Old and New JAK Inhibitors Make Headway for the Treatment of Myelofibrosis

Raajit K. Rampal, MD, PhD

The current landscape of MPN treatments, including myelofibrosis, is evolving with newer JAK inhibitors that have demonstrated significant improvements in clinical outcomes with favorable safety profiles.

For over a decade, ruxolitinib (Jakafi) has been the main therapy for patients with myelofibrosis as it was the first approved JAK inhibitor by the FDA. Ruxolitinib improved splenomegaly and constitutional symptoms for patients and provided survival benefit.¹

Then, the JAK2 inhibitor fedratinib (Inrebic) was approved and has provided a good second-line option for patients who are ruxolitinib-resistant. Pacritinib (Vonjo), an oral macrocyclic JAK inhibitor specifically used to inhibit JAK2, IRAK1, and CSFIR, also gained FDA approval for patients with myelofibrosis and severe thrombocytopenia and continues to serve as a good treatment option.

In addition to these already approved agents, another JAK1/2 inhibitor that is in advanced clinical development is momelotinib.² The agent is currently being evaluated in patients who are symptomatic and anemic with advanced myelofibrosis who have previously been treated with a JAK inhibitor, in the phase 3 MOMENTUM trial (NCT04173494).

While these agents continue to help treat patients with myelofibrosis, investigators, including Raajit K. Rampal, MD, PhD, are interested in looking into what treatments beyond JAK inhibitors may be beneficial.

In an interview with Targeted Oncology^TM, Raajit K. Rampal, MD, PhD, hematologic oncologist, Memorial Sloan Kettering Cancer Center, discusses the currently approved JAK inhibitors used to treat patients with myelofibrosis, and exciting movements in the field. Rampal gave a talk on this subject during the 4th Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies.

Targeted Oncology: Can you discuss the current treatment landscape for MPNS?

Rampal: The current landscape of MPN treatments is evolving. For diseases like essential thrombocytopenia and polycythemia vera, we've had drugs that we've used for years like hydroxyurea and interferons. But now, JAK inhibitors have moved into that space, with ruxolitinib, in the last few years. But in myelofibrosis, we've seen a market expansion in the treatments. The mainstays of therapies for patients with enlarged spleens or with symptoms have been JAK inhibitors, and the number of JAK inhibitors is currently expanding.

Can you discuss some of those JAK inhibitors that are already approved?

The 3 approved drugs are ruxolitinib, fedratinib, and pacritinib. Ruxolitinib and fedratinib are approved for patients with over 50,000 platelets who have intermediate or high-risk disease. Pacritinib is different as it was approved for patients with less than 50,000 platelets in the first-line. It is for a distinct group of patients with myelofibrosis.

Now that's in the first-line, and in the second-line, somebody who has been on a JAK inhibitor, you can use any of the ones that you haven't used. For example, someone who started on ruxolitinib can use pacritinib or fedratinib, regardless of platelet count. We have more options than we've ever had.

What factors go into deciding what to use for certain patients?

That depends on what their other issues are. For example, patients with low blood counts, pacritinib makes sense and that's where it's been well studied. Increasingly, some of the new data that has come forward has to do with anemia. Pacritinib, as well as a drug called momelotinib, which is on the horizon for approval, both inhibit a pathway called ACVR1, which we think is involved in improving anemia in patients with myelofibrosis. I think it is becoming a differentiating factor and something that may point us towards using those drugs in patients who are transfusion dependent, or otherwise, profoundly anemic.

Are there any exciting trials or research ongoing that you're excited to hear about?

There are so many things in this space. Currently, there are several different drugs that are non-JAK inhibitors. The idea is to try to combine them with the JAK inhibitors to see if you can extend what the JAK inhibitors are able to do or add them on in patients who don't have a great response to a JAK inhibitor.

There are a number of drugs that are in late phase trials or phase 3 trials. These include, but are not limited to, things like BET inhibitors, or BCL-xL inhibitors, PI3k delta inhibitors, as well as telomerase inhibitors. Again, those are in late phase clinical development. There are also drugs in earlier development, such as PIM kinase inhibitors, that are showing some early promise. It's really an expansive area.

What are the unmet needs that still exist in the space of myelofibrosis?

The major unmet need is that we need disease modifying therapy. Disease modifying can mean a lot of things. It's a debatable point, but to me, disease modifying therapy is something that allows the patient to live as close to a normal lifespan as possible with as few symptoms from their disease. All the drugs will have improved some things. They shrink the spleen; they can make people feel better. There's some evidence that they can improve survival, but these are all to a limited extent. We need drugs that can improve upon that.

All these other drugs that are in development are being tested against spleen and symptoms because that has been the approval pathway for these other drugs. But the question I think we have to ask is, are they ultimately making people live longer and better? We have 3 approved JAK inhibitors currently, with another potentially on the way this year. But now the question is, what happens beyond that?

REFERENCES:

1. Bose P, Verstovsek S. JAK Inhibition for the Treatment of Myelofibrosis: Limitations and Future Perspectives. Hemasphere. 2020;4(4):e424. Published 2020 Jul 21. doi:10.1097/HS9.0000000000000424

2. Verstovsek S, Gerds AT, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0