Current and Future Myelofibrosis Landscape: Expert Insights on Treatment, Costs and Unmet Needs

PRITHVIRAJ BOSE, M.D.
Professor, Department of Leukemia
Co-Leader, Section of Myeloproliferative Neoplasms
The University of Texas MD Anderson Cancer Center
Houston, Texas

MHE: What is the prevalence of myelofibrosis? How do patients with myelofibrosis typically present?

Bose: Myelofibrosis has a relatively low prevalence, estimated at approximately four to six cases per 100,000 individuals in the United States.

Patients with myelofibrosis can have a wide range of presentations. In some cases, individuals present with more advanced disease, which is characterized by severe anemia, splenomegaly, cachexia and multiple symptoms such as night sweats, pruritus, bone pain and weight loss.

However, it is increasingly common to encounter patients with earlier-stage disease who may be nearly asymptomatic. Myelofibrosis is now often identified through abnormal blood counts. Prefibrotic primary myelofibrosis is being diagnosed more frequently. Often, the condition is discovered due to a slightly or significantly elevated platelet count. Initially, these cases may be mistaken for essential thrombocythemia, but further evaluation reveals a diagnosis of prefibrotic primary myelofibrosis.

For patients with traditional presentations, symptoms often include anemia, constitutional symptoms, splenomegaly, fatigue and a general decline in well-being. Blood counts can be variable; for example, patients may have low hemoglobin levels and elevated white blood cell and platelet counts.

In rare cases, patients may present in an accelerated or blast phase at initial diagnosis. These cases are unfortunate, as treatment options are limited. Additionally, some patients may present with thrombocytopenia, although this is less common.

Overall, most patients present with classic features such as anemia, splenomegaly, constitutional symptoms and elevated white blood cell or platelet counts. Still, it is important to emphasize that asymptomatic individuals with early or prefibrotic disease are being identified more frequently.

MHE: What are the treatment goals for a patient with myelofibrosis, and how does risk stratification factor into treatment decisions?

Bose: The goal of treatment in myelofibrosis, as for most cancers, is ultimately to improve survival. Median survival for patients with primary myelofibrosis typically ranges between six and seven years. In contrast, outcomes tend to be better in patients with post-polycythemia vera (post-PV) and post-essential thrombocythemia (post-ET) myelofibrosis. For context, median survival in post-PV myelofibrosis is approximately 8.5 years, and in post-ET myelofibrosis, it is around 14 years.

While improved survival remains the ultimate goal, the reality is that current therapies generally do not have a significant impact on the underlying disease biology or malignant clone. Aside from stem cell transplantation, we do not have a well-established or proven therapy that meaningfully alters the course of the disease. As a result, treatment in clinical practice is often focused more on symptom management and disease burden rather than on modifying disease progression.

Currently, there are four approved JAK inhibitors [ruxolitinib (Jakafi; Incyte), fedratinib (Inrebic; Bristol Myers Squibb), pacritinib (Vonjo; Sobi) and momelotinib (Onjjaara; GSK)], which are best known for improving splenomegaly, alleviating symptoms and, in some cases, improving anemia. These therapies are more effective in managing disease manifestations than addressing the disease at a biological level.

It is worth noting that one of these agents, ruxolitinib, has demonstrated a survival benefit. However, that benefit is not clearly linked to a reduction in driver mutations or improvement in marrow fibrosis. Instead, the survival advantage is believed to stem from its anti-inflammatory effects, resulting in better overall patient well-being, such as improved energy, appetite and weight gain.

So, while JAK inhibitors offer clear and sometimes dramatic symptom relief, their effect on the malignant clone and overall disease biology remains limited.

Prognostication plays a critical role in treatment strategy but not necessarily in drug selection. While the FDA approvals for all four JAK inhibitors are based on risk categories, typically for intermediate- and high-risk patients, those of us who treat myelofibrosis do not generally use risk scores to guide drug selection. Instead, we use prognostic scoring primarily to determine whether a patient should be referred for hematopoietic stem cell transplantation.

Drug selection is based on several clinical factors, such as the drug’s efficacy in treating anemia, spleen size or symptom burden, as well as the patient’s platelet count. Prognostic tools are available online and can be used to calculate risk scores, but their principal purpose is to guide transplant decisions, not to select among available pharmacologic therapies.

MHE: How have the JAK inhibitors changed the treatment landscape for myelofibrosis? What are some of the benefits and limitations of JAK inhibitors?

Bose: JAK inhibitors are currently the only FDA-approved therapies for myelofibrosis, with four approvals occurring in 2011, 2019, 2022 and 2023.^1-4 These therapies have been life-changing for many patients. In fact, patients often describe the experience as being given a new lease on life. That level of impact should not be underestimated or undervalued.

