Fedratinib Shows Safety, Potential as Post-Transplant Therapy in MPNs
Hany Elmariah, MD, discussed the safety profile of fedratinib and its evolving role in the post-transplant setting for patients with myeloproliferative neoplasms.
Hany Elmariah, MD
Fedratinib (Inrebic) as a maintenance therapy following allogeneic hematopoietic cell transplant given at a 400 mg daily dose was determined to be safe and established as the maximum tolerated dose (MTD) for patients with myeloproliferative neoplasms (MPNs).1
Findings come from a recent phase 1 trial where experts explored the potential of fedratinib, a JAK2 inhibitor already approved for pre-transplant myelofibrosis, as a post-transplant maintenance therapy to reduce relapse risk and mitigate graft-vs-host disease (GVHD).
In an interview with Targeted OncologyTM, Hany Elmariah, MD, associate member at the Moffitt Cancer Center in the department of bone marrow transplant and cellular immunotherapy, discussed the trial’s findings, the safety profile of fedratinib, and its evolving role in the post-transplant setting.
Targeted Oncology: Could you discuss the background of this study and what motivated the research?
Elmariah: One of my areas of research is transplant for myelofibrosis and myeloproliferative neoplasms. While transplant can be curative, the cure rate, depending on the study, is generally in the 40% to 60% range. The main reason patients are not cured by transplant is largely the risk of relapse, which [occurs when] the cancer returns after the transplant. For those who do not relapse, there is also the risk of toxicity, such as GVHD, where the transplant attacks the patient's own body. There are many strategies in development, both for myelofibrosis and other cancers, to reduce the risks of relapse and GVHD.
One commonly used strategy to reduce relapse risk is maintenance therapy, which means finding a low-toxicity drug, generally an oral drug, that is continued after transplant to suppress the cancer and prevent relapse while the transplant ultimately takes over the bone marrow and cures the patient. In the case of myelofibrosis, one appealing class of drugs is called JAK2 inhibitors. We specifically chose fedratinib, which is FDA-approved for treating myelofibrosis in patients before transplant, to see if it could reduce the risk of post-transplant relapse in patients with myelofibrosis.
Secondarily, JAK2 inhibitors have been shown to be effective in treating GVHD, so we hoped that fedratinib could also reduce GVHD by blocking the JAK2 pathway, which is known to be involved in GVHD's pathophysiology.
Close-up of a blood sample showing polycythemia vera cells: © sawaratch - stock.adobe.com
What were the objectives, methods, and design of the trial?
This was a traditional phase 1, 3+3 dose escalation study. We started patients on half of the FDA-approved dose of fedratinib. The FDA-approved dose for pre-transplant patients is 400 mg per day, so in this study, the first 2 patients were given 200 mg per day. If that was well tolerated, we increased the dose to 300 mg per day for the next 3 patients, and then 400 milligrams per day for the next group, [which is the] standard dose. We did this because combining fedratinib with transplant might cause more toxicity than in patients who have not had a transplant, so we did not assume that the standard dose would be appropriate post-transplant.
Patients enrolled in the study had undergone their first allogeneic transplant for myelofibrosis or another MPN. We even included patients with myelodysplastic syndromes [MDS] and MPNs, which include conditions like chronic myelomonocytic leukemia and atypical chronic myelogenous leukemia. After recovering from the transplant and fully engrafting—meaning the transplant has taken hold in the bone marrow—patients started fedratinib between 60 to 100 days post-transplant. They continued on the drug for up to 1 year after the transplant.
We had a 30-day cycle: patients would come in for a checkup each month, and if they were doing okay, we'd refill the drug and continue. The primary end point was to determine the maximum tolerated dose, and the secondary end point was disease-free survival or progression-free survival, meaning the percentage of patients who were alive and had not relapsed.
How did the fedratinib safety profile compare with expectations? Were there any unexpected toxicities observed?
Typically, with fedratinib, the main toxicities are cytopenia, which is low blood counts, and [gastrointestinal] toxicity, such as nausea, vomiting, or diarrhea. Before the drug was widely recognized, there were reports of Wernicke's encephalopathy, which is a type of confusion due to a deficiency in vitamin B1. In this study, we were proactive about ensuring patients had adequate thiamine levels before starting fedratinib, [following the FDA's guidelines].
What we saw in terms of toxicity was mainly cytopenias. We did have some grade 3 cytopenias and even 1 patient with grade 4 thrombocytopenia, which required stopping the drug for that patient. But overall, it was fairly well tolerated. Nausea, vomiting, and diarrhea were generally mild—grade 1 or 2—and we did not see any other dose-limiting toxicities during the 30-day dose-limiting toxicity window. However, some patients did withdraw from the study early due to side effects, even though these weren’t severe enough to be classified as dose-limiting. Blood level changes, especially after a transplant, can be worrying for patients, and I realized this was psychologically difficult for some of them.
Did the data suggest that fedratinib maintenance therapy helped reduce the risk of disease relapse?
Yes, we treated 12 patients in total, and the dose level of 400 mg per day was determined to be the recommended phase 2 dose, meaning it was deemed safe. Now, in terms of relapse, we saw that 4 patients relapsed within the first year, which is probably on par with what you would expect for patients who are not in this study. However, when we looked closer, we saw a dose-dependent response. Three out of three patients at the lowest dose level (200 mg) relapsed, and 1 out of 3 patients at the middle dose (300 mg) relapsed. But at the highest dose level (400 mg), none of the 6 patients relapsed at the time of reporting.
There is 1 patient still on fedratinib who has not completed the full 1-year follow-up, so it is not confirmed whether he’ll relapse, but overall, the data suggest that higher doses might be more effective at preventing relapse.
Were any quality of life assessments conducted during the study?
No formal quality of life assessments were conducted. However, GVHD in general is a major contributor to reduced quality of life. We did see a dose-dependent response in terms of GVHD as well. At the lowest dose level, we had 1 patient with moderate-to-severe chronic GVHD, but no patients at the higher dose levels had moderate-to-severe GVHD. This suggests that fedratinib may help improve quality of life by reducing GVHD. That said, we did not assess quality of life formally, though some patients who withdrew from the study early cited adverse events like nausea and blood level changes as factors in their decision.
Based on these findings, how do you see fedratinib’s role evolving for patients with MPNs?
My hope is that fedratinib can become a standard maintenance therapy. These results suggest that it warrants further investigation. While we have only treated 12 patients, the promising results justify larger trials. The next step would be a phase 2 trial with a larger patient population, and if that is successful, we could move on to phase 3, where patients are randomized to receive fedratinib or not as part of maintenance therapy.
We will need to be selective about which patients benefit most. Not all MPN patients will respond to maintenance therapy. For example, myelofibrosis patients seemed to have a better response to fedratinib than chronic myelomonocytic leukemia patients, with lower relapse rates in the former. Additionally, patients with a JAK2 mutation seem to have a better response, so we might focus on those patients moving forward. Ultimately, I could see fedratinib becoming a maintenance therapy for JAK2-positive patients, especially those who are at high risk for relapse post-transplant.
For the community oncology audience, what would you say are the key takeaways from this research?
The key takeaway is that fedratinib in the post-transplant setting is safe, well-tolerated, and shows potential to prevent both relapse and chronic graft-vs-host disease. Importantly, while the study was conducted at a large cancer center, fedratinib is a drug that can be prescribed and managed in the community setting. Many patients have their transplant at a major center like Moffitt, but then return to their local oncologists for follow-up care. So, this drug could be used by community physicians to manage these patients post-transplant.
