MSC and HSC Coinfusion in Mismatched Minitransplants

• Incidence of grade II-IV and grade III-IV acute GVDH [ Time Frame: 100 days ] [ Designated as safety issue: No ]
• Number of absolute donor T cells after HCT in each arm [ Time Frame: 28 ] [ Designated as safety issue: No ]
• Cumulative incidence of non-relapse mortality [ Time Frame: 100, 365 and 730 days ] [ Designated as safety issue: Yes ]
• Incidence of extensive chronic GVHD in each arm [ Time Frame: 365 days ] [ Designated as safety issue: No ]
• Incidence of graft rejection in each arm. [ Time Frame: 365 days ] [ Designated as safety issue: No ]
• Quality and timing of immunologic reconstitution in each arm. [ Time Frame: 100, 365 and 730 days ] [ Designated as safety issue: No ]
• Detection of MSC from donor origin in recipient marrow after HCT in patients given MSC [ Time Frame: 40 days ] [ Designated as safety issue: No ]
• Proportion of patients with measurable disease at HCT who achieve a complete response in each arm. [ Time Frame: 100, 365 and 730 days ] [ Designated as safety issue: Yes ]
• Cumulative incidence of relapse [ Time Frame: 365 and 730 days ] [ Designated as safety issue: Yes ]
• Incidence of progression-free survival [ Time Frame: 365 and 730 days ] [ Designated as safety issue: No ]
• Incidence of infections [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]

• Incidence of grade II-IV and grade III-IV acute GVDH [ Time Frame: 100 days ] [ Designated as safety issue: No ]
• Number of absolute donor T cells after HCT in each arm [ Time Frame: 28 ] [ Designated as safety issue: No ]
• Cumulative incidence of non-relapse mortality [ Time Frame: 100, 365 and 730 days ] [ Designated as safety issue: Yes ]
• Incidence of extensive chronic GVHD in each arm [ Time Frame: 365 days ] [ Designated as safety issue: No ]
• To evaluate the incidence of graft rejection in each arm. [ Time Frame: 365 days ] [ Designated as safety issue: No ]
• Quality and timing of immunologic reconstitution in each arm. [ Time Frame: 100, 365 and 730 days ] [ Designated as safety issue: No ]
• Detection of MSC from donor origin in recipient marrow after HCT in patients given MSC [ Time Frame: 40 days ] [ Designated as safety issue: No ]
• Proportion of patients with measurable disease at HCT who achieve a complete response in each arm. [ Time Frame: 100, 365 and 730 days ] [ Designated as safety issue: Yes ]
• Cumulative incidence of relapse [ Time Frame: 365 and 730 days ] [ Designated as safety issue: Yes ]
• Incidence of progression-free survival [ Time Frame: 365 and 730 days ] [ Designated as safety issue: No ]
• Incidence of infections [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]

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.

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

• Biological: Mesenchymal stem cells
  Mesenchymal stem cell injection
• Other: Isotonic solution
  Isotonic solution injection

• 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.

  Intervention: Biological: Mesenchymal stem cells
• 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.

  Intervention: Other: Isotonic solution

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.

• AZ Sint-Jan AV
• Ziekenhuis Netwerk Antwerpen (ZNA)
• Jules Bordet Institute
• Universiteit Antwerpen
• Katholieke Universiteit Leuven
• AZ-VUB
• Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• University Hospital, Ghent
• University Hospital of Mont-Godinne
• Queen Fabiola Children's University Hospital