ASH 2024 | Oral decitabine/cedazuridine for patients with myelofibrosis refractory to JAK2 inhibitors

We know that the outcomes are really dismal for patients with advanced myelofibrosis who are refractory to JAK2 inhibitors or have increasing circulating blasts. And although prior reports suggest the benefit of intravenous decitabine with ruxolitinib for MPN-accelerated and blast phase patients, decitabine cedazuridine, which is an oral formulation providing equivalent pharmacokinetic exposure to the IV version has not been formally evaluated in myelofibrosis. So we conducted a retrospective analysis of 14 patients with high-risk myelofibrosis refractory to ruxolitinib or MPN accelerated phase patients who were treated off-label with decitabine, cetazuridine with or without a JAK inhibitor at the Mount Sinai Hospital in New York. So this cohort was elderly with a median age of 76. They uniformly possessed high molecular risk mutations and 13 of the 14 patients had progressed on ruxolitinib. So with a median follow-up of about nine months, the median overall survival for this cohort was 29 months, which compares favorably to the overall survival of 11 to 16 months reported for patients with JAK2 inhibitor refractory disease. And then looking at the MPN accelerated phase patients, their median overall survival was about 11 months, which is similar to what’s reported with the intravenous decitabine. And importantly, all patients who were able to receive more than four cycles of the oral decitabine had some sort of clinical benefit, be it a reduction in their blast count or spleen size or lack of progression to blast phase. We were also able to bridge three patients to transplant with this therapy. And then we saw some impressive responses, including one patient who had a massive splenomegaly and portal hypertension and had previously progressed on ruxolitinib, who then achieved a marked reduction in spleen size and reversal of portal hypertension with the combination. And then we also saw some durable responses, including one patient who had a sustained spleen volume reduction and symptom improvement for over 26 months on the oral decitabine. So like any other therapy, this therapy is not without side effects. So myeloid suppression was seen almost universally, but this was mitigated by reducing the treatment length from five days to three days per cycle. So we do believe that these findings are of relevance to the field, especially since most patients with advanced myelofibrosis are elderly, frail, they’re not candidates for intensive therapies or transplant, and developing an exclusively ambulatory regimen can significantly improve their quality of life, as well as reduce healthcare resource utilization. So we do believe that this combination of an oral hypomethylating agent with a JAK2 inhibitor should be taken forward in clinical trials.

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