MSC and HSC Coinfusion in Mismatched Minitransplants

University of Liege

Status and phase: Terminated; Phase 2

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

Treatments: Biological: Mesenchymal stem cells; Other: Isotonic solution

Study type: Interventional

Funder types: Other

Identifiers

NCT01045382

TJB0909

Details and patient eligibility

About

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.

Enrollment: 39 patients

Sex: All

Ages: Under 75 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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39 participants in 2 patient groups, including a placebo group

Mensenchymal Stem Cells

Experimental group

Description:

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.

Treatment:

Biological: Mesenchymal stem cells

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Other: Isotonic solution