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Individualizing Myelofibrosis Treatment in the Era of Multiple JAK Inhibitors

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Released: November 09, 2026

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In this commentary, an expert discusses individualized treatment selection and sequencing in myelofibrosis, emphasizing the integration of prognostic risk, clinical phenotype, and patient-specific factors. The commentary examines the role of anemia, thrombocytopenia, splenomegaly, and symptom burden in guiding JAK inhibitor selection, including considerations for ruxolitinib, fedratinib, pacritinib, and momelotinib. Drawing on clinical trial evidence, prescribing information, and expert experience, the discussion addresses assessment of treatment response, recognition of JAK inhibitor resistance or intolerance, and strategies for managing evolving clinical needs. The expert also highlights the importance of early transplant evaluation, clinical trial participation, and patient-centered decision-making to inform treatment sequencing and optimize care throughout the disease course.

Abdulraheem Yacoub
Abdulraheem Yacoub, MD
Individualizing MF Treatment

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The expanding therapeutic landscape in myelofibrosis (MF) has provided more treatment options but has also made treatment selection more nuanced. In practice, the central question is no longer simply, “Which JAK inhibitor should I use?” Rather, treatment decisions require an understanding of which aspect of the disease is driving the patient’s current needs, whether it’s anemia, thrombocytopenia, splenomegaly, constitutional symptoms, molecular risk, disease progression, or a combination of these factors.

Start With the Patient Phenotype, Not Just the Risk Score
Risk stratification remains fundamental, particularly when considering prognosis and allogeneic hematopoietic cell transplantation (allo-HCT). Traditional clinical systems such as the Dynamic International Prognostic Scoring System remain useful, and molecularly informed models such as the MIPSS70/MIPSS70+ for primary MF and disease-specific models such as the MYSEC-PM for secondary MF can provide additional prognostic context. The EBMT Handbook similarly emphasizes the role of molecular features and adverse clinical characteristics when considering transplant candidacy.

However, I would caution against allowing a prognostic score alone to dictate systemic treatment. For day-to-day clinical decision-making, begin by answering questions about the patient’s clinical phenotype: What is the platelet count? How significant is the anemia? Is the patient transfusion dependent? Are constitutional symptoms or splenomegaly the predominant issue? How is the disease changing over time?

Molecular and cytogenetic findings can be particularly influential when they identify higher-risk disease in a patient who otherwise appears clinically lower risk. This becomes especially relevant when deciding how early to initiate a transplant discussion. Current EBMT guidance supports considering allo-HCT in patients with intermediate-2 or high-risk disease and in selected patients with intermediate-1 disease who have additional adverse features, including high-risk mutations, adverse cytogenetics, increased peripheral blasts, or refractory transfusion-dependent anemia.

Beyond Hemoglobin: Assessing Anemia in MF
One of the most important changes in contemporary MF care is that anemia has become a treatment-selection variable rather than simply a toxicity that is managed after starting therapy.

I do not think anemia should be defined by hemoglobin concentration alone. A patient with a hemoglobin of 9 g/dL who remains active and minimally symptomatic is very different from a patient with the same hemoglobin level who has cardiovascular disease, substantial fatigue, dyspnea, or escalating transfusion needs. Clinical impact, trajectory, transfusion burden, comorbidities, and other manifestations of MF all matter. 

Momelotinib has expanded our ability to address anemia in patients with MF and is currently FDA approved for treatment of intermediate- or high-risk primary or secondary MF in adults with anemia. In the phase III MOMENTUM trial, which enrolled symptomatic patients with anemia and MF who had previously received a JAK inhibitor, momelotinib demonstrated benefits across symptom, anemia, and spleen response endpoints compared with danazol.

However, this does not mean that every patient whose hemoglobin falls below an arbitrary threshold should automatically receive momelotinib. Instead, we need to ask whether anemia is one of the dominant clinical problems and how it intersects with spleen burden, symptoms, platelet count, prior therapy, and patient preferences. Because treatment decisions must balance disease characteristics, clinical outcomes, and individual patient priorities, shared decision-making is essential when evaluating therapeutic options.

It is also essential to distinguish baseline disease-related anemia from treatment-emergent anemia. If a patient develops anemia early after starting ruxolitinib but has an excellent spleen and symptom response, our instinct is not necessarily to abandon an effective therapy. Depending on severity and feasibility, supportive strategies may allow us to preserve that clinical benefit. By contrast, anemia that arises later during an otherwise stable treatment course, particularly when accompanied by decreasing platelet counts, spleen enlargement, recurrent symptoms, or increasing blasts, should prompt reassessment for disease progression. 

