Determining Molecular Mutations Driving Decisions in Myelofibrosis Therapy

At the Society of Hematologic Oncology 2025 Annual Meeting, CancerNetwork® spoke with Prithviraj Bose, MD, about the intricacies of myelofibrosis therapy and the tools physicians have to decide which agents are most suitable for a specific patient.

When prompted about the usefulness of molecular mutations, Bose mentioned the driver mutations, including JAK2, MPL, and CALR. On the driver mutations, he added that patients with CALR typically do worse than those with JAK2. Beyond that, he also highlighted the usefulness of the non-driver mutations, which are “more informative”. Some of the non-driver mutations he discussed were ASXL1, SRSF2, and TP53.

Knowing what non-driver mutations a patient has is useful to decide who should receive transplantation, although they do not weigh heavily on therapy considerations. Bose said that patients with several mutations are less likely to perform well with ruxolitinib (Jakafi) compared with other patients.

The interview came after Bose delivered a presentation titled, “Individualizing Treatment Selection for [myelofibrosis]”. Bose is a professor in the Department of Leukemia in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center.

Transcript:

There are a number of molecular mutations beyond JAK2, the so-called non-driver mutations. The driver mutations are JAK2, MPL, and CALR, but the parts that are more informative for us clinicians are the non-driver ones. Between the drivers, we do know a few things. We know our [patients who are] CALR-mutated do better than [patients who are] JAK2-mutated—[patients who are] triple negative probably have the worst [outcomes]. This is all in the context of myelofibrosis, but for non-driver [mutations], there have been a few that have been known for a while, like ASXL1, SRSF2, U2AF1 Q157, and a few others like IDH1 and [IDH2], et cetera, which we know are adverse; TP53, particularly multi-hit, is very bad. That information is very helpful, particularly to decide who to send to transplant, not necessarily to pick therapy because therapy is agnostic of these considerations, although we know that if you have several mutations, you are less likely to do well on ruxolitinib. That is known, but it does not help you choose which drug to use. Instead, the value of the mutations is in deciding who should go to transplant. For example, certain pairings are bad, like ASXL1 and ECH2 or SRSF2 with IDH. Those are bad combinations and should concern you…The transplant decision can be highly informed by these molecular data.

Reference

Bose P. Individualizing treatment selection for MF. Presented at the Society of Hematologic Oncology 2025 Annual Meeting; September 3-6, 2025; Houston, TX.