In this study, the background is that post-transplant cyclophosphamide represents standard of care for graft-versus-host disease prophylaxis in patients undergoing reduced-intensity transplant with a HLA-matched donor. While this represents standard of care, there’s still about 25% of patients who develop clinically significant graft-versus-host disease, so that’s either severe acute GVHD or chronic graft-versus-host disease requiring systemic immune suppression...
In this study, the background is that post-transplant cyclophosphamide represents standard of care for graft-versus-host disease prophylaxis in patients undergoing reduced-intensity transplant with a HLA-matched donor. While this represents standard of care, there’s still about 25% of patients who develop clinically significant graft-versus-host disease, so that’s either severe acute GVHD or chronic graft-versus-host disease requiring systemic immune suppression. Furthermore, there’s still a moderate amount of toxicity doing transplant with PTCy. So approximately 35% of patients who undergo this approach experience cardiac toxicity. Nearly 20% experience some sort of pulmonary toxicity. And almost 15% experience some sort of significant renal toxicity. So to essentially expand access to transplant in a frailer population, so older patients who may have more comorbidities, there’s certainly a need for a GVH prophylaxis regimen that is less toxic and that also can further reduce rates of severe acute GVHD. So this study, the basis is there have been several recent publications that indicate in the alternative donor setting, so haploidentical transplant, giving an intermediate dose of cyclophosphamide at 25 mg per kg per day is feasible, so it allows for engraftment and has reasonable rates of graft-versus-host disease. Furthermore, there have been recent sort of studies that indicate that ruxolitinib, which is actually a treatment for acute graft-versus-host disease in chronic GVHD, may also serve as a prophylaxis against graft-versus-host disease. And so a large study in the reduced-intensity conditioning setting with TAC methotrexate as the background, patients were administered ruxolitinib as GVH prophylaxis, and low rates of chronic GVHD were reported in patients treated in that fashion. To build on PTCy and to reduce toxicity, we designed a study where an intermediate dose of PTCy would be given at 25 mg per kg per day on day 3 and 4. Then patients would receive prophylactic ruxolitinib upon engraftment through one year. This presentation reports on the early feasibility and safety of this study. This study has now been open for about one year and two months. And so we report on the first 25 patients or half the enrollment, and we report on outcomes within the first 100 days of these patients. So all patients that will be presented will have 100 day follow up and really the purpose is to sort of present the early feasibility and safety of this approach. So first of all, you know, reporting on sort of engraftment, so with this reduced dose of cyclophosphamide, what we observed actually was improved engraftment kinetics. So first of all, all patients who had chimerism studies at day 30 demonstrated engraftment, and additionally, when looking at kinetics of neutrophil recovery and platelet recovery, what we observed on this study was patients tended to recover their neutrophils and platelets a median two to three days earlier than what we saw with standard dose cyclophosphamide. So neutrophil recovery occurred around day 13. Platelet recovery also occurred around this time compared to our patients who are typically treated with 50 mg x 2 who see their counts recover around 15 to 16 days. This overall resulted in a shorter hospital stay. So we don’t have all our safety data in terms of cardiac toxicities or other sort of toxicities, but we did capture how long patients were hospitalized for their whole transplantation, and reporting that. And what we found that was that patients who were treated with this prophylaxis regimen who received standard conditioning with Flu/Bu2 predominantly were hospitalized on average about 19 to 20 days for their transplantation. This is moderately shorter than what we normally experience for patients treated with standard dose cyclophosphamide. Our conditioning regimen of choice here is two days busulfan for reduced intensity conditioning. That was one signal of efficacy. We looked at grade 2-3 infections as well amongst the patients who were treated. Within 100 days, we saw three grade 2-3 infection occurrences, one due to CMV reactivation to bacteremia. This overall represents a reduction compared to what was recently published at a rate of around 40%. Furthermore, looking at the incidence of grade 3 for acute graft-versus-host disease, that was seen to be around 5% by 100 days with standard cyclophosphamide dosing. In our 25 patients that we had enrolled, we saw zero cases of grade 3 for acute graft-versus-host disease within the first 100 days. So another sort of signal that this regimen potentially is sufficient and efficacious in preventing graft-versus-host disease. Looking at sort of toxicity further, at 100 days, we had zero mortalities for treatment-related mortality, so no patients had died within the first 100 days of transplant. So the main finding for this presentation is that this de-escalated regimen has adequate signal to support continued investigation with no significant signal of increased toxicity, if anything, lower toxicity, or no signal of increased graft-versus-host disease. In fact, in line with what was published with PTCy at a very low rate. And so really this presentation supports further investigation of this combination, and what we hope to find is that you know an overall lower rate of toxicity is sustained, a lower rate of graft versus host disease is sustained, which then in the older patients that we are enrolling in this study may improve access and allow for transplant in frailer individuals who otherwise aren’t considered for transplant right now due to pre-existing toxicity that occurs with transplant.
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