Low-Dose ATG/PTCy Plus Ivarmacitinib for aGVHD Prevention in Haplo-PBSCT From Parous Female Donors

Official title

Low-Dose ATG/PTCy Plus Ivarmacitinib to Prevent Acute Graft-versus-Host Disease Following Haploidentical Peripheral Blood Stem Cell Transplantation From Parous Female Donors: A Prospective, Single-Arm, Multicenter Trial

Overview

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), significantly affecting survival and quality of life. Acute GVHD (aGVHD) typically occurs within 100 days post-transplant, commonly involving skin, gastrointestinal tract, and liver. Chronic GVHD (cGVHD) can appear months to years later. Despite prophylaxis with calcineurin inhibitors (e.g., cyclosporine or tacrolimus), methotrexate, mycophenolate mofetil, and post-transplant cyclophosphamide (PTCy), patients receiving haploidentical transplantation from parous female donors remain at high risk for moderate-to-severe aGVHD. JAK1-dependent cytokine signaling (IL-6, IFN-γ) is central to GVHD pathogenesis. Selective JAK1 inhibition may attenuate T cell-mediated inflammation while preserving hematopoiesis. Ivarmacitinib (SHR0302) is a highly selective oral JAK1 inhibitor, showing favorable safety and preliminary efficacy in autoimmune and GVHD settings, making it a candidate for early GVHD prophylaxis.

Detailed description

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative approach for various hematologic malignancies, marrow failure syndromes, and selected genetic disorders. Despite advances in donor selection, including unrelated, haploidentical, and peripheral blood stem cell (PBSC) sources, graft-versus-host disease (GVHD) continues to be the most common and clinically significant complication, adversely affecting both short- and long-term outcomes. Acute GVHD (aGVHD) typically occurs within the first 100 days post-transplant, primarily involving the skin, gastrointestinal tract, and liver, whereas chronic GVHD (cGVHD) may develop months to years later, often affecting multiple organs. Over the past decades, GVHD prophylaxis has evolved from calcineurin inhibitors (cyclosporine, tacrolimus) combined with methotrexate or mycophenolate mofetil to more targeted strategies. In haploidentical transplantation, post-transplant cyclophosphamide (PTCy) has markedly reduced the incidence of both acute and chronic GVHD. However, moderate-to-severe GVHD still occurs in a subset of recipients, highlighting the need for enhanced prophylactic strategies. Low-dose anti-thymocyte globulin (ATG) combined with PTCy has emerged as a promising regimen, with systematic reviews demonstrating significant reductions in grade II-IV aGVHD and cGVHD without increasing relapse risk, thereby improving GVHD-free survival.

Notably, recipients of haploidentical transplants from parous female donors constitute a high-risk population. Prior studies indicate that such recipients exhibit substantially elevated rates of grade II-IV aGVHD and moderate-to-severe cGVHD compared with recipients from nulliparous female or male donors. For instance, retrospective analyses reported grade III-IV aGVHD incidence of 55.3% and extensive cGVHD of 64.3% in recipients from parous female donors, significantly higher than in recipients from male donors, emphasizing the need for additional prophylactic interventions in this group.

Mechanistically, the JAK-STAT signaling pathway plays a central role in GVHD pathogenesis. Alloreactive donor T cells release proinflammatory cytokines such as IFN-γ, IL-6, and TNF-α, leading to tissue injury. JAK1 mediates critical signaling for IL-6 and IFN-γ, suggesting that selective JAK1 inhibition may attenuate pathogenic T cell responses while preserving hematopoiesis. JAK inhibitors such as ruxolitinib and baricitinib have demonstrated efficacy in steroid-refractory GVHD, and highly selective JAK1 inhibitors like itacitinib have shown promising results in early-phase studies, reducing both acute and chronic GVHD incidences with minimal myelosuppression.

Ivarmacitinib (SHR0302), a novel, orally bioavailable, highly selective JAK1 inhibitor developed in China, exhibits potent JAK1 blockade with limited JAK2 inhibition, theoretically minimizing hematopoietic toxicity. Preclinical models show SHR0302 prevents and mitigates aGVHD without impairing graft-versus-leukemia effects. Early-phase clinical studies in cGVHD patients indicate favorable safety and high response rates, supporting its potential application for aGVHD prophylaxis.

In summary, combining high-selectivity JAK1 inhibition with the established low-dose ATG/PTCy regimen offers a mechanistically rational strategy to further reduce GVHD risk in high-risk haploidentical PBSC recipients from parous female donors. This approach is expected to lower the incidence of acute GVHD without significantly increasing infection or relapse risk, improve long-term GVHD outcomes, and enhance overall survival and quality of life for these high-risk transplant recipients.

Interventions

• Drug Low-dose ATG + PTCy + Ivarmacitinib
  Patients will receive rabbit ATG 2.5 mg/kg on Day -2 and -1 (total 5 mg/kg), post-transplant cyclophosphamide 50 mg/kg on Day +3, cyclosporine/MMF starting Day +4, and Ivarmacitinib 4 mg PO daily from Day -3 to +45, reduced to 2 mg PO daily from Day +46 to +60

Primary outcome measures

• Number of Participants With Grades II-IV Acute GVHD [Time frame: From Day 0 to Day 180 post-transplant]

Secondary outcome measures (2)

• Number of Participants With Graft Failure [Time frame: Day 28 post-transplant]
• Number of Participants With Non-Relapse Mortality by Day +180 [Time frame: Up to 180 days post-transplant]

