Umbilical Cord Mesenchymal Stem Cells as First-line Treatment for Patients With Acute Graft Versus Host Disease

Study Overview
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Brief Summary
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Allogenic haemopoietic stem cell transplantation (allo-HSCT) is the effective treatment for many hematologic malignancies and some non-malignant diseases. In recent years, with the rapid improvement of economy and medical level, the number of cases of hematopoietic stem cell transplantation (HSCT) develops rapidly in China. In 2019, 12,323 cases of HSCT were completed in China, with allo-HSCT accounting for 9600 cases of which. However, Graft versus host disease (GVHD) is one of the most common and serious complications after Allo-HSCT. The incidence of acute GVHD (aGVHD) is as high as 40%-60% in HLA-matched sibling transplantation, and the incidence is even higher in haplo-hematopoietic stem cell transplantation(haplo-HSCT) and unrelated donor transplantation. By Glucksberg grading standard, the 5-year survival rates of grade III and IV aGVHD are 25% and 5% respectively, indicating severe GVHD directly affects the survival of Allo-HSCT patients. The first-line treatment for aGVHD is still glucocorticoid, while the effective rate is only 30%-50%. Moreover, due to immunosuppression and increasing risk of infection, the efficacy of second-line treatments including polyclonal antibodies, monoclonal antibodies, immunosuppressants, immunotoxins, chemotherapy drugs, and light therapy for steroid resistant aGVHD is also poor, with the overall survival rate of 5%-30%. Mesenchymal stem cells (MSCs) are multipotent cells, which can promote engraftment and hematopoietic reconstruction by secreting a variety of hematopoietic promoting factors, expressing adhesion molecules supporting hematopoietic stem cells, guiding homing of hematopoietic stem cells and providing hematopoietic microenvironment. At the same time, MSCs can modulate immune responses by affecting the proliferation of T cells and the migration of T cells and DC, inducing the expansion of Treg cells, inhibiting the secretion of antibodies by B lymphocytes, and regulating the secretion of soluble factors such as NO and IDO. As a result of these characteristics and the poor immunogenicity, MSCs are a promising alternative treatment for GVHD. Currently, UK and EU guidelines has recommended MSC as a third-line treatment for grade 2-4 acute GVHD, and the safety and efficacy of umbilical cord derived MSCs in the prevention and treatment of GVHD has also been reported by several transplantation centers in China.However, MSCs have not been used for first-line treatment of aGVHD. Therefore, the investigators designed this study to evaluate the safety and efficacy of UC-derived MSCs as the first line treatment in patients with aGVHD.

Detailed Description
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This prospective, randomized and controlled study is to investigate the efficacy and safety of Umbilical Cord Mesenchymal Stem Cells as First-line Treatment for Patients With Acute Graft Versus Host Disease. Investigators will recruit 182 patients with acute leukemia, with 91 of them entering the hUC-MSCs combined with glucocorticoids group. and receiving hUC-MSCs at a dose of 1×10^6 /kilogram (kg) actual body weight at Screening for twice per week in 1-2 weeks and once a week in 3-4 weeks after being rolled into this study, with the glucocorticoid given at the same time. while the other 91 entering the glucocorticoids group receiving glucocorticoids only. Then primary outcomes including the ORR at day 180 post initiation of therapy, as well the secondary outcomes including cumulative relapse incidence、cumulative incidence of chronic GVHD 、cumulative Incidence of infectious complications and cumulative Incidence of lymphoproliferative disease will be measured during 180 days after the intervention being finished.

Official Title
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Clinical Study of Umbilical Cord Mesenchymal Stem Cells as First-line Treatment for Patients With Acute Graft Versus Host Disease

Conditions
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aGVHD

Intervention / Treatment
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* Other: hUC-MSCs
* Other: glucocorticoids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient who has undergone an allogeneic haematopoietic stem cell transplantation (HSCT) and developed acute graft versus host disease (aGVHD) Eastern Cooperative Oncology Group (ECOG) Performance status 0-2 serum creatinine less than twice the upper limit of normal or creatinine clearance greater 50 ml/min within 28 days. Patients had recovered from previous treatments Signing written informed consent and agreeing with taking designated umbilical cord blood Exclusion Criteria: Patients had severe allergy history Patients with unstable angina or whose cardiac function grading III-IV. Patients with chronic respiratory disease requiring continuous oxygen supplement Patients with active hepatitis B or active hepatitis C or AIDS infection Patients with Uncontrolled viral or bacterial infections Patients with severe psychiatric or physical illness that would limit compliance with study requirements Patients who received any other investigational study or treatment within 30 days Secondary malignancy Allergic to blood products Other causes which are not suitable for the trial in investigator's consideration
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hUC-MSCs combined with glucocorticoids group.<br>91 patients will be involved in this group | Other: hUC-MSCs<br>* Participants will be treated with hUC-MSCs at a dose of 1×10^6 /kilogram (kg) actual body weight at Screening for twice per week in 1-2 weeks and once a week in 3-4 weeks after being rolled into this study. At the same time, patients will be treated with glucocorticoids according to patients' condition.<br>|
| Active Comparator: glucocorticoids group<br>91 patients will be involved in this group | Other: glucocorticoids<br>* Participants were treated with glucocorticoids only.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) at Day 28 Post Initiation of Therapy | ORR was defined as the percentage of participants who had achieved overall response. Overall response was defined as complete response (CR) plus partial response (PR) according to aGVHD response criteria. CR was defined as resolution of aGVHD in all involved organs. PR was defined as organ improvement of at least 1 stage without worsening of any other organ. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative relapse incidence | Defined as the cumulative incidence of relapse after the day of transplantation. | 180 days | 
| cumulative incidence of chronic GVHD at one year | chronic graft versus host disease will be diagnosed and graded by National Institute of Health Consensus (NIH Consensus). | 180 days | 
| Cumulative Incidence of Infectious Complications | Defined as cumulative incidence of viral, fungal and bacterial infections. | 180 days | 
| Cumulative Incidence of lymphoproliferative disease | Defined as the cumulative incidence of lymphoproliferative disease after the day of transplantation. | 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aGVHD, Umbilical Cord Mesenchymal Stem Cell