Although PTCy is a very efficient GvHD prophylaxis, it has like any other drug, side effects and the main side effects are cardiac toxicity, hemorrhagic cystitis, and delayed engraftment and immune reconstitution. The toxicities are, at least partly, dose-dependent. So we hypothesized that reducing PTCy dose will help to mitigate the toxicities. And several studies have been conducted.
I’ve presented the results of studies showing that reducing the dose to 80mg per kilo was safe, without increasing the risk of GvHD, and then other studies have been conducted with a wider, a broader dose reduction...
Although PTCy is a very efficient GvHD prophylaxis, it has like any other drug, side effects and the main side effects are cardiac toxicity, hemorrhagic cystitis, and delayed engraftment and immune reconstitution. The toxicities are, at least partly, dose-dependent. So we hypothesized that reducing PTCy dose will help to mitigate the toxicities. And several studies have been conducted.
I’ve presented the results of studies showing that reducing the dose to 80mg per kilo was safe, without increasing the risk of GvHD, and then other studies have been conducted with a wider, a broader dose reduction. The take home message is that reducing PTCy dose is a feasible approach that preserves an efficient GvHD prevention and also adds clinical benefits. There is an improved neutrophil and platelet recovery, and there is a reduction in the incidences of mucositis, cardiac complications and infectious disease such as bacteremia and BK virus cystitis.
Overall, it enables haplo for more fragile patients, such as those who are older or those who have cardiac comorbidities.
I think now the data are mature enough to investigate further in randomized controlled trials. And those trials will have to answer, in my eye three, important questions. The first one is what is the optimal dose? Is it 40, 35, 25, or even lower 15 milligram per kilo per day on day plus three and plus four? Is it the same for bone marrow or peripheral blood stem cells? The second question is that those ongoing and future trials will have to confirm the clinical benefit in terms of organ injury and in terms of engraftment, but also in terms of immune reconstitution and in particular, TCR diversity, and in terms of quality of life for the patient. And finally, I think the third important question is to define the optimal combination of immunosuppressive agents with a reduced PTCy dose. Is it PTCy with MMF and a calcineurin inhibitor or sirolimus? Or should we add ATG? Many studies have shown that it is safe to add it, and it may reduce the risk of GvHD. Other drugs are currently investigating with promising results such as abatacept, vedolizumab or obinutuzumab combined with PTCy. That’s other options that we should investigate.
