan S, Hu L, Gao S, Liu C, Liu X, Yan J, Zhang X, Zhou F, Lu P, Liu D. Ruxolitinib plus steroids for acute graft versus host disease: a multicenter, randomized, phase 3 trial. Signal Transduct Target Ther. 2024 Oct 23;9(1):288. doi: 10.1038/s41392-024-01987-x. PMID 39438467