Tandem Meetings 2026 | De-escalated PTCy plus ruxolitinib for GvHD prophylaxis in older patients undergoing RIC alloSCT

So, just a little background to begin. For older patients undergoing allogeneic transplant, the primary GVHD prophylaxis that’s used for these patients is post-transplant cyclophosphamide at a standard dose, which is defined as 50 mg per kg per day on days 3 and 4, along with calcineurin inhibitor, usually tacrolimus and MMF. With this, there was a previous study, BMT CTN 1703, that caused this change for standard of care because of lower rates of clinically significant graft-versus-host disease. But the cost with giving an additional chemo agent is toxicity. So compared to sort of standard transplantation, particular toxicities that persist with PTCy include infections – so about 40% of patients had clinically significant infections after PTCy – cardiac toxicity, which has been defined previously, renal and pulmonary toxicity as well. So significant toxicities that still plague transplant. And for older patients, these could be particularly important as they may come into transplant in a little bit frailer health compared to younger patients undergoing transplant. 

So to address these toxicities, there have been two sort of updates or two sort of developments as it pertains to GVH prophylaxis. Number one, there have been efforts primarily led by NIH looking at attenuated doses of cyclophosphamide. So research that was really led by Chris Connelly preclinically and then in a couple of clinical studies have indicated that perhaps cyclophosphamide at a dose of 25 mg per kg on day three or four would offer significant control of GVH, offer sort of significant control to allow for engraftment amongst a variety of donor sources. And so what we saw from their presentations was something that we thought was particularly favorable for older adults, which is, what it does do is it improves engraftment kinetics. Whereas with standard doses of PTCy, neutrophil recovery, platelet recovery can take between 16 and 25 days, with this lower dose of cyclophosphamide, these studies have demonstrated that engraftment occurs closer to 13 days. Where it may help patients is the sooner that you have neutrophil engraftment, for instance, you know, that also prevents or protects against significant infections, including bacteremia. 

A second update that we were aware of kind of within the literature was the use or incorporation of ruxolitinib as GVHD prophylaxis. So this was primarily performed in studies where ruxolitinib is combined with CNI-based prophylaxis or tacrolimus-methotrexate. But with combining it, what was demonstrated were very low rates of chronic graft-versus-host disease, which in older adults may be impactful because while they’re not necessarily life-threatening in younger adults, kind of consistent comorbidities, you know, consistent chronic graft-versus-host disease does potentially lead to increased mortality, morbidity in the older population. 

So taking these sort of updates or, you know, recent findings, what we wanted to study was whether attenuating cyclophosphamide, adding ruxolitinib, whether that in an older population in particular, you know, may offer some benefit. And the primary way that we wanted to measure benefit was to look at GVHD-free survival at one year. So for our study, again, in terms of how we treated patients, they received reduced intensity conditioning. These are patients 60 and older with a hematologic malignancy undergoing an HLA-matched donor. So these are RIC candidates. They get peripheral blood stem cell infusion. And then for GVH prophylaxis, what we administered was cyclophosphamide at 25 mg per kg on days three and four. Tacrolimus-MMF as standard of care. And then ruxolitinib initiated post-engraftment and continued through one year. And the ruxolitinib dose that we used was a half dose or 5 milligrams twice daily. 

In this study, we enrolled 56 patients. These were older patients. So half of these patients were 70 or older. And these were frailer patients with a median HCTCI of three. Their KPS…90% had a KPS less than 90. And so these were patients primarily with acute leukemia or MDS. And for our particular study at our institution, the primary RIC regimen that we use is fludarabine and busulfan, so about 70% of patients received that. 

In terms of safety, the way that we captured safety was we looked at engraftment kinetics with reduced cyclophosphamide. So neutrophil engraftment, platelet engraftment in our study occurred at a median of 13 days. Just as a frame of reference, BMT CTN 1703 was a large study that randomized older adults to PTCy and took about 16 to 26 days to see neutrophils and platelets recover on that study. So we saw potentially improved kinetics in terms of count recovery. We also looked at hospital duration. And so patients from transplant to discharge were in the hospital for an average of 15 days. And that compares favorably where other studies have demonstrated that typically with PTCy reduced intensity conditioning from transplant to discharge, on average, it’s about 20 to 25 days. So potentially a five-day improvement for that. 

Other sort of measures for safety included looking at our infection rate, looking at rates of organ toxicity. So looking at infection, we looked at the rate of severe infections within the first 100 days. As a reference again, on 1703, 40% had significant infections within 100 days. On our study, the rate of significant infections was around 11%. We looked at organ toxicity, so significant cardiac pulmonary or renal events. We had one cardiac event on study, but no other sort of significant organ toxicity events in our study. And so, you know, we felt that this regimen was safe, you know, for the reasons of rapid engraftment, short hospitalization, low infections, low organ toxicity or significant organ toxicity. 

We next look at efficacy. So our primary efficacy measure was GVHD-free survival at one year. And as a frame of reference, again, for BMT CTN 1703, the one-year GFS for patients 60 and older was around 61%. On our study, what we estimate was a one-year GFS of around 76%, so 75.8%. Using the more traditional Griffiths endpoint, we looked at one-year Griffiths, and that was 75% on this study. And then looking at overall survival, we had a one-year overall survival estimate at around 82%. 

And so just to conclude, really what we were looking for was a regimen for GVH prophylaxis that would reduce toxicity, particularly for older patients who are undergoing transplant, you know, by seeing shorter hospitalizations, seeing faster count recovery, and also seeing low infection and organ toxicity rates, we suspect that this is sort of a more tolerable prophylaxis regimen for this older population. In terms of efficacy, we’ve seen sort of best efficacy, you know, in terms of GVH-free survival compared to what’s in the literature, particularly when compared to what’s historically seen with PTCy.

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