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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Bone Marrow Transplantation; Graft-Versus-Host Disease(GVHD)
• Intervention / Treatment: Drug: Low-dose ATG + PTCy + Ivarmacitinib

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.

• Study Type: Interventional
• Enrollment (Estimated): 82
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xianmin Song, PhD; Phone Number: +021-63240090; Email: shongxm@sjtu.edu.cn
• Study Contact Backup: Name: Xianmin Song, PhD

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 210000
      • Recruiting
      • Shanghai General Hospital Affiliated to Shanghai Jiao Tong University
      • Contact: Xuemei Jia, PhD; Phone Number: +021-63240090; Email: xuemei.jia@shgh.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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).
2. 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.
3. 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.
4. 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.
5. No significant psychiatric disorders; able to understand and voluntarily consent to participate in the study.
6. The patient has signed the informed consent form and agrees to comply with follow-up and related examinations.

Exclusion Criteria:

1. History of prior hematopoietic stem cell transplantation (including autologous or allogeneic transplant).
2. Presence of donor-specific antibodies (DSA) with a mean fluorescence intensity (MFI) ≥5000.
3. History of severe hypersensitivity or allergy to JAK inhibitors or the investigational drug.
4. Prior treatment with JAK1/2 inhibitors.
5. 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.
6. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Grades II-IV Acute GVHD	Acute graft-versus-host disease (aGVHD) will be assessed according to standard criteria (Glucksberg or MAGIC). The primary measure is the occurrence of grade II-IV aGVHD in any organ (skin, liver, gastrointestinal tract) within 180 days after haploidentical peripheral blood stem cell transplantation. Severity will be graded based on clinical manifestations, laboratory results, and endoscopic or biopsy findings where applicable.	From Day 0 to Day 180 post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Graft Failure	Primary graft failure is defined as failure to achieve sustained neutrophil engraftment (ANC ≥ 0.5 × 10⁹/L for 3 consecutive days) and/or platelet engraftment (Platelet ≥ 20 × 10⁹/L without transfusion for 7 consecutive days) by Day 28 post-transplant. Assessment is based on peripheral blood counts and confirmed by the study team.	Day 28 post-transplant
Number of Participants With Non-Relapse Mortality by Day +180	NRM is defined as death occurring after allogeneic hematopoietic stem cell transplantation without evidence of relapse of the underlying hematologic malignancy. Causes include transplant-related complications such as acute or chronic GVHD, severe infections, organ toxicity, or graft failure. All deaths will be adjudicated by the study team based on clinical, laboratory, and imaging data.	Up to 180 days post-transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Chronic Graft-Versus-Host Disease by 1 Year	The cumulative incidence of chronic GVHD will be measured as the occurrence of chronic GVHD (limited or extensive) diagnosed according to NIH consensus criteria within 1 year after transplantation. cGVHD will be assessed clinically using standardized criteria, including organ involvement and requirement for systemic immunosuppressive therapy.	Up to 1 year post-transplant
Number of Participants With Relapse by 1 Year	Relapse rate is defined as the proportion of patients who develop recurrence of the underlying hematologic malignancy after achieving initial engraftment. Relapse will be confirmed by bone marrow examination, cytogenetic/molecular criteria, or imaging evidence consistent with disease recurrence. Competing risk analysis will treat non-relapse mortality as a competing event.	Up to 1 year post-transplant
Number of Participants Alive at 1 Year	Overall survival (OS) is defined as the time from the date of transplantation to death from any cause. Patients alive at the end of the follow-up period will be censored at the last known date alive. OS will be estimated using Kaplan-Meier methods.	Up to 1 year post-transplant
Number of Participants Alive and Disease-Free at 1 Year	Disease-free survival (DFS) is defined as the time from transplantation to the first occurrence of relapse or death from any cause. Patients without relapse or death at the end of the follow-up period will be censored at last follow-up. DFS will be estimated by Kaplan-Meier analysis.	Up to 1 year post-transplant
Number of Participants With GVHD-Free and Relapse-Free Survival at 1 Year	GVHD-free/relapse-free survival (GRFS) is a composite endpoint defined as survival without grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD, relapse of underlying disease, or death within 1 year after transplantation. Patients who do not experience any of these events will be censored at last follow-up.	Up to 1 year post-transplant
Number of Participants With Any Adverse Event by Day +180	All adverse events will be recorded and graded according to CTCAE v5.0. Specific monitoring includes hematologic toxicity, liver and renal function abnormalities, metabolic disturbances, and infections (bacterial, viral, fungal). The frequency, severity, and type of AEs will be summarized throughout the 180-day post-transplant period.	From Day 0 to Day 180 post-transplant

Collaborators and Investigators

• Sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
• Investigators: Principal Investigator: Xianmin Song, PhD, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University

Publications and helpful links

General Publications

• 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 Disease. Biol Blood Marrow Transplant. 2017 Feb;23(2):211-234. doi: 10.1016/j.bbmt.2016.09.023. Epub 2016 Oct 3.
• Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012 May 11;12(6):443-58. doi: 10.1038/nri3212.
• Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009 May 2;373(9674):1550-61. doi: 10.1016/S0140-6736(09)60237-3. Epub 2009 Mar 11.
• 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.
• 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.
• 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.
• 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.
• 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.
• Yang J Sr, 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. Randomized trial of GvHD Prophylaxis in Haploidentical PBSC Transplantation: ATG, PTCy, and Low-Dose Combination Therapy. Blood. 2026 Mar 18:blood.2025032569. doi: 10.1182/blood.2025032569. Online ahead of print.
• 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 transplantation combined with unrelated cord blood. Bone Marrow Transplant. 2021 Mar;56(3):705-708. doi: 10.1038/s41409-020-01047-2. Epub 2020 Sep 1. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: May 1, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 1, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Graft-versus-host disease; Haploidentical transplantation; Low-dose ATG/PTCy; JAK1 inhibitor (Ivarmacitinib / SHR0302)
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; ivarmacitinib
• Other Study ID Numbers: SHSYXY-PARITY-aGVHD-20251007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No