MSC and HSC Coinfusion in Mismatched Minitransplants

Study Overview
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Brief Summary
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The present project aims at evaluating the capacity of MSC to improve one-year overall survival of patients transplanted with HLA-mismatched PBSC from related or unrelated donors after non-myeloablative conditioning. Co-infusion of MSC has been shown to facilitate engraftment of hematopoietic stem cell (HSC) in an immunodeficient mouse model. In addition, it has been shown that infusion of third party MSC in HSC transplantation could be successfully used as treatment for grade II-IV steroid-refractory acute graft versus host disease. One hundred and twenty patients with HLA-mismatched donors will be included over 6 years at multiple centers across Belgium through the transplant committee of the Belgian Hematological Society. The conditioning regimen will consist of fludarabine and 2 Gy TBI, followed by the infusion of donor HSC. Patients will be randomized 1/1 in double-blind fashion to receive or not MSC (1.5-.3.0 x106/kg) from third-party (either haploidentical family members or unrelated volunteer) donors on day 0. Postgrafting immunosuppression will combine tacrolimus and MMF. Except for the collection, expansion and infusion of MSC, the clinical management of the patient will not differ from that of routine NM-HCT.

Official Title
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Co-transplantation of Mesenchymal Stem Cells and HLA-mismatched Allogeneic Hematopoietic Cells After Nonmyeloablative Conditioning: a Phase II Randomized Double-blind Study

Conditions
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Leukemia, Myeloid, Acute, Leukemia, Lymphoblastic, Acute, Leukemia, Myelocytic, Chronic, Myeloproliferative Disorders, Myelodysplastic Syndromes, Multiple Myeloma, Leukemia, Lymphocytic, Chronic, Hodgkin's Disease, Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Biological: Mesenchymal stem cells
* Other: Isotonic solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Theoretical indication for a standard allo-transplant, but not feasible because: Age > 55 yrs. Unacceptable end organ performance. Patient's refusal. Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant. Male or female; fertile female patients must use a reliable contraception method Age ≤ 75 year old Informed consent given by patient or his/her guardian if of minor age. One or two HLA mismatches with PBSC: One antigenic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1 Two allelic mismatches at HLA-A or -B or -C or -DRB1 or -DQB1 One antigenic mismatch: 1 allelic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1. One antigenic mismatch at -DQB1 and one other antigenic mismatch at HLA-A or -B or -C or -DRB1 Patients with one single allelic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1 can also be included in the protocol. Hematological malignancies confirmed histologically and not rapidly progressing: AML in complete remission ALL in complete remission CML unresponsive/intolerant to Imatinib but not in blast crisis Other myeloproliferative disorders not in blast crisis and not with extensive myelofibrosis MDS with <5% blasts Multiple myeloma not rapidly progressing CLL Non-Hodgkin's lymphoma (aggressive NHL should be chemosensitive) Hodgkin's disease Exclusion Criteria: Any condition not fulfilling inclusion criteria HIV positive Terminal organ failure, except for renal failure (dialysis acceptable) Cardiac: Symptomatic coronary artery disease or other cardiac failure requiring therapy; ejection fraction <35%; uncontrolled arrhythmia; uncontrolled hypertension Pulmonary: DLCO < 35% and/or receiving supplementary continuous oxygen Hepatic: Fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease Uncontrolled infection, arrhythmia or hypertension Previous radiation therapy precluding the use of 2 Gy TBI 10/10 HLA-A, -B, -C, DRB1 and DQBI allele-matched donor fit to/willing to donate PBSC.

Ages Eligible for Study
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Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mensenchymal Stem Cells<br>Efficacy of MSC infusion on one-year overall survival of patients transplanted with HLA-mismatched PBSC. Patients will receive a conditioning regimen consisting in fludarabine (total dose 90 mg/square meter) and 2 Gy total body irradiation. MSC cells (1,5-3,0 x 10E6 MSC/Kg BW) will be injected, followed, at least one hour later, by the infusion of HLA-mismatched PBSC from related or unrelated donor. | Biological: Mesenchymal stem cells<br>* Mesenchymal stem cell injection<br>|
| Placebo Comparator: Placebo<br>Patients will receive a conditioning regimen consisting in fludarabine (total dose 90 mg/square meter) and 2Gy total body irradiation. Isotonic solution will be injected will be injected, followed, at least one hour later, by the infusion of HLA-mismatched PBSC from related or unrelated donor. | Other: Isotonic solution<br>* Isotonic solution injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year overall survival in the 2 arms. |  | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade II-IV and grade III-IV acute GVDH |  | 100 days | 
| Number of absolute donor T cells after HCT in each arm |  | 28 | 
| Cumulative incidence of non-relapse mortality |  | 100, 365 and 730 days | 
| Incidence of extensive chronic GVHD in each arm |  | 365 days | 
| Incidence of graft rejection in each arm. |  | 365 days | 
| Quality and timing of immunologic reconstitution in each arm. |  | 100, 365 and 730 days | 
| Detection of MSC from donor origin in recipient marrow after HCT in patients given MSC |  | 40 days | 
| Proportion of patients with measurable disease at HCT who achieve a complete response in each arm. |  | 100, 365 and 730 days | 
| Cumulative incidence of relapse |  | 365 and 730 days | 
| Incidence of progression-free survival |  | 365 and 730 days | 
| Incidence of infections |  | 100 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HSC transplantation, HLA-mismatched, Mesenchymal stem cells, GVHD, co-infusion