Mesenchymal Stem Cells as First Treatment Line for Resistant Acute Graft Versus Host Disease
NCT ID: NCT02770430
Last Updated: 2016-05-12
Study Results
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Basic Information
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UNKNOWN
PHASE2
90 participants
INTERVENTIONAL
2015-09-30
2018-12-31
Brief Summary
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In the case of failure after corticosteroid treatment, different therapeutic options have been introduced as second or third-line strategies. In this scenario, infusion of ex vivo expanded mesenchymal stromal cells (MSCs) has emerged as an additional tool for treatment of GVHD.
The purpose of this work is conduct a study in patients with refractory and/or resistant GVHD corticosteroids treatment. It will be randomized into two groups: one group that will receive the MSCs and the other group will follow the acute GVHD steroid-resistant and/or refractory treatment according to the routines of the Bone Marrow Transplantation (BMT) service of Hospital de Clinicas de Porto Alegre. It will be evaluated aspects of immune recovery early after MSCs infusion.
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Detailed Description
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Steroids are still the first line treatment for established aGVHD, with a response rate of 30-50%, and there is no established and effective therapy for severe steroid-refractory aGVHD. The outcome for patients is poor and overall survival low, with few patients alive at 2 years.
In the case of failure after corticosteroid treatment, different therapeutic options have been introduced as second or third-line strategies. In this scenario, infusion of ex vivo expanded mesenchymal stem cells (MSCs) has emerged as an additional tool for treatment of GVHD.
MSCs are non hematopoietic multipotent cells with self-renewal properties and the ability to differentiate into mesenchymal tissues. Several lines of evidence in the past few years have confirmed the ability of theses cells differentiate into cells derived form embryonic mesoderm, such as osteocytes, adipocytes and chondroblasts. In vitro, culture-expanded MSCs express membrane antigens that can be immunophenotyped by flow cytometry. The most widely accepted antigen expression pattern is cluster of differentiation (CD) 29, CD105, CD73, and CD90 positivity in 97 % of cells and minimal expression of CD45, CD34, CD3, CD14, CD19, or human leukocyte antigen (HLA) -DR, which should be positive in less than 3 % of cells.
Because they are easy to isolate and culture and due to their differentiation potential and production of growth factors and cytokines, MSC have become ideal candidates for regenerative protocols.
The purpose of this work is conduct a study in patients with refractory and/or resistant GVHD corticosteroids treatment. It will be randomized into two groups: one group that will receive the MSCs and the other group will follow the acute GVHD steroid-resistant and/or refractory treatment according to the routines of the Bone Marrow Transplantation service of Hospital de Clinicas de Porto Alegre. It will be evaluated aspects of immune recovery early after MSCs infusion.
METHOD: This is a prospective, randomized, controlled, open label study to evaluate the effectiveness of early treatment of steroid-resistant acute GVHD with MSC. All patients with refractory and/or resistant steroids GVHD will be included after signing of free and informed consent.
After randomization, patients will be allocated to receive conventional treatment:
1. Basiliximab 20mg dose for adults and 10mg for children, 1 time a week or every 3 days if worsens the stage of GVHD until reaching Very Good Partial Response (VGPR) or for a maximum of 4 doses, whichever comes first.
2. If after the item (1) will not obtained VGPR: Infliximab 5 to 10 mg/kg dose, 1 time a week, four weeks or even VGPR.
Patients in the study group will receive two infusions of MSC per week during two weeks and 1 more MSC infusion (2 + 2 + 1 scheme).
After 28 days, if VGPR is not obtained, crossover between groups will be allowed as well as for the patients with progressive GVHD in spit of treatment arm, before day +28. The latter group of patients, who use both treatments (MSC + Conventional treatment) before day + 28 will be analyzed separately.
Bone marrow (BM) derived MSCs from normal BMT donors (third part) will be isolated and expanded under conditions of Good Manufacturing Practice. The quality control involves immunophenotyping, differentiation, microbiological control, mycoplasma and endotoxin tests.
Patients response evaluation will be at Day + 28:
1. Complete response: disappearance of all symptoms
2. Partial response: with a decrease at least of one degree of GVHD
3. VGPR: decrease to the stage I of GVHD
4. Stable disease: when there is a stability of the disease
5. Number and type of infection in the first 100 days after transplant
The transplant-related mortality, disease-free survival, overall survival and the development of chronic GVHD or not, will also be evaluated.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
NONE
Study Groups
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conventional treatment
After randomization, patients will be allocated to receive conventional treatment:
1. Basiliximab 20mg dose for adults and 10mg for children, 1 time a week or every 3 days if worsens the stage of GVHD until reaching Very Good Partial Response (VGPR) or for a maximum of 4 doses, whichever comes first.
2. If after the item (1) will not obtained VGPR: Infliximab 5 to 10 mg/kg dose, 1 time a week, four weeks or even VGPR.
conventional treatment
1. Basiliximab 20mg dose for adults and 10mg for children, 1 time a week or every 3 days if worsens the stage of GVHD until reaching Very Good Partial Response (VGPR) or for a maximum of 4 doses, whichever comes first.
2. If after the item (1) will not obtained VGPR: Infliximab 5 to 10 mg/kg dose, 1 time a week, four weeks or even VGPR.
mesenchymal stem cells
Patients in the study group will receive two infusions of MSC per week during two weeks and 1 more MSC infusion (2 + 2 + 1 scheme). Dosage: 2x10E6/Kg
mesenchymal stem cells
MSCs derived from bone marrow (BM) will be isolated and expanded in the laboratory under conditions of Good Manufacturing Practice. The quality control involves immunophenotyping, differentiation, microbiological control, mycoplasma and endotoxin tests. Patients will receive five infusions of MSC. Dosage: 2x10E6 cells/Kg
Interventions
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mesenchymal stem cells
MSCs derived from bone marrow (BM) will be isolated and expanded in the laboratory under conditions of Good Manufacturing Practice. The quality control involves immunophenotyping, differentiation, microbiological control, mycoplasma and endotoxin tests. Patients will receive five infusions of MSC. Dosage: 2x10E6 cells/Kg
conventional treatment
1. Basiliximab 20mg dose for adults and 10mg for children, 1 time a week or every 3 days if worsens the stage of GVHD until reaching Very Good Partial Response (VGPR) or for a maximum of 4 doses, whichever comes first.
2. If after the item (1) will not obtained VGPR: Infliximab 5 to 10 mg/kg dose, 1 time a week, four weeks or even VGPR.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
Exclusion Criteria
ALL
No
Sponsors
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Hospital de Clinicas de Porto Alegre
OTHER
Responsible Party
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Principal Investigators
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Lucia S Silla
Role: PRINCIPAL_INVESTIGATOR
Hospital de Clínicas de Porto Alegre
Locations
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Centro Terapia e Tecnologia Celular
Porto Alegre, Rio Grande do Sul, Brazil
Countries
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Central Contacts
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Facility Contacts
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Other Identifiers
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12-0407
Identifier Type: -
Identifier Source: org_study_id
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