<p>Significant progress has been made in graft-versus-host disease (GVHD) prophylaxis; however, unmet needs remain. Posttransplant cyclophosphamide (PTCy)–based prophylaxis has advanced GVHD prevention, but ways to optimize dosing and combination strategies are being considered. Looking ahead, novel precision-engineered grafts may also help to reshape GVHD prophylactic strategies.</p>

In the United States, PTCy has become the leading GVHD prophylactic approach. The current standard is to give PTCy with a calcineurin inhibitor, plus or minus mycophenolate mofetil. People are asking whether a lower dose of PTCy could result in reduced side effects or toxicities, but that is a difficult question to answer. We do not routinely reduce the dose of PTCy below 50 mg/kg. To date, I have not seen evidence that a lower dose of PTCy reduces toxicity in a meaningful way beyond possibly increasing the time to neutrophil recovery post transplant, but it remains an area of interest. Moreover, I am very interested to see the results of current approaches in which abatacept is added to PTCy without a calcineurin inhibitor.

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I was fascinated by a finding from an analysis of the phase 3 BMT CTN 1703 study that explored the impact of PTCy in patients aged 70 years or older. This was a randomized controlled trial of PTCy, tacrolimus, and mycophenolate mofetil vs tacrolimus and methotrexate following reduced-intensity conditioning allogeneic hematopoietic stem cell transplants (allo-HCTs). Approximately one-quarter of the patients in the study were aged 70 years or older. One would think that the PTCy, tacrolimus, and mycophenolate mofetil regimen would be more toxic in older people, who are more likely to have underlying cardiac disease, arrhythmias, and reduced cardiac function. In this analysis, however, this regimen was associated with a significant reduction in nonrelapse mortality and no increase in cardiac toxicity in this population.

We use abatacept in some patients receiving grafts matched at 7/8 and, in some cases, 8/8 human leukocyte antigen alleles in whom we do not feel that PTCy is the right choice. Typically, abatacept is used in somebody who has preexisting cardiac disease or somebody about whom we might have engraftment concerns, including patients with myeloproliferative neoplasms. These are the patients for whom I think there is still room to improve the dosing of PTCy and partner agents. We use prophylactic B-cell depletion, but we are testing other approaches that involve agents such as abatacept for acute GVHD prophylaxis in combination with B-cell depletion for chronic GVHD prophylaxis. There is also nice work coming out on αβ T-cell depletion.

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Although not prophylaxis itself, Orca-T (Orca Bio) has the potential to shake up the prophylaxis space, too. It is going to be very tricky, though, because those who routinely use conventional allo-HCT with PTCy will not have a reason to change from that to Orca-T based on the design of the phase 3 Precision-T trial, which compared Orca-T plus tacrolimus with conventional allo-HCT plus tacrolimus and methotrexate. However, those who are still bound to using conventional allo-HCT with tacrolimus and methotrexate are really going to have a dilemma on their hands because, while the Precision-T trial was strikingly positive, Orca-T costs significantly more. I think that it will be really interesting to see how the field reacts outside of clinical trials.

It is noteworthy that the Precision-T trial reported a low relapse rate with the Orca-T trial. One avenue for further exploration could be identifying subsets of patients who may derive greater benefit from this approach. For instance, patients with high-risk disease might benefit more than those with intermediate-risk disease. Personally, I am eager to see how the data evolve moving forward.

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Returning to PTCy, I found the mechanistic companion study to BMT CTN 1703, the phase 3 BMT CTN 1801 study, particularly intriguing. It showed a reduction in T-cell receptor diversity in patients who received PTCy compared with those who received tacrolimus and methotrexate for GVHD prophylaxis. While the benefits from PTCY therapy are clear, I believe that longer-term follow-up is needed to better understand immune reconstitution and its role in relapse with PTCy therapy over time.

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Another study, the phase 3 BMT CTN 2203 trial, is comparing PTCy, tacrolimus, and mycophenolate mofetil vs tacrolimus, methotrexate, and ruxolitinib for GVHD prophylaxis in recipients of nonmyeloablative and reduced-intensity conditioning. We look forward to seeing the data from this trial, which is currently ongoing.