MSC and HSC Coinfusion in Mismatched Minitransplants

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

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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • Hôpital Stuyvenberg
  • Brussels, Belgium, 1050
    • Vrije Universiteit Brussel
  • Brussels, Belgium, 1000
    • Bordet Institute
  • Liège, Belgium, 4000
    • CHU-ULG
  • Antwerpen
    • Edeghem, Antwerpen, Belgium, 2650
      • UZA
  • Brabant
    • Brussels, Brabant, Belgium, 1200
      • St-Luc UCL
  • Flamish Brabant
    • Leuven, Flamish Brabant, Belgium, 3000
      • AZ Gasthuisberg Leuven
  • Flanders Ost
    • Gent, Flanders Ost, Belgium, 9000
      • UZ Gent
  • Flanders West
    • Brugge, Flanders West, Belgium, 8000
      • AZ St-Jan
  • Namur
    • Yvoir, Namur, Belgium, 5530
      • Cliniques Universitaires Mont-Godinne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Liege
• Collaborators: University Hospital, Ghent; AZ Sint-Jan AV; Cliniques universitaires Saint-Luc- Université Catholique de Louvain; Ziekenhuis Netwerk Antwerpen (ZNA); Jules Bordet Institute; Universiteit Antwerpen; AZ-VUB
• 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 record dates

Study Major Dates

• Study Start (Actual): July 1, 2010
• Primary Completion (Actual): August 1, 2021
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: January 8, 2010
• First Submitted That Met QC Criteria: January 8, 2010
• First Posted (Estimate): January 11, 2010

Study Record Updates

• Last Update Posted (Actual): September 8, 2021
• Last Update Submitted That Met QC Criteria: August 31, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Mesenchymal stem cells; GVHD; HLA-mismatched; HSC transplantation; co-infusion
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, B-Cell; Lymphoma; Myelodysplastic Syndromes; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Hodgkin Disease; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myeloproliferative Disorders
• Other Study ID Numbers: TJB0909