Cyclophosphamide Versus Anti-thymocyte Globulin for GVHD Prophylaxis After RIC Allo-SCT
Condition: Graft vs Host Disease
MeSH terms: Graft vs Host Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      The study is designed as a two arm randomized Phase II, multicenter trial comparing
      cyclophosphamide to anti-thymocyte globulin for Graft-versus-Host Disease (GVHD) prophylaxis
      in patients with hematologic malignancies undergoing reduced intensity conditioning
      hematopoietic stem cell transplantation.
    

Detailed description: 
      Allogeneic stem cell transplantation (allo-SCT) is a well-established therapy for different
      hematologic malignancies. Reduced-intensity conditioning (RIC) regimens can decrease the rate
      of toxicity/mortality in elderly patients, or in patients with poor medical condition. GVHD
      prophylaxis remains a challenging task after allo-SCT. The Flu-ivBu combination is a widely
      used RIC regimen, endorsed by EMA since July 2014. ATG in combination with cyclosporine-A
      ±mycophenolate mofetil is the backbone for GVHD prophylaxis in this setting. ATG can prevent
      GVHD with a good efficacy, but at the cost of a higher toxicity and profound
      immunosuppression, calling for more effective therapies. The most widely used RIC regimen in
      France incorporates fludarabine (Flu), intermediate doses of IV-busulfan (Bu) and
      anti-thymocyte globulins (ATG). While the use of ATG can prevent severe acute and chronic
      GVHD after allogeneic peripheral blood stem cell (PBSC) transplantation from both
      HLA-identical sibling and unrelated donors, some data suggested that in-vivo T-cell depletion
      with ATG in the RIC setting may induce a higher risk of disease relapse. Also, ATG induces
      profound immune suppression and increase incidence of opportunistic infections, especially
      EBV-related complications (relative risk=4.9; 95% CI[ 1.1-21.0]; P=0.03).

      On the other hand, high-dose post-transplantation cyclophosphamide (PTCy) was developed to
      facilitate HLA-haploidentical allo-SCT using unmanipulated bone marrow (BM) cells. PTCy was
      effective in preventing both acute and chronic GVHD given its capacity to preferentially
      eliminate allo-reactive T cells and preserve regulatory T cells, both of which impact
      allogeneic immune reactions. Subsequently, the efficacy of PTCy as sole GVHD prophylaxis
      after myeloablative conditioning when using BM was also shown. However, BM is not the
      preferred source of stem cells after RIC allo-SCT, and the potential efficacy of PTCy on
      preventing GVHD when using PBSCs (which is the most frequently used source of allogeneic
      cells worldwide) is debated.

      The advent of PTCy therapy is nowadays on the cutting edge. Thus, the potential efficacy (and
      cost-effectiveness) of PTCy for GVHD prophylaxis may have a major ATG sparing potential. A
      recent single centre phase 2 study (n=49) suggested that PTCy alone may not be the preferred
      GVHD prophylaxis following a RIC transplant with PBSCs. Indeed, A matched cohort analysis
      compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of
      acute GVHD grade II to IV (46% versus 19%; hazard ratio [HR], 2.8; P =0.02) and
      treatment-related mortality (HR, 3.3; P =0.035) and worse overall survival (HR, 1.9; P=0..04)
      with post-CY. Interpretation of the above non-randomized data is further complicated by
      heterogeneity (related and unrelated donors, BM and PBSC as stem cell source, different
      conditioning regimen), highlighting the need for a controlled randomized trial in a
      standardized setting.

      The ultimate goal of this Phase IIB study is to assess the feasibility and inform the design
      of a subsequent phase III study. The present randomized trial is designed to compare the
      efficacy of the addition of PTCy to current standard of care with ATG after a Flu-Bu-based
      RIC regimen on GVHD prophylaxis. The protocol will use a novel endpoint for benchmarking
      interventions based on a composite primary endpoint of GVHD-free, relapse-free survival which
      measures freedom from ongoing morbidity and represents an ideal outcome measure after
      allo-SCT.
    

Intervention name(s): Cyclophosphamide; Anti-Thymocyte Globulin; Conditioning regimen
Intervention type(s): Drug; Drug; Drug
Intervention description(s): GVHD prophylaxis: All patients will receive post-transplant 50mg/Kg/day cyclophosphamide (day +3 and +4) AND cyclosporine-A alone in case of an HLA-sibling donor, or cyclosporine-A and mycophenolate-mofetil in case of an HLA-matched unrelated donor; GVHD prophylaxis: 2.5 mg/Kg/day ATG (Thymoglobuline®) for 2 consecutive days (day -2 and -1) All patients will receive cyclosporine-A alone in case of an HLA-sibling donor, or cyclosporine-A and mycophenolate-mofetil (MMF) in case of an HLA-matched unrelated donor.; 30 mg/m2/day fludarabine for 5 days (day-6 to day-2) 130 mg/m2/day IV busulfan once daily for 2 days (day -4 and -3)
Other intervention name(s): Cyclophosphamide + cyclosporine-A +/-mycophenolate-mofetil; Anti-Thymocyte Globulin + cyclosporine-A +/-mycophenolate-mofetil
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Cyclophosphamide; Cyclosporins; Antilymphocyte Serum
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Hematopoietic Stem Cell; Transplantation; Graft vs Host Disease; Cyclophosphamide; Anti-Thymocyte Globulin; GVHD prophylaxis