Mesenchymal Stem Cell Infusion as Treatment for Steroid-Resistant Acute Graft Versus Host Disease (GVHD) or Poor Graft Function

Infusion of Mesenchymal Stem Cells as Treatment for Steroid-Resistant Grade II to IV Acute GVHD or Poor Graft Function: a Multicenter Phase II Study

The present project aims at investigating the role of MSC for the treatment of patients with

Part 1: Steroid-refractory grade II-IV acute GVHD.

Part 2: Poor graft function (PGF)

Part 3: Low or falling donor T-cell chimerism after allogeneic HCT.

This is a multicenter phase II study examining the feasibility and efficacy of this approach.

Study Overview

• Status: Recruiting
• Conditions: Graft-versus-host Disease; Poor Graft Function; Low Donor T-cell Chimerism
• Intervention / Treatment: Biological: Mesenchymal stem cells

Detailed Description

Part 1: complete recruitment Part 2: complete recruitment Part 3: recruiting

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yves Beguin, MD, PhD; Phone Number: 32-4-366 72 01; Email: yves.beguin@chu.ulg.ac.be
• Study Contact Backup: Name: Frederic Baron, MD, PhD; Phone Number: 32-4-366 72 01; Email: F.Baron@ulg.ac.be

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • Recruiting
    • Hôpital Stuyvenberg
    • Principal Investigator: Pierre Zachée, MD, PhD
    • Contact: Pierre Zachée, MD, PhD; Phone Number: 32(03)2177111; Email: pierre.zachee@zna.be
  • Liege, Belgium, 4000
    • Recruiting
    • CHU Sart Tilman
    • Principal Investigator: Yves Beguin, MD, PhD
    • Sub-Investigator: Evelyne Willems, MD
    • Contact: Yves Beguin, MD/PhD; Phone Number: 32-4-366 72 01; Email: yves.beguin@chu.ulg.ac.be
    • Contact: Frederic Baron, MD/PhD; Phone Number: 32-4-366 72 01; Email: F.Baron@ulg.ac.be
    • Principal Investigator: Frederic Baron, MD, PhD
    • Principal Investigator: Chantal Lechanteur, PhD
    • Sub-Investigator: Etienne Baudoux, MD
    • Sub-Investigator: Pascale Frère, MD, PhD
    • Sub-Investigator: Bernard De Prijck, MD
  • Antwerpen
    • Edeghem, Antwerpen, Belgium, 2650
      • Recruiting
      • UZA
      • Principal Investigator: Zwi Berneman, MD, PhD
      • Contact: Zwi Berneman, MD, PhD; Phone Number: 32(03)8213250; Email: zwi.berneman@uza.be
  • Brabant
    • Brussels, Brabant, Belgium, 1020
      • Recruiting
      • Hôpital des enfants Reine Fabiola
      • Contact: Alice Ferster, MD; Phone Number: 32(02)4773283; Email: alice.ferster@huderf.be
      • Principal Investigator: Alice Ferster, MD
    • Brussels, Brabant, Belgium, 1090
      • Recruiting
      • AZ VUB Jette
      • Contact: Rik Schots, MD, PhD; Phone Number: 32 (02) 4763105; Email: Rik.Schots@uzbrussel.be
      • Principal Investigator: Rick Schots, MD, PhD
    • Brussels, Brabant, Belgium, 1200
      • Recruiting
      • Cliniques universitaires Saint-Luc- Université Catholique de Louvain
      • Contact: Augustin Ferrant, MD, PhD; Phone Number: 32 (02) 7641880; Email: Augustin.Ferrant@uclouvain.be
      • Principal Investigator: Augustin Ferrant, MD, PhD
  • Flamish Brabant
    • Leuven, Flamish Brabant, Belgium, 3000
      • Recruiting
      • AZ Gasthuisberg Leuven
      • Contact: Johan Maertens, MD; Phone Number: 32- 16 33 22 11; Email: johan.maertens@uz.kuleuven.ac.be
      • Contact: Koen Theunissen, MD; Phone Number: 32- 16 33 22 11; Email: koen.theunissen@uz.kuleuven.ac.be
      • Principal Investigator: Johan Maertens, MD
      • Principal Investigator: Koen Theunissen, MD
  • Flanders Ost
    • Gent, Flanders Ost, Belgium, 9000
      • Recruiting
      • UZ Gent
      • Contact: Lucien Noens, MD, PhD; Phone Number: 32(09) 332 21 31; Email: Lucien.Noens@Ugent.be
      • Principal Investigator: Lucien Noens, MD, PhD
  • Hainaut
    • Haine St Paul, Hainaut, Belgium, 7100
      • Recruiting
      • Hopital de Jolimont
      • Contact: Nicole Straetmans, MD; Phone Number: 32(064) 235071; Email: nicole.straetmans@scarlet.be
      • Principal Investigator: Nicole Straetmans, MD
  • Namur
    • Yvoir, Namur, Belgium, 5530
      • Recruiting
      • Cliniques Universitaires Mont-Godinne
      • Contact: Chantal Doyen, MD; Phone Number: 32(081)423831; Email: chantal.doyen@sang.ucl.ac.be
      • Principal Investigator: Chantal Doyen, MD
  • West Flanders
    • Brugge, West Flanders, Belgium, 8000
      • Recruiting
      • AZ St Jan
      • Principal Investigator: Dominik Selleslag, MD
      • Contact: Domonik Selleslag, MD; Phone Number: 32 (050) 453060; Email: dominik.selleslag@azbrugge.be
• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6200
      • Not yet recruiting
      • University Hospital Maastricht
      • Contact: Harry Schouten, MD; Phone Number: +31-43-3876543; Email: h.schouten@intmed.unimaas.nl
      • Principal Investigator: Harry Schouten, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patient eligibility criteria