However, as previously noted, JAK inhibitors do not significantly affect the underlying malignant clone. Specifically, they do not reduce the driver mutation allele burden, and they do not substantially reverse marrow fibrosis. Their clinical benefits are generally considered to be indirect, primarily resulting from anti-inflammatory effects.

Ruxolitinib, the first approved JAK inhibitor, has demonstrated remarkable improvements in splenomegaly and symptom burden, along with a documented survival advantage. That said, one limitation is its effect on blood counts — it tends to cause or worsen cytopenias and does not improve anemia. This presents a challenge, as the presence of cytopenias often necessitates dose reductions, which, in turn, may compromise therapeutic benefit.

Newer agents, such as momelotinib and pacritinib, offer important advantages in this context. These therapies can be administered at full dose even in patients with baseline cytopenias and, particularly in the case of momelotinib, may improve anemia. This ability to maintain full-dose treatment regardless of blood counts represents a significant clinical benefit.

To date, survival benefits with the newer agents have not been as clearly demonstrated. Ruxolitinib remains the only JAK inhibitor with a well-documented survival advantage. It is important to understand that this benefit is closely tied to the ability to administer the drug at full therapeutic doses, something that is ultimately dependent on the patient’s blood counts.

MHE: With multiple JAK inhibitors now available, how do you approach frontline therapy?

Bose: Broadly speaking, most clinicians still start with ruxolitinib. It has been available the longest, receiving FDA approval in 2011,¹ and it has a demonstrated survival benefit, which I’ve mentioned previously. That said, it is important to use ruxolitinib at an optimal dose. It tends to be most effective when administered at 20 milligrams twice daily, which is increasingly recognized as the ideal dose. A dose of 15 milligrams twice daily may be acceptable in some cases, but lower doses are often subtherapeutic.

Historically, when ruxolitinib was the only option, clinicians often became accustomed to using it regardless of dosing limitations. Now that we have additional agents, the decision around frontline therapy has become more nuanced. There are patients for whom momelotinib may be the more appropriate initial agent, and in other cases, pacritinib may be preferred. Fedratinib is also an option; all four JAK inhibitors have line-agnostic indications, meaning they can be used regardless of treatment line.

That said, fedratinib — like ruxolitinib — is generally more suitable for patients with preserved blood counts. In contrast, momelotinib and pacritinib are better suited for those with cytopenias. I tend to think of ruxolitinib and fedratinib as one category and momelotinib and pacritinib as another, based on their clinical profiles.

MHE: Please discuss the impact of financial toxicity on patients receiving care for myelofibrosis. How might clinicians and managed care organizations help mitigate this burden for patients?

Bose: Financial toxicity is always a concern, particularly in the United States, given the high cost of oncology therapies. Currently, all four approved JAK inhibitors are branded drugs. Ruxolitinib is expected to come off patent in the next few years, which could change the pricing landscape. The other three agents are likely to remain on patent longer.

Even today, for example, momelotinib is more expensive than ruxolitinib. However, when considering combination therapy, the cost picture becomes more complex. Take a scenario in which a patient is receiving ruxolitinib for spleen and symptom control but also requires treatment for anemia. In this case, luspatercept may be added to address the anemia. Luspatercept is a well-tolerated agent, and a phase 3 trial by Bristol Myers Squibb has completed enrollment. We are awaiting the results with anticipation, as this could lead to an additional FDA-approved indication for luspatercept.

However, adding luspatercept to ruxolitinib will significantly increase the overall cost of treatment. In contrast, momelotinib may offer a more cost-efficient option, as it provides benefits across spleen reduction, symptom control and anemia improvement in a single agent. From a financial standpoint, that could make momelotinib the more pragmatic choice.

That said, clinical considerations always take precedence. If ruxolitinib is effectively managing spleen size and symptoms, it may still be appropriate to add luspatercept to address anemia. There is no one-size-fits-all approach; it depends on the individual patient’s clinical needs and how one chooses to prioritize therapeutic goals.

Transfusions themselves also carry a financial and logistical burden. Beyond the direct costs to the healthcare system, transfusions are taxing on patients, requiring time, repeated visits and an overall disruption to daily life. Reducing or eliminating the need for transfusions is a clinically important goal and one that also alleviates broader financial strain. Whether through the use of momelotinib, luspatercept or other agents, minimizing transfusion dependence can contribute to both improved patient experience and cost reduction.

MHE: How might therapies with a lower wholesale acquisition cost impact the cost of care for patients, particularly those with high-deductible health plans?

Bose: I want to acknowledge that I am not an expert in health policy or formulary management. However, lower drug costs would certainly be desirable. There has been some discussion around the anticipated availability of generic ruxolitinib in the near future, which could shift the cost dynamics.

