Donor Mesenchymal Stem Cell Infusion in Treating Patients With Acute or Chronic Graft-Versus-Host Disease After Undergoing a Donor Stem Cell Transplant

Study Overview
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Brief Summary
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RATIONALE: Donor mesenchymal stem cell infusion may be an effective treatment for acute or chronic graft-versus-host disease caused by a donor stem cell transplant. PURPOSE: This phase I trial is studying the side effects and best dose of donor mesenchymal stem cells in treating patients with acute or chronic graft-versus-host disease after undergoing a donor stem cell transplant.

Detailed Description
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OBJECTIVES: Primary Determine the safety of donor mesenchymal stem cell (MSC) infusion in patients with acute or extensive chronic graft-vs-host disease (GVHD) after undergoing HLA-identical sibling donor stem cell transplant. Secondary Describe the rates of complete and partial resolution of GVHD when MSCs are used in addition to the standard GVHD therapy. Determine inflammatory cytokine levels, lymphocyte subsets, and donor-reactive lymphocyte numbers in blood of patients with acute GVHD prior to therapy and at 7 and 14 days post-MSC therapy. Determine if donor MSCs engraft in tissues inflamed by GVHD in patients who have undergone gender-mismatched transplantation. OUTLINE: This is a multicenter, dose-escalation study of donor mesenchymal stem cells (MSC). Within 72 hours after the initiation of medical therapy (e.g., corticosteroids, cyclosporine) for graft-vs-host disease, patients undergo donor MSC infusion over 10-15 minutes. Cohorts of 3-6 patients receive escalating doses of donor MSCs until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Blood samples are obtained periodically and examined by immunoenzyme techniques for mixed lymphocyte reaction (as a surrogate marker for alloreactivity) and cytokine levels (TH1 [i.e., interleukin (IL)-2 and interferon-gamma], TH2 [i.e., IL-10 and IL-4], and inflammatory cytokines [i.e., tumor necrosis factor-alpha and IL-1]). Tissue specimens are examined by CD45 immunohistochemistry and fluorescent in situ hybridization to detect hematopoietic and nonhematopoietic cells. After completion of study treatment, patients are followed periodically for 1 year. PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study.

Official Title
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Donor Mesenchymal Stem Cell Infusion for Treatment of Graft Versus Host Disease: A Phase I Trial

Conditions
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Cancer

Intervention / Treatment
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* Biological: graft versus host disease prophylaxis/therapy
* Genetic: fluorescence in situ hybridization
* Other: immunoenzyme technique
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis
* Procedure: in vitro-treated bone marrow transplantation
* Procedure: management of therapy complications


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Developed acute graft-vs-host disease (GVHD) of clinical grade II-IV or extensive chronic GVHD after undergoing HLA-identical sibling donor hematopoietic stem cell transplant for any indication, malignant or nonmalignant Requires systemic immunosuppressive therapy with systemic corticosteroids (methylprednisone dose 2 mg/kg/day or equivalent) and concurrent cyclosporine or tacrolimus May have been enrolled on an institutional allogeneic stem cell transplant protocol using either ablative or nonmyeloablative preparative regimens No evidence of relapsed or progressive malignant disease at the time of GVHD PATIENT CHARACTERISTICS: Not pregnant Negative pregnancy test Creatinine clearance ≥ 20 mL/min Oxygen saturation ≥ 90% on room air No severe or symptomatic restrictive or obstructive lung disease or respiratory failure requiring ventilator support No uncontrolled hypertension or congestive heart failure, active angina pectoris requiring the use of nitrates, myocardial infarction within the past 6 months, or major ventricular arrhythmia or cardiac failure requiring active treatment No significant organ dysfunction No active severe infections, including sepsis, pneumonia with hypoxemia, persistent bacteremia, or meningitis Fever without a source is allowed PRIOR CONCURRENT THERAPY: See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 18 Years

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: graft versus host disease prophylaxis/therapy|Within 72 hours after the initiation of medical therapy (e.g., corticosteroids, cyclosporine) for graft-vs-host disease, patients undergo donor MSC infusion over 10-15 minutes.|
|Genetic: fluorescence in situ hybridization|Tissue specimens are examined by CD45 immunohistochemistry and fluorescent in situ hybridization to detect hematopoietic and nonhematopoietic cells.|
|Other: immunoenzyme technique|Tissue specimens are examined by CD45 immunohistochemistry and fluorescent in situ hybridization to detect hematopoietic and nonhematopoietic cells.|
|Other: immunohistochemistry staining method|Tissue specimens are examined by CD45 immunohistochemistry and fluorescent in situ hybridization to detect hematopoietic and nonhematopoietic cells.|
|Other: laboratory biomarker analysis|Tissue specimens are examined by CD45 immunohistochemistry and fluorescent in situ hybridization to detect hematopoietic and nonhematopoietic cells.|
|Procedure: in vitro-treated bone marrow transplantation|Within 72 hours after the initiation of medical therapy (e.g., corticosteroids, cyclosporine) for graft-vs-host disease, patients undergo donor MSC infusion over 10-15 minutes.|
|Procedure: management of therapy complications|Patients will be evaluated for clinical signs and symptoms of GVHD weekly for up to 28 days.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety |  | Monitored for 6 hours for infusion related toxicity. Temperature, blood pressure, pulse and O2 saturation will be measured at baseline and every 10 minutes x 2, every 30 minutes x 2, and every hour x 3. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete and partial resolution of graft-vs-host disease (GVHD) |  | Patients will be evaluated for clinical signs and symptoms of GVHD weekly for up to 28 days. | 
| Cytokine levels, lymphocyte subsets, and donor-reactive lymphocyte numbers in patients with acute GVHD |  | Pre-transplant, at diagnosis, 7 and 14 days after MSC infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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graft versus host disease, unspecified adult solid tumor, protocol specific, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, atypical chronic myeloid leukemia, blastic phase chronic myelogenous leukemia, chronic eosinophilic leukemia, primary myelofibrosis, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, chronic phase chronic myelogenous leukemia, de novo myelodysplastic syndromes, disseminated neuroblastoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, myelodysplastic/myeloproliferative disease, unclassifiable, nodal marginal zone B-cell lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, poor prognosis metastatic gestational trophoblastic tumor, previously treated myelodysplastic syndromes, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, splenic marginal zone lymphoma, stage I multiple myeloma, stage II multiple myeloma, stage II ovarian epithelial cancer, stage III adult Burkitt lymphoma, stage III adult Hodgkin lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III chronic lymphocytic leukemia, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage III multiple myeloma, stage III ovarian epithelial cancer, stage III small lymphocytic lymphoma, stage III malignant testicular germ cell tumor, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV adult Burkitt lymphoma, stage IV adult Hodgkin lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV breast cancer, stage IV chronic lymphocytic leukemia, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, stage IV ovarian epithelial cancer, stage IV small lymphocytic lymphoma