1. Male or female of any age.
2. Previous allogeneic transplantation (related or unrelated donor, any degree of HLA matching) or autologous transplantation (for part 2 only) of HSC at any time before.
3. Any source of HSC (marrow, PBSC, cord blood) and any conditioning regimen.
4. Informed consent given by donor or his/her guardian if of minor age.
5. Additional criteria for each part of the protocol:

Part 1: MSC for steroid-refractory grade II-IV acute GVHD

1. Allogeneic transplantation.
2. Grade II-IV acute GVHD (see appendix A for acute GVHD grading) de novo or following DLI.

3. Acute GVHD refractory to mPDN 2 mg/kg/day or equivalent, defined as

   • progression of GVHD on day 3 after initiation of steroids
   • no improvement of GVHD on day 7 after initiation of steroids
   • absence of complete resolution of acute GVHD on day 14 after initiation of steroids
   • relapse of acute GVHD during or after steroid taper.
4. Ongoing therapy with Ciclosporine or Tacrolimus at therapeutic doses.
5. Patient may have received previously any other form of treatment for acute GVHD, but no new treatment started within 1 month of study entry.

Part 2: MSC for poor graft function (PGF)

1. Allogeneic or autologous transplantation.

2. Cytopenia in 2 or 3 lineages:

   • Hb < 8.0 g/dL and reticulocytes < 1%, with or without transfusion
   • Plt < 20,000/µL without transfusion
   • Neutrophils < 500/µL, without G-CSF administration

   OR severe cytopenia in 1 lineage:

   • RBC transfusion dependent (if autologous transplantation; despite EPO administration if allogeneic transplantation)
   • Plt transfusion dependent
   • Neutrophils < 500/µL despite G-CSF administration
3. Cytopenia duration ≥ 2 weeks beyond day 28 after autologous HCT, or day 42 (day 60 for cord blood transplantation) after allogeneic HCT.
4. Cytopenia is not related to CMV or other infection, myelosuppressive/toxic drugs, renal failure, peripheral cell destruction or other identifiable cause.
5. In case of HLA-identical related donor and full donor chimerism, patient can only be included if a boost of donor CD34+ cells has been unsuccessful or is not feasible.

Part 3: MSC + DLI for poor donor T-cell chimerism

1. Nonmyeloablative allogeneic transplantation.

2. Donor T-cell chimerism < 50% for at least 2 consecutive weeks beyond day 21 after HCT OR

   • 20% decrease in donor T-cell chimerism with the second value < 50%.

