MSC and HSC Coinfusion in Mismatched Minitransplants
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Mensenchymal Stem Cells 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
Mesenchymal stem cell injection
|
| Placebo Comparator: Placebo 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
Isotonic solution injection
|
Outcome Measures
Primary Outcome Measures
- One-year overall survival in the 2 arms. [One year]
Secondary Outcome Measures
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Theoretical indication for a standard allo-transplant, but not feasible because: Age > 55 yrs. Unacceptable end organ performance. Patient's refusal.
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Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant.
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Male or female; fertile female patients must use a reliable contraception method
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Age ≤ 75 year old
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Informed consent given by patient or his/her guardian if of minor age.
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One or two HLA mismatches with PBSC:
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One antigenic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1
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Two allelic mismatches at HLA-A or -B or -C or -DRB1 or -DQB1
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One antigenic mismatch: 1 allelic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1.
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One antigenic mismatch at -DQB1 and one other antigenic mismatch at HLA-A or -B or -C or -DRB1
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Patients with one single allelic mismatch at HLA-A or -B or -C or -DRB1 or -DQB1 can also be included in the protocol.
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Hematological malignancies confirmed histologically and not rapidly progressing:
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AML in complete remission
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ALL in complete remission
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CML unresponsive/intolerant to Imatinib but not in blast crisis
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Other myeloproliferative disorders not in blast crisis and not with extensive myelofibrosis
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MDS with <5% blasts
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Multiple myeloma not rapidly progressing
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CLL
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Non-Hodgkin's lymphoma (aggressive NHL should be chemosensitive)
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Hodgkin's disease
Exclusion Criteria:
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Any condition not fulfilling inclusion criteria
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HIV positive
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Terminal organ failure, except for renal failure (dialysis acceptable)
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Cardiac: Symptomatic coronary artery disease or other cardiac failure requiring therapy; ejection fraction <35%; uncontrolled arrhythmia; uncontrolled hypertension
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Pulmonary: DLCO < 35% and/or receiving supplementary continuous oxygen
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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
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Uncontrolled infection, arrhythmia or hypertension
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Previous radiation therapy precluding the use of 2 Gy TBI
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10/10 HLA-A, -B, -C, DRB1 and DQBI allele-matched donor fit to/willing to donate PBSC.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UZA | Edeghem | Antwerpen | Belgium | 2650 |
| 2 | St-Luc UCL | Brussels | Brabant | Belgium | 1200 |
| 3 | AZ Gasthuisberg Leuven | Leuven | Flamish Brabant | Belgium | 3000 |
| 4 | UZ Gent | Gent | Flanders Ost | Belgium | 9000 |
| 5 | AZ St-Jan | Brugge | Flanders West | Belgium | 8000 |
| 6 | Cliniques Universitaires Mont-Godinne | Yvoir | Namur | Belgium | 5530 |
| 7 | Hôpital Stuyvenberg | Antwerpen | Belgium | 2060 | |
| 8 | Bordet Institute | Brussels | Belgium | 1000 | |
| 9 | Vrije Universiteit Brussel | Brussels | Belgium | 1050 | |
| 10 | CHU-ULg | Liège | Belgium | 4000 |
Sponsors and Collaborators
- University of Liege
- AZ Sint-Jan AV
- Ziekenhuis Netwerk Antwerpen (ZNA)
- Jules Bordet Institute
- Universiteit Antwerpen
- AZ-VUB
- Cliniques universitaires Saint-Luc- Université Catholique de Louvain
- University Hospital, Ghent
Investigators
- Principal Investigator: Yves Beguin, MD, PhD, CHU-ULg
- Study Chair: Frédéric Baron, MD, PhD, CHU-ULg
- Principal Investigator: Evelyne Willems, MD, CHU-ULg
- Principal Investigator: Dominik Selleslag, MD, PhD, AZ Brugge
- Principal Investigator: Pierre Zachée, MD, PhD, ZNA Antwerpen
- Principal Investigator: Philippe Lewalle, MD, PhD, Bordet Institute, Brussels
- Principal Investigator: Dominique Bron, MD, PhD, Bordet Institute, Brussels
- Principal Investigator: Wilfried Schroyens, MD, PhD, UZA Antwerpen
- Principal Investigator: Chantal Lechanteur, PhD, CHU-ULg
- Principal Investigator: Etienne Baudoux, MD, CHU-ULg
- Principal Investigator: Johan Maertens, MD, KUL, Leuven
- Principal Investigator: Rik Schots, MD, PhD, AZ VUB, Brussels
- Principal Investigator: Augustin Ferrant, MD, PhD, UCL St. LUC, Brussels
- Principal Investigator: Lucien Noens, MD, PhD, UZG Gent
- Principal Investigator: Chantal Doyen, MD, PhD, Cliiques Universitaire Mont-Godinne, Yvoir
- Principal Investigator: Tessa Kerre, MD, PhD, UZA, Antwerpen
- Principal Investigator: Carlos Graux, MD, PhD, Cliniques Universitaires, Mont-Godinne
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TJB0909