Novel three-drug combination improves GVHD-free and relapse-free survival and relapse after allogeneic transplant

A phase III study conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)  assessed outcomes of a novel three-drug combination for graft-versus-host disease (GVHD) prevention following allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning (RIC). This research presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition shows patients who received post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF) demonstrated significantly improved GVHD-free and relapse-free survival (GRFS) compared to patients who received the standard combination of tacrolimus plus methotrexate (Tac/MTX).  

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The management of GVHD and disease relapse is an essential focus for patients undergoing alloHCT to optimize outcomes. For three decades, the standard GVHD prophylaxis strategy has been a calcineurin inhibitor (Tac) with MTX, but several approaches have been tried in recent years to improve this combination. However, intensifying immunosuppression comes with an increased risk of serious infections or relapse.

The previous phase II study (BMT CTN 1203) compared three novel GVHD prophylaxis regimens to current controls receiving Tac/MTX to determine the most favorable approach with RIC alloHCT. The most promising GVHD prophylaxis regimen was a three-drug combination of PTCy/Tac/MMF. 

Study Details  

The study included adult patients (18 years and older) with hematological malignancies who underwent RIC alloHCT. Recipients of 128 matched related, 288 fully matched unrelated, and 15 single-mismatched unrelated (7/8 HLA matched) donor transplants were randomized into two patient groups who received PTCy/Tac/MMF or Tac/MTX. The patients were balanced between the two groups by patient sex, age, Karnofsky status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance.    


Results showed a significantly higher GRFS in the PTCy treatment group than in the Tac/MTX group, as shown in Figure 1 below. There was a lower proportion of GRFS events in the PTCy treatment group, due to a reduction in acute and chronic GVHD. There was no difference in relapse, progression rate or overall survival rate at 1-year post-transplant in either group.

The trial met its primary endpoint, which demonstrated a higher 1-year GRFS with the combination PTCy/Tac/MMF compared to Tac/MTX and significant improvements to acute and chronic GVHD risk without increased relapse or death. 

Key Takeaways  

These results support a paradigm shift in the standard approach to GVHD prevention in the setting of well-matched alloHCT for patients with hematologic malignancies receiving RIC. The use of the PTCy combination was associated with lower rates of both acute and chronic GVHD without increasing the risk of disease relapse. Adopting this new approach will likely increase the possibility of event-free survival post-transplant, allowing more patients to survive and thrive.   

Figure 1 

Holtan SG, et al. ASH poster abstract   FIGURE 1  

Holtan SG, et al. ASH poster abstract