ASH 2024 | The safety of fedratinib as a maintenance strategy after alloSCT for MPNs: Phase I results

Allogeneic transplant is the only curative therapy for a group of hematologic malignancies called myeloproliferative neoplasms. And despite the curative potential, there is still a high risk of relapse in about 50 to 60 percent of patients that get a transplant. So one of the prime objectives of research in the field right now is how can we reduce relapse for those patients that get a transplant for these diseases. One of the common strategies employed across the board in hematologic malignancies to reduce relapse after transplant is what’s called maintenance therapy, where we use a low-intensity treatment that’s continued after transplant for some extended period of time to try to suppress the cancer. 

In the group of diseases called myeloproliferative neoplasms, or MPNs, there is a group of drugs called JAK2 inhibitors, which are approved for therapy in the pre-transplant setting. These are oral treatments that can be continued indefinitely. And so the point of this study was could we employ a JAK2 inhibitor to suppress the disease and improve cure rates after transplant. 

We chose specifically a JAK2 inhibitor called fedratinib, which is approved in the pre-transplant setting. And also, in addition to trying to reduce relapse, there’s some preclinical data that blocking the JAK pathway with a drug like fedratinib in mouse models also can suppress a complication of transplant called graft versus host disease. So as we did this study, we were thinking maybe we can actually kill two birds with one stone, so to speak, where we can prevent relapse and also suppress graft versus host disease. 

The study design was a safety-based Phase I trial. So we’re looking at a dose escalation where we studied fedratinib first at a low dose level of 200 milligrams daily. If tolerated we go to 300 milligrams daily and if well tolerated then the final patients go to 400 milligrams daily which is the standard dose that’s approved in the pre-transplant setting. Patients were started on the fedratinib about two months after transplant, two to three months depending on meeting eligibility criteria, and then continued on the fedratinib through one year after transplant. 

The results that we found was number one, the drug was safe in the post-transplant setting. So in terms of what we call dose-limiting toxicities or severe toxicities that would limit the ability to continue on that treatment, at the lowest dose level there were no dose-limiting toxicities. At the second dose level there were no dose-limiting toxicities. And at the third dose level, we had a dose limiting toxicity in one out of six patients. Based on the study design, that was deemed the maximum safe dose, and so that was what would be recommended for a subsequent Phase II study in the future. 

And then thinking about efficacy, just preliminarily, because again, the study was focused on safety, but we did want to see the signal of efficacy. So again, hoping to reduce graft versus host disease, we had one case of severe chronic graft versus host disease across the whole patient population that’s treated, which is 12 patients, and that one patient was in the lowest dose level. So moving into the highest dose levels, there were no cases of chronic graft versus host disease. 

And then also in terms of relapse reduction, we had a 40% rate of relapse, which is similar to historical data, but at the same time, those relapses that occurred were in the lowest dose level. So as we moved into the high dose level, there was one out of six patients that had disease relapse, which looks promising that maybe that could be a reduction compared to the lower dose levels. So that gives us a signal that maybe this drug is giving some disease control. 

So in summary, we treated patients with fedratinib for myeloproliferative neoplasms in the post-transplant setting, continuing the drug for one year. We found that the drug was safe and well tolerated. The maximum tolerated dose, or the recommended Phase II dose, is 400 milligrams per day. And we saw at least an early signal that maybe at that 400 milligram daily dose, rates of chronic GvHD were low, actually zero in this study, and that rates of relapse look like they may be low. Having said that, the study is ongoing and we would need to do a larger study in the future to confirm these results. But we’re very excited about this promising data.

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