MSC and HSC Coinfusion in Mismatched Minitransplants

Phase 2

Terminated

• Conditions: Myelodysplastic Syndromes; Leukemia, Lymphocytic, Chronic; Lymphoma, Non-Hodgkin; Leukemia, Lymphoblastic, Acute; Leukemia, Myelocytic, Chronic; Myeloproliferative Disorders; Hodgkin's Disease; Multiple Myeloma; Leukemia, Myeloid, Acute
• Interventions: Biological: Mesenchymal stem cells; Other: Isotonic solution

• Registration Number: NCT01045382
• Lead Sponsor: University of Liege

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2010-01-08
• Study First Submitted QC: 2010-01-08
• Study First Posted: 2010-01-11
• Study Start: 2010-07
• Status Verified: 2021-08
• Primary Completion: 2021-08
• Study Completion: 2021-08
• Last Update Submitted: 2021-08-31
• Last Update Posted: 2021-09-08

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 39

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mensenchymal Stem Cells	Mesenchymal 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.
Placebo	Isotonic solution	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.

Primary Outcome Measures

Name	Time	Method
One-year overall survival in the 2 arms.	One year

Secondary Outcome Measures

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

Trial Locations

Locations (10)

Bordet Institute; 🇧🇪 Brussels, Belgium

UZA; 🇧🇪 Edeghem, Antwerpen, Belgium

AZ St-Jan; 🇧🇪 Brugge, Flanders West, Belgium

CHU-ULg; 🇧🇪 Liège, Belgium

UZ Gent; 🇧🇪 Gent, Flanders Ost, Belgium

Hôpital Stuyvenberg; 🇧🇪 Antwerpen, Belgium

Vrije Universiteit Brussel; 🇧🇪 Brussels, Belgium

Cliniques Universitaires Mont-Godinne; 🇧🇪 Yvoir, Namur, Belgium

St-Luc UCL; 🇧🇪 Brussels, Brabant, Belgium

AZ Gasthuisberg Leuven; 🇧🇪 Leuven, Flamish Brabant, Belgium