JAK2 and IRAK1 in Myelofibrosis - Episode 3

Role of Molecular Testing in Myelofibrosis Treatment

Ruben Mesa, MD, and John Mascarenhas, MD, review the patient selection of extended molecular panels and the appropriate interval for molecular profiling for the management of myelofibrosis.

Ruben Mesa, MD: Perhaps before we pivot to the issue of challenges in treating MF [myelofibrosis], as you’re dealing with your wonderful and evolving trainees there at Icahn School of Medicine at Mount Sinai, who do you tell that they should be getting these extended molecular panels? Is it everybody? Is it in a subset? Who should have these panels?

John Mascarenhas, MD: That’s a great question because it comes up often. It begs the question of what is the utility, and what do we do with these results? And who’s paying for them and where’s the cost going? I will acknowledge that we pretty much get next-generation sequencing on every patient we see, at least up front. We incorporate it into our prognostication and even our therapeutic decision-making. For the most part, it has not been an issue in terms of cost and financial burden to patients, but that’s always on my mind. There’s no specific interval in which we repeat these in serial fashion. It’s often done upon a diagnosis, or initiation of therapy. Then at some point, whether it’s on a clinical trial, it may be serially every 6 months or a year, or if it’s at the time of discontinuation of a commercial agent and then moving onto a different therapy, in which you want to get a sense of whether there’s been clonal evolution and inherent change in the disease that may shape and formulate the treatment decision. It’s something we rarely did a decade ago, but we probably do it on every patient at the first visit here at Mount Sinai. For example, for tumor boards, we invite the molecular pathologist, and they go through the next-generation sequencing results and help us understand the meaning of it.

Although I think it’s still in its infancy of knowing how to exploit that for its fullest benefit, as we learn more about the role of all of these mutations beyond prognostication and as our therapies mature, we will likely have a more molecularly targeted therapeutic approach. We’ve already begun to do this, and you and I are involved. For example, in the MPN-RC [Myeloproliferative Neoplasms Research Consortium] 119 study, which is, as far as I know, the first molecularly targeted therapeutic approach in myelofibrosis for those patients who harbor an IDH2 mutation. We know from extensive data that patients who are IDH2 mutated with myelofibrosis tend to have a poor outcome and represent an unmet need. Due to the availability of IDH2 selective inhibitors and data that would confirm in preclinical testing, there is synergy between combining ruxolitinib and enasidenib, an IDH2 selective inhibitor, in MF. We’ve taken that into the clinic and are treating patients with advanced chronic phase disease or even accelerated blast phase disease. That’s an example of a molecularly directed therapeutic approach that’s defined on the knowledge that the patient harbors an IDH2 mutation.

Ruben Mesa, MD: Very good.

Transcript edited for clarity.