That said, clinical decision-making must be grounded in the data. Ultimately, it is always a balance between what is clinically appropriate for the patient and what is financially feasible. In the U.S. healthcare environment, most treatment decisions are still made based on clinical evidence and what seems best for the patient rather than on cost considerations. Nonetheless, drug pricing and access significantly influence formulary and payer decisions, including the algorithms they choose to implement.

It’s important to note that all four JAK inhibitors have very broad FDA-approved indications. The labels are line agnostic, meaning they do not specify treatment lines, which makes it challenging to determine preferred sequences based on labeling alone.

Specifically, ruxolitinib is approved for patients with intermediate-1, intermediate-2 and high-risk myelofibrosis without any blood count restrictions, although it has not been studied in patients with platelet counts below 50 × 10⁹ per liter (/L). Fedratinib is approved for intermediate-2 and high-risk myelofibrosis, also without count restrictions, but similarly lacks data for use in patients with platelets below 50 × 10⁹/L. In contrast, pacritinib is specifically approved for intermediate- and high-risk myelofibrosis in patients with platelet counts below 50 × 10⁹/L, and momelotinib is approved for intermediate- and high-risk patients with anemia.

So, back to your question. While clinical considerations should remain the primary guide, drug cost and payer coverage will inevitably play a role in shaping treatment access and sequencing in practice.

MHE: How do you foresee the treatment landscape evolving over the next five to 10 years, particularly regarding patient access and affordability?

Bose: I do anticipate significant evolution in the treatment landscape over the next decade. This is a good opportunity to highlight an area we haven’t yet discussed: the high level of interest from the pharmaceutical industry in developing therapies for myelofibrosis. In fact, we may be on the brink of a transformation in how we approach this disease.

First, there is a substantial focus on JAK inhibitor-based combination therapies. This stems from the understanding that while JAK inhibitors provide symptomatic relief, such as reducing spleen size and improving quality of life, they do not appear to meaningfully alter the disease’s underlying biology. As a result, ongoing research is investigating the combination of JAK inhibitors, particularly ruxolitinib, with non-JAK inhibitor agents to achieve disease modification, which is a major emerging goal in this field.

Second, we are seeing a new generation of more selective and potent JAK inhibitors entering clinical trials. Unlike current JAK inhibitors, which do not differentiate between the mutant and wild-type forms of JAK2, some of these investigational agents aim to target the mutant JAK2 protein specifically. Some may also have activity in overcoming resistance mechanisms to existing JAK inhibitors. This category of research also extends to other molecular targets, such as mutant calreticulin (CALR), which is the driver mutation in up to 30% of patients with myelofibrosis. While existing therapies provide benefit regardless of mutation status, directly targeting mutant CALR could offer a more precise and potentially curative approach.

The third area of focus is the development of agents aimed at improving anemia. As we’ve discussed, ruxolitinib is not effective for anemia and may, in fact, worsen it. Therefore, there is growing interest in therapies that can be combined either with JAK inhibitors or used as standalone agents to address this unmet need.

It is quite remarkable how much attention this disease is receiving, given its relatively low prevalence. The level of innovation and drug development activity suggests that new combination regimens and novel agents are likely to gain approval in the coming years.

From the payer perspective, however, these advancements raise new challenges. The cost of treatment will almost certainly rise, especially with the introduction of combination therapies and next-generation agents. If new drugs can clearly demonstrate improvements in overall survival or progression-free survival, payers may be more willing to cover higher-cost regimens. On the other hand, if the clinical benefit is limited to improved spleen responses, symptom relief or anemia correction, it may be more difficult to justify broader reimbursement from a cost-effectiveness standpoint.

Ultimately, access and affordability will hinge not only on clinical efficacy but also on how compelling the value proposition is from the perspective of health plans and pharmacy benefit managers. It will be very interesting to see how this balance evolves as newer therapies enter the market.

MHE: From your perspective, how could payers and managed care develop coverage criteria and prior authorization requirements to promote appropriate use and timely access to novel therapies for patients?

Bose: This will always be a challenge. On one hand, I am a clinical trialist and drug developer, and I find the science and rationale behind emerging drugs and combinations to be very exciting. On the other hand, I fully recognize that cost must be a major consideration.

If I were in the position of a payer, I would look for end points that provide meaningful evidence of long-term benefit. Overall survival is, of course, the most definitive end point, but in chronic diseases like myelofibrosis, demonstrating an overall survival benefit is difficult, particularly in the frontline setting. It may be somewhat unrealistic to expect this as a standard requirement across all studies.

