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Mesenchymal Stem Cells as First Treatment Line for Resistant Acute Graft Versus Host Disease

H

Hospital de Clinicas de Porto Alegre

Status and phase

Unknown
Phase 2

Conditions

Graft vs Host Disease

Treatments

Biological: mesenchymal stem cells
Drug: conventional treatment

Study type

Interventional

Funder types

Other

Identifiers

NCT02770430
12-0407

Details and patient eligibility

About

Steroids are still the first line treatment for established severe acute-graft-versus-host-disease (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 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.

Full description

Allogeneic hematopoietic stem cell transplant (AlloSCT) is the treatment of choice for many malignant and non-malignant hematological disorders. However, this treatment is frequently complicated by acute graft-versus-host-disease (aGVHD), wich can be associated with high morbidity and mortality.

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.

Enrollment

90 estimated patients

Sex

All

Volunteers

No Healthy Volunteers

Inclusion criteria

  • All patients with refractory and/or resistant steroids GVHD will be included after signing of free and informed consent.

Exclusion criteria

  • They will be excluded from the study, patients who did not agree to participate and don't sign an informed consent (which is going to receive conventional treatment) and that patients who is a Grade I refractory GVHD.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Crossover Assignment

Masking

None (Open label)

90 participants in 2 patient groups

conventional treatment
Active Comparator group
Description:
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.
Treatment:
Drug: conventional treatment
mesenchymal stem cells
Experimental group
Description:
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
Treatment:
Biological: mesenchymal stem cells

Trial contacts and locations

1

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Central trial contact

Vanessa Valim, Msc; Lucia Silla, PhD

Data sourced from clinicaltrials.gov

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