Thrombocytopenia Changes the Therapeutic Equation
Severe thrombocytopenia is among the most challenging MF phenotypes because it often coexists with anemia and other features of advanced disease. I would not set the expectation that a JAK inhibitor will increase the platelet count. Rather, treatment needs to address the MF while minimizing additional hematologic toxicity.

Pacritinib has a particularly defined role in this setting. Its current US indication is for adults with intermediate- or high-risk primary or secondary MF with a platelet count below 50 x 10⁹/L. The prescribing information notes that this indication remains under accelerated approval based on spleen volume reduction.

For patients with platelet counts between 50 and 100 x 10⁹/L, the choice is less straightforward. Ruxolitinib can be used with platelet-adjusted dosing, whereas fedratinib or momelotinib may be considered depending on the patient’s clinical characteristics and the agents’ approved indications. Pacritinib may also be considered in selected circumstances, although its US indication is specifically for adults with platelet counts below 50 x 10⁹/L. Thrombocytopenia rarely exists in isolation, and individualized treatment selection requires consideration of anemia, spleen burden, bleeding risk, comorbidities, treatment history, and drug interactions. 

Recognize When Treatment Is No Longer Meeting the Goal
Another major educational challenge is defining JAK inhibitor “failure.” I do not think there is a single presentation. Some patients have primary resistance. Others lose a previous spleen response, develop recurrent symptoms, experience progressive cytopenias or treatment intolerance, or demonstrate evidence of clonal evolution. 

The practical question is whether treatment is still producing a meaningful benefit for that patient. I monitor spleen size, symptoms, blood counts, transfusion burden, and evidence of disease progression over time. The ruxolitinib prescribing information has historically advised discontinuation when there is no spleen size reduction or symptom improvement after 6 months, reinforcing the principle that response should be actively reassessed rather than assumed.

When benefit is lost, that is an opportunity to reassess the disease rather than reflexively substitute one drug for another. The dominant phenotype can help guide the next step: spleen-dominant disease, for example, may lead us toward a different decision than progressive anemia or severe thrombocytopenia.

Fedratinib remains an approved therapy for adults with intermediate-2 or high-risk primary or secondary MF. Its prescribing information carries a boxed warning for serious and fatal encephalopathy, including Wernicke’s encephalopathy, and requires assessment of thiamine before treatment as well as prophylactic daily oral thiamine during therapy. Those practical considerations need to be incorporated into treatment selection.

Proactive adverse event management, including appropriate monitoring and supportive interventions, is essential when selecting and maintaining JAK inhibitor therapy.

Keep Transplant and Clinical Trials in the Conversation
I also want to move away from the idea that transplant and clinical trials belong only at the end of the treatment pathway.

For an otherwise transplant-eligible patient with higher-risk disease, early referral can serve as an educational and planning step rather than a commitment to immediate transplantation. Identifying a donor, discussing risks and goals, and understanding whether transplant should occur now or later are all valuable even when systemic therapy is being initiated. Current transplant references similarly emphasize disease risk, molecular features, age, fitness, comorbidities, and transplant-specific factors rather than relying on any one characteristic in isolation.

Clinical trials may likewise be appropriate both before and after exposure to approved therapy. At the same time, access is a very real issue. Travel distance, caregiver support, repeated visits, cost, and access to an MPN or transplant center can determine whether an otherwise reasonable strategy is actually feasible. For us, patient-centered decision-making must include those practical realities.

Summary
With 4 approved JAK inhibitors available for MF, management has become increasingly phenotype driven. The goal is not simply to select a drug but to identify the clinical problem that matters most for the individual patient and continually reassess whether treatment is meeting that goal.

Anemia, thrombocytopenia, spleen burden, symptom burden, molecular risk, treatment history, transplant eligibility, access, and patient priorities should all shape the discussion. The growing number of therapeutic options gives us greater flexibility, but it also makes careful reassessment and individualized treatment more important than ever.

To help you navigate the complexity of treatment for patients with MF, there is an online tool that allows you to enter key patient- and disease-specific factors that expert faculty consider important to individualize treatment decisions. Visit this interactive decision support tool and answer a few quick questions about your real or hypothetical patient so that you can compare your choice of individualized treatment selection with ours. Have a patient in mind? Submit your case now!

Your Thoughts
When you see a patient with MF whose anemia or thrombocytopenia is worsening but whose spleen and symptoms remain reasonably controlled, what clinical change prompts you to move from supportive management to a change in systemic therapy?

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