GVHD Prevention Strategies and the Underappreciated Toxicity of Post-Transplant Cyclophosphamide

Caspian Oliai, MD, MS, reviews how graft-vs-host disease (GVHD) prophylaxis has evolved and where its toxicity is underappreciated. Historically, tacrolimus and methotrexate with reduced-intensity conditioning left patients at substantial risk of GVHD and nonrelapse mortality, and BMT CTN 1703 showed that post-transplant cyclophosphamide in that setting yields lower nonrelapse mortality and less GVHD; anecdotally, transplants simply go more smoothly. He cautions, however, that post-transplant cyclophosphamide can cause substantial toxicity in patient populations that were excluded from trials but receive it in real-world practice. Cyclophosphamide carries direct cardiotoxicity, and preventing hemorrhagic cystitis requires a hyperhydration protocol that commonly delivers 7 to 8 L of intravenous fluid over 2 days, a large volume for an older patient or one with cardiomyopathy. He cites a recent publication linking severe fluid overload on days 3 through 8 after transplant to higher nonrelapse mortality and lower overall survival. Because post-transplant cyclophosphamide remains the unequivocal standard for reduced-intensity conditioning, Dr Oliai outlines 2 paths to innovation. The first modifies its use: reducing the dose, which a number of trials are now studying; giving less intravenous fluid and accepting some additional hemorrhagic cystitis; and risk-stratifying patients likely to experience toxicity, with the caveat that dose reduction needs prospective data. The second path avoids post-transplant cyclophosphamide altogether. Returning to tacrolimus and methotrexate is not an option, since it was shown to be inferior, but an approach such as Orca-T, currently approved in the myeloablative setting, uses tacrolimus alone and removes the additional chemotherapeutic agent for patients at higher risk of toxicity.