However, alternative end points such as progression-free survival and event-free survival could serve as more feasible yet still meaningful indicators of long-term efficacy. If a therapy, particularly a combination regimen, can show improvements in those end points, that might justify the added cost better than shorter-term data alone, such as enhanced spleen or symptom response at 24 weeks.

That said, from the perspective of the pharmaceutical industry, the 24-week point is an established, validated and regulatory-accepted end point. It is much more practical for sponsors to use in their trials, especially in early-phase or registration studies. But there is a leap of faith involved, essentially assuming that a deeper response at 24 weeks will translate to a more durable or clinically meaningful long-term outcome.

In some cases, that assumption is supported by data. For example, in the case of ruxolitinib, it has been shown that greater spleen response at 24 weeks correlates with improved overall survival. Similarly, with momelotinib, better anemia response at 24 weeks has been linked with better survival outcomes. These types of correlations help make the case for earlier end points.

Still, survival-based data would be preferable whenever possible. It provides the strongest justification for coverage, especially in the face of rising costs associated with novel agents and combinations. I believe payers could begin to stratify or rank therapies based on the quality and durability of the clinical evidence, giving greater weight to those that demonstrate sustained benefit or long-term outcome improvements.

MHE: What are some of the unmet needs among patients with myelofibrosis? And from your perspective, what are the most important next steps in terms of research to help address these unmet needs?

Bose: We’ve touched on several of these already. I believe the key unmet need in myelofibrosis is that while JAK inhibitors are effective for symptom control and improving quality of life — and, in the case of momelotinib and pacritinib, even improving anemia — they do not meaningfully alter the course of the disease. These agents have modest effects on survival, but they are not transforming the disease landscape in a way that leads to durable disease control or significant biological impact.

From a research standpoint, I see two major areas of focus moving forward. First, we need rational combination strategies that can offer greater clinical benefit, ideally achieving true disease modification and significantly improving overall survival. These combinations may involve pairing JAK inhibitors with novel agents with complementary mechanisms of action, and the goal would be to enhance both depth and durability of response.

Second, there is a need for a new generation of targeted therapies that directly and more effectively inhibit disease-driving mutations, such as JAK2 and CALR, which together account for the vast majority of cases. These therapies should aim to target the malignant clone more precisely and effectively, similar to what we’ve achieved in other hematologic malignancies like chronic lymphocytic leukemia and multiple myeloma. In those diseases, we’ve been able to knock out progenitor or stemlike cells to such an extent that patients can reach a state of minimal residual disease. That concept is not something we can yet apply to myelofibrosis. We are still far from achieving that level of disease control in this setting.

Anemia is another area of unmet need, albeit a more practical one. For patients who benefit from ruxolitinib but develop anemia, it would be ideal to have agents that can address that side effect without necessitating a switch in therapy. There is ongoing development in that space, and I am encouraged by some of the investigational agents aimed specifically at treating anemia in myelofibrosis.

Overall, I would rank the need for disease-modifying therapies and durable survival benefits as the top priorities in future research. While symptom control and anemia management are important, the field must move toward treatments that can more fundamentally alter the disease course.

MHE: Is there anything else that I haven’t touched upon or that you’d like to share with our managed care audience?

Bose: I would like to discuss a few broader themes that are shaping the future of myelofibrosis management.

First, combination strategies are being explored to achieve disease modification, particularly by pairing JAK inhibitors with novel agents. Allogeneic stem cell transplantation is still the only known curative option. Unfortunately, it is not appropriate or accessible for every patient, but for now, it remains a critical part of the treatment landscape. I don’t see any current therapies on the near horizon that will eliminate the need for transplant. That could change, of course, if some of the investigational agents in early-phase trials deliver truly transformative results, but we’re not there yet. Also, we are seeing growing efforts to more effectively target driver mutations, such as JAK2 and CALR, with the goal of more deeply suppressing the malignant clone and achieving a more durable response.

There is continued attention on the management of anemia, which remains a practical and persistent challenge, especially in patients receiving ruxolitinib.

Finally, one other topic we did not cover in depth is thrombocytopenia. Patients with platelet counts below 50 × 10⁹/L remain a particularly difficult subgroup to manage. While pacritinib is approved for that population in the United States, it does not fully address the clinical challenges, and this remains an area of significant unmet need.

REFERENCES

1. Jakafi new drug application approval. FDA. November 16, 2011. Accessed July 8, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202192Orig1s000Approv.pdf

2. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed July 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis

3. FDA approves drug for adults with rare form of bone marrow disorder. FDA. March 1, 2022. Accessed July 8, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-adults-rare-form-bone-marrow-disorder

4. Ojjaara new drug application approval. FDA. September 15, 2023. Accessed July 8, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/216873Orig1s000ltr.pdf