Eligibility criteria

Inclusion criteria

• Age 18-70 years, any gender. Recipients must be diagnosed with hematologic malignancies, such as acute leukemia, myelodysplastic syndrome, or malignant lymphoma, and are planned to undergo haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT).
• The donor must be a haploidentical relative within three degrees of kinship and a parous female (having given birth; number of pregnancies not limited), aged 18-55 years, in good health, and cleared by donor screening.
• Karnofsky performance status ≥70. The recipient is expected to tolerate transplant-related toxicity. Major organ functions must meet transplantation requirements: cardiac and pulmonary function essentially normal; liver function: ALT/AST <2× upper limit of normal, total bilirubin <1.5× upper limit of normal; renal function: creatinine clearance >50 mL/min.
• No active infection prior to transplantation (or infection effectively controlled). Chronic infections such as HBV, HCV, or syphilis must be stable under treatment; HBV DNA negative or receiving antiviral therapy is acceptable.
• No significant psychiatric disorders; able to understand and voluntarily consent to participate in the study.
• The patient has signed the informed consent form and agrees to comply with follow-up and related examinations.

Exclusion criteria

• History of prior hematopoietic stem cell transplantation (including autologous or allogeneic transplant).
• Presence of donor-specific antibodies (DSA) with a mean fluorescence intensity (MFI) ≥5000.
• History of severe hypersensitivity or allergy to JAK inhibitors or the investigational drug.
• Prior treatment with JAK1/2 inhibitors.
• Uncontrolled comorbidities prior to transplantation, such as uncontrolled hypertension, diabetes complications, or active gastrointestinal ulcer bleeding, which may increase unacceptable risk for trial participation as evaluated by investigators.
• Receipt of other investigational drugs within 2 weeks prior to transplantation (excluding standard chemotherapy), or simultaneous participation in other interventional clinical studies, or any other condition deemed by the investigator to make the patient unsuitable for study participation, including poor compliance or inability to complete follow-up (e.g., severe psychiatric disorders preventing cooperation).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Prevention

Study locations

China · 1 center

• Shanghai General Hospital Affiliated to Shanghai Jiao Tong University — Shanghai

Publications

• He Q, Sun X, Niu J, Yang J, Wang Y, Huang C, Zhou K, Tong Y, Cai Y, Dong B, Wan L, Song X, Qiu H. A Novel JAK1 Inhibitor SHR0302 Combined With Prednisone for First-Line Treatment of Chronic Graft-Versus-Host Disease: A Phase I Clinical Trial. Cell Transplant. 2024 Jan-Dec;33:9636897241254678. doi: 10.1177/09636897241254678. PMID 38798038
• Sun X, He Q, Yang J, Wang A, Zhang F, Qiu H, Zhou K, Wang P, Ding X, Yuan X, Li H, Zhang Y, Song X. Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease. Cell Transplant. 2021 Jan-Dec;30:9636897211033778. doi: 10.1177/09636897211033778. PMID 34269100
• Schroeder MA, Khoury HJ, Jagasia M, Ali H, Schiller GJ, Staser K, Choi J, Gehrs L, Arbushites MC, Yan Y, Langmuir P, Srinivas N, Pratta M, Perales MA, Chen YB, Meyers G, DiPersio JF. A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease. Blood Adv. 2020 Apr 28;4(8):1656-1669. doi: 10.1182/bloodadvances.2019001043. PMID 32324888
• Kim S, Ashami K, Lim S, Staser K, Vij K, Santhanam S, Ritchey J, Peterson S, Gao F, Ciorba MA, Cooper ML, DiPersio JF, Choi J. Baricitinib prevents GvHD by increasing Tregs via JAK3 and treats established GvHD by promoting intestinal tissue repair via EGFR. Leukemia. 2022 Jan;36(1):292-295. doi: 10.1038/s41375-021-01360-9. Epub 2021 Jul 24. No abstract available. PMID 34304247
• Loren AW, Bunin GR, Boudreau C, Champlin RE, Cnaan A, Horowitz MM, Loberiza FR, Porter DL. Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006 Jul;12(7):758-69. doi: 10.1016/j.bbmt.2006.03.015. PMID 16785065
• Yang J, Jia Y, Hu X, Zhou F, Ni X, Wan J, Ding Y, Kang M, Yu X, Jiang C, Wang L, Wan L, Cai Y, Huang C, Qiu H, Ding X, Tong Y, Dong B, Zhou K, Song X. A randomized trial of GVHD prophylaxis in haploidentical PBSC transplantation: ATG, PTCy, and low-dose combination therapy. Blood. 2026 Jun 25;147(26):3168-3178. doi: 10.1182/blood.2025032569. PMID 41849227
• Xu X, Yang J, Cai Y, Li S, Niu J, Zhou K, Jiang Y, Xu X, Shen C, Huang C, Qiu H, Wei D, Kang M, Tong Y, Wei Z, Liu P, Wan L, Song X. Low dose anti-thymocyte globulin with low dose posttransplant cyclophosphamide (low dose ATG/PTCy) can reduce the risk of graft-versus-host disease as compared with standard-dose anti-thymocyte globulin in haploidentical peripheral hematopoietic stem cell transplanta PMID 32873913
• Cooke KR, Luznik L, Sarantopoulos S, Hakim FT, Jagasia M, Fowler DH, van den Brink MRM, Hansen JA, Parkman R, Miklos DB, Martin PJ, Paczesny S, Vogelsang G, Pavletic S, Ritz J, Schultz KR, Blazar BR. The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host PMID 27713092

Identifiers

NCT: NCT07570745 · SHSYXY-PARITY-aGVHD-20251007

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