MSC donor inclusion criteria

1. Related to the recipient (sibling, parent or child) or unrelated.
2. Male or female.
3. Age > 16 yrs (no age limit if same as HSC donor).
4. No HLA matching required.
5. Fulfills generally accepted criteria for allogeneic HSC donation.
6. Informed consent given by donor or his/her guardian if of minor age.

Exclusion Criteria:

Patient exclusion criteria

1. HIV positive.
2. Active uncontrolled infection at time of scheduled MSC infusion.
3. Relapsing or progressing malignancy.

MSC donor exclusion criteria

1. HIV positive
2. Known allergy to Lidocaine
3. If donor other than HSC donor : any risk factor for transmissible infectious diseases.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; MSC infusion for steroid-refractory grade II-IV acute GVHD. In this arm, 4 x 10E6 MSC/Kg BW of the recipient will be injected during the first hour after thawing.	Biological: Mesenchymal stem cells; Mesenchymal Stem Cell infusion
Experimental: 2; MSC infusion for poor graft function. In this arm, 2 x 10E6 MSC/Kg BW of the recipient will be injected during the first hour after thawing.	Biological: Mesenchymal stem cells; Mesenchymal Stem Cell infusion
Experimental: 3; MSC + DLI for poor donor T-cell chimerism after allogeneic HCT. In this arm, 2 x 10E6 MSC/Kg BW of the recipient will be injected during the first hour after thawing.	Biological: Mesenchymal stem cells; Mesenchymal Stem Cell infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Arm 1. Efficacy of MSC infusion as treatment for steroid-resistant grade II - IV acute GVHD.	30 days
Arm 2. Efficacy of MSC infusion as treatment for poor graft function	180 days
Arm 3. Efficacy of MSC infusion followed by donor lymphocyte infusion for preventing graft rejection in patients with low or failing donor T-cell chimerism after allogeneic HCT	180 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Toxicity of MSC infusion	180 days

Collaborators and Investigators

• Sponsor: University of Liege
• Collaborators: KU Leuven; Maastricht University Medical Center; University Hospital, Ghent; Queen Fabiola Children's University Hospital; University Hospital, Antwerp; AZ Sint-Jan AV; Cliniques universitaires Saint-Luc- Université Catholique de Louvain; Ziekenhuis Netwerk Antwerpen (ZNA); University Hospital of Mont-Godinne; AZ-VUB; Jolimont Hospital Haine Saint Paul
• Investigators: Study Chair: Yves Beguin, MD, PhD, CHU-ULG; Study Chair: Frédéric Baron, MD, PhD, CHU-ULG; Principal Investigator: Harry Schouten, MD, Maastricht University Medical Center; Principal Investigator: Johan Maertens, MD, KU Leuven; Principal Investigator: Pierre Zachée, MD, Stuyvenberg Hospital Antwerpen; Principal Investigator: Zwi Berneman, MD, UZA Antwerpen; Principal Investigator: Lucien Noens, MD, PhD, UZ-Gent; Principal Investigator: Rick Schots, MD, PhD, AZ VUB Jette; Principal Investigator: Dominik Selleslag, MD, AZ St. Jan Bugge; Principal Investigator: Augustin Ferrant, MD, PhD, UCL St. Luc Brussels; Principal Investigator: Chantal Doyen, MD, Cliniques Universitaires Mont-Godinne at Yvoir; Principal Investigator: Nicole Straetmans, MD, Hôpital de Jolimont at Haine-St-Paul; Principal Investigator: Nicole Ferster, MD, Hôpital des enfants Reine Fabiola at Brussels

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2008
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): August 1, 2024

Study Registration Dates

• First Submitted: January 16, 2008
• First Submitted That Met QC Criteria: January 28, 2008
• First Posted (Estimate): January 29, 2008

Study Record Updates

• Last Update Posted (Actual): September 21, 2022
• Last Update Submitted That Met QC Criteria: September 19, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Mesenchymal stem cells; Graft-versus-host disease; Chimerism; Poor graft function; Hematopoietic cell transplantation recipients; Low donor T-cell chimerism
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: TJB0703P1