<p>Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplant. Progress has been made in cGVHD prevention with the use of posttransplant cyclophosphamide (PTCy), but this approach is associated with significant toxicities. Newer strategies and modifications to the PTCy regimen are under investigation to reduce cGVHD incidence while minimizing adverse events.</p>

I do not think that I can underscore enough that progress has been made in reducing cGVHD rates, and PTCy has been an important factor in this progress. The use of this prophylactic regimen has markedly reduced moderate to severe cGVHD incidence. Historically, our ways of preventing GVHD were primarily focused on reducing acute GVHD, but, with few exceptions, we did not have a strong ability to reduce cGVHD.

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There are a lot of exciting areas of research that may perhaps further reduce overall cGVHD incidence and its severe manifestations beyond what we are seeing with PTCy therapy. One area that appears quite promising is graft manipulation through allogeneic T-cell immunotherapy, where a CD34-positive cell–enriched graft and regulatory T cells are infused, followed 2 days later by the infusion of a smaller-than-typical amount of conventional T cells. Preliminary data from studies using this approach in patients receiving myeloablative transplants have been very promising, showing reduced cGVHD rates.

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A phase 2 study is looking at the addition of maintenance ruxolitinib to tacrolimus and methotrexate prophylaxis, and preliminary data on cGVHD incidence appear quite promising. Another area of research is the use of B-cell–depleting therapies to prevent cGVHD, and there are encouraging and interesting data with posttransplant obinutuzumab suggesting that it may help reduce the risk of steroid-requiring cGVHD.

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Finally, studies are looking to optimize PTCy therapy by examining whether we can minimize some of its potential toxicities, which can include blood count abnormalities, infections, cardiovascular complications, and hemorrhagic cystitis. A single-center trial is looking at adding ruxolitinib to PTCy, with the hope that decreasing the dose of PTCy can perhaps reduce some of its associated toxicities and that the prolonged ruxolitinib exposure will reduce cGVHD rates. Whether this will be a successful approach has yet to be determined, but this is an area of active research.

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I think that the research community can be proud to have achieved reduced cGVHD rates with the use of PTCy. However, there is still work to be done, and the next 5 to 10 years will be an exciting time as we see the results of some studies that are currently in the works exploring other methods of lowering the risk of cGVHD.