JAK Inhibitors and Emerging Combination Strategies Advance Personalized Treatment in Myelofibrosis

Clinical Summary: 

• John Mascarenhas, MD, examines the evolving treatment landscape for patients with myelofibrosis, including individualized JAK inhibitor selection, emerging targeted therapies, novel combination strategies, and the role of stem cell transplantation.
• Four approved JAK inhibitors offer distinct clinical benefits based on anemia, thrombocytopenia, splenomegaly, and toxicity profiles, while investigational therapies targeting JAK2, mutant CALR, and other pathways may improve disease control and address treatment resistance.
• These developments support increasingly personalized treatment strategies for myelofibrosis, with emerging combination regimens and novel targeted agents offering opportunities to improve outcomes beyond conventional JAK inhibition.

John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai, New York, New York, discusses the evolving treatment landscape for patients with myelofibrosis, including approved JAK inhibitors, emerging targeted therapies, and novel combination strategies following his presentation at the Lymphoma, Leukemia & Myeloma Congress in New York, New York.

Dr Mascarenhas reviews how ruxolitinib, fedratinib, pacritinib, and momelotinib can be individualized according to anemia, thrombocytopenia, splenomegaly, and treatment-related toxicity. He also discusses emerging therapies targeting mutant CALR and type II JAK inhibition, as well as investigational combinations involving pelabresib, selinexor, and navtemadlin, highlighting ongoing efforts to improve disease control, overcome treatment resistance, and refine the role of stem cell transplantation.

Transcript: 

Hi, I'm John Mascarenhas from the Icahn School of Medicine at Mount Sinai. Today I'll be talking at the LL&M Congress meeting and covering myelofibrosis– where we are today and what are our options for patients. 

We know that myelofibrosis is a chronic progressive disease and we know that it's driven in large part by aberrant JAK stat signaling. We have 4 approved JAK inhibitors for the treatment of myelofibrosis that now allow us to personalize that therapy for our patients, that includes ruxolitinib, it’s the oldest from 2011, fedratinib (2019), pacritinib (2022), and momelotinib (2023). 

With these 4 drugs, although they're all JAK2 inhibitors, there are non-JAK2 kinome profile aspects that likely allow these drugs to be tailored in different niches and have different toxicities. For example, pacritinib is ideal in patients with lower platelets, less than 50,000 by label, but less than 100,000 by clinical trials, and also as an ACVR1 inhibitor, can improve hemoglobin as demonstrated in ad hoc analyses from the PERSIST-2. 

Momelotinib is now a drug that has a label that's broad for anemia, and this is a drug that's well suited for patients that have anemia, particularly with higher platelet counts where pacritinib may not be the ideal choice. They have different toxicity profiles. Pacritinib is a FLT3 inhibitor, it does have more potential for GI toxicity, which is manageable, but need to be aware of it. Momelotinib can have peripheral neuropathy. One should be aware of patients who might have underlying diabetes or other issues where peripheral neuropathy could be at play. 

Fedratinib is, I would say, the forgotten child of the four JAK inhibitors. It's very active, selective JAK2 inhibitor, also a FLT3 inhibitor, and is probably best suited for those patients that have progressive resistant splenomegaly– that's where the data speaks the greatest, particularly from the early studies and more recently from the FREEDOM phase 3 follow-up studies. 

Beyond JAK inhibitors, we are now looking at other alternative JAK inhibitors, like type II JAK inhibitors, like the Ajax AJ1-11095, which we'll present data on today. A very potent type II inhibitor that can induce very significant spleen and symptom and reduction in VAF in patients who failed multiple type I JAK inhibitors. 

Now we've moved into the era of mutant CALR antibodies, targeting for those patients, about 30% that harbor a CALR mutation, targeting that mutant CALR that's aberrantly expressed on the surface of MPN hematopoietic stem and progenitor cells, and that data looks very encouraging. 

Beyond that, the therapies really are add-on strategies. It's add-on to JAK inhibitor upfront. This includes pelabresib, the pan-bet inhibitor, selinexor, the XPO1 inhibitor, and even navitoclax, the Bcl-2 xL inhibitor that has stopped development. We'll review the upfront combination strategy data, and the longest data to date with follow-up will be presented at ASH in 2026 with 144-week follow-up data with the MANIFEST-2 pelabresib study.

MANIFEST-3 is now targeting patients with higher symptom burden at baseline, combining both ruxolitinib and pelabresib versus ruxolitinib first plus placebo, these studies continue to go on.  We've seen data now at ASCO published in JCO with selinexor, a drug that's thought of as a myeloma drug, but also has rationale and activity in myelofibrosis and the SENTRY study has demonstrated efficacy from a spleen and improvement in symptom but not bettering that of ruxolitinib alone, but intriguingly which we'll review today is a survival signal, albeit early 11 to 12 months follow-up, but a survival signal that's linked to SVR35 at week 24. 

We have drugs like navtemadlin which are very potent drugs that are going at it by a different route adding on to ruxolitinib after a minimum of 18 weeks for those patients who have suboptimal response. This is not assuming everyone needs a combination up front but strategizing for patients who don't achieve optimal disease control and then outside of those drugs we have imetelstat, the telomerase inhibitor approved for transfusion dependent MDS patients that are lower risk but in myelofibrosis as a single agent in the relapsed or refractory setting where we know survivals are poor with a primary end point of the phase 3 study of overall survival and that I'm hoping will read out by 2027.

A lot is going on in myelofibrosis, a lot is going on today that was not present in 20 years ago, mainly because the science is really driving the field forward so i'm optimistic about how things are progressing. Of course we will also cover the only curative option, which is transplant, when and where to use transplant.