Optimizing PTCy Dosage to Reduce Transplant-Related Toxicities

Heather Stefanski, MD, PhD, of the National Marrow Donor Program, discusses the ongoing efforts to refine the use of post-transplant cyclophosphamide (PTCy), a regimen that has revolutionized human leukocyte antigen (HLA) matching but remains associated with significant clinical challenges. Although PTCy has enabled a surge in mismatched unrelated donor (MMUD) transplantations, its standard administration comes with complications include delayed immune reconstitution and a high incidence of infections; data from the ACCESS study (NCT04904588) indicated that two-thirds of patients experienced a grade 2 or higher infection, often leading to prolonged hospitalizations and increased medical intervention.

Beyond infectious risks, standard-dose PTCy is linked to severe morbidities such as hemorrhagic cystitis, a painful and difficult-to-treat inflammation of the bladder, and potential cardiac toxicities. To address these issues, the OPTIMIZE trial (NCT06001385) is investigating whether reducing the standard PTCy dose from 50 mg/kg to 25 mg/kg can mitigate these adverse events without compromising the drug's ability to prevent graft-vs-host disease (GVHD). The study specifically focuses on infection-free survival in patients receiving peripheral blood stem cells from mismatched donors.

Early results from the OPTIMIZE trial have been promising, showing a reduction in infection rates with the lower dose. However, Stefanski emphasizes the necessity of long-term monitoring. Although infection-free survival is typically measured at day 100, a complete assessment of the dose reduction requires data on GVHD relapse-free survival at the 1-year mark and beyond. This extended follow-up is critical to ensure that lowering the dose does not result in an uptick in chronic GVHD or disease recurrence.

If subsequent data confirms that the 25 mg/kg dose maintains the same level of protection against GVHD and relapse while significantly lowering the burden of toxicity, it could fundamentally shift the standard of care. This evolution would allow patients to benefit from the expanded donor options provided by the PTCy platform while experiencing a much safer and more tolerable recovery period.