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.