Tailoring Myelofibrosis Treatment Through JAK Inhibitors

Jessica Lewis-Gonzalez, PharmD, BCOP, discusses the complexity of myelofibrosis, a rare chronic myeloproliferative neoplasm marked by abnormal stem cell proliferation in the bone marrow. This leads to fibrosis, cytopenias such as anemia and thrombocytopenia, and compensatory blood cell production in the spleen and liver, often causing splenomegaly, hepatomegaly, and a wide constellation of symptoms. She highlights how these challenges—ranging from disease heterogeneity to treatment resistance, progression, and the limited curative options available—make management difficult for both clinicians and patients, especially given the ongoing treatment burden and financial toxicity.

Lewis-Gonzalez also emphasizes the evolution of therapy in this space. Since the 2011 approval of the first JAK inhibitor, ruxolitinib, the treatment landscape has broadened to include four JAK inhibitors, allowing for more tailored approaches.

Pharmacy Times: Can you give an overview of myelofibrosis? What are the main challenges clinicians face in treating patients with this disease today?

Jessica Lewis-Gonzalez, PharmD, BCOP: So myelofibrosis is a rare and chronic myeloproliferative neoplasm, or MPN, that's characterized by abnormal proliferation of hematopoietic stem cells in the bone marrow. This leads to some bone marrow fibrosis, or scarring of the bone marrow, which is going to impair the production of healthy blood cells and results in some low blood cell counts, cytopenias, especially anemia and thrombocytopenia.

Then, as a compensatory mechanism, blood cell production can shift to other organs like the spleen and the liver, and that can cause some significant splenomegaly and hepatomegaly for patients, which can also cause a lot of symptoms in and of itself. That's really the biggest problem with myelofibrosis—this constellation of symptoms that patients can experience, which can really decrease the quality of life for these patients. These include fatigue, which is one of the biggest ones, night sweats, fever, and weight loss, and those can all be driven by the inflammatory process that starts from that scarring of the bone marrow.

In terms of the main challenges that clinicians face in treating myelofibrosis today, the biggest one is the heterogeneity of the disease. It's not one single entity. When we're thinking about myelofibrosis, there's a variety of clinical manifestations, genetic mutations, and risk profiles, and this makes it difficult to really apply a one-size-fits-all approach to myelofibrosis treatment for patients.

Other things that can be challenging are treatment resistance and disease progression on therapies, managing the cytopenias, and just the very limited curative options we have for myelofibrosis. On top of that, there's also treatment burden, in the sense that patients are usually having to take daily oral medications to help manage their symptoms and keep their disease at bay. That, in and of itself, comes along with some financial toxicity as well.

Pharmacy Times: JAK inhibitors have been central to treatment for over a decade. How has their role evolved in recent years?

Lewis-Gonzalez: Having the one JAK inhibitor, ruxolitinib, originally, which got approved around 2011 in the myelofibrosis space, to now we have four JAK inhibitors on the market. And so we can now, using that clinical manifestation and the symptom burden patients have, tailor things much more.

So we have fedratinib in the primary or secondary myelofibrosis setting. We have pacritinib, which is really going to be our go-to with patients with severe thrombocytopenia. And then we also have momelotinib, which is going to be for patients with myelofibrosis and anemia. So we can take a more targeted approach.

The evolution of the JAK inhibitors has really gone from just this one-size-fits-all ruxolitinib approach to really tailoring based on the patient's presentation, the cytopenias that they're coming in with, and their symptom burden.