Determining Who Has “Early Myelofibrosis” Involves a Broad Look at Patient Factors

Patients considered to have early myelofibrosis are a heterogeneous group for whom disease risk, best treatment strategies, and the probability of mortality are best determined individually by looking at patient’s clinical characteristics and molecular markers together.

Patients considered to have early myelofibrosis are a heterogeneous group for whom disease risk, best treatment strategies, and the probability of mortality are best determined individually by looking at patient’s clinical characteristics and molecular markers together.

“The burden of myelofibrosis is variable. Risk in terms of survival is a factor, but not the only factor in treatment,” Ruben Mesa, MD, said in a presentation during the Texas Virtual MPN (Myeloproliferative Neoplasm) Workshop.1 “It is looking at the entire clinical picture for a patient as well as understanding their wishes [about how aggressive they want to be with the disease] that is important.”

Regarding the term “early myelofibrosis,” Mesa, who is the director of the University of Texas Health San Antonio MD Anderson Cancer Center, said that this term may apply to a case of mild anemia, splenomegaly, or other myelofibrosis symptoms. But, he said that multiple patient factors are involved in determining who it should apply to, such as burden of vascular events, risk of progression, splenomegaly, and baseline health or comorbidities. Generally, he discussed the treatment of patients with low- or intermediate 1–risk disease, as those who typically present with more favorable prognosis.

Assessing Patients

Management of all patients with myelofibrosis should progress through the same steps of evaluating survival and disease burden; developing a treatment plan of either observation, stem cell transplant, or frontline systemic therapy; and creating strategies for eventual disease progression.

Patient-reported symptom assessment tools are valuable and may help calculate symptom burden. Mesa cited using versions of both the MPN-Symptom Assessment Form (SAF) and the MPN-SAF Total Symptom Score (TSS) to look at effects such as fatigue, satiety, and pruritis.

“Just as we think of different prognostic scores, so too can there be different quartiles in terms of the severity and intensity of symptoms,” Mesa said. “These things are not necessarily linked to their risk score, which is predictive of survival,” he said, noting that disease burden and disease risk scores are not interchangeable.

Risk scores, such as the Dynamic International Prognostic Scoring System (DIPSS)–Plus, take constitutional symptoms as well as clinical features like age, degree of cytopenia, and karyotype into account when evaluating patients for prognosis. Using this risk scoring system, one study of 520 patients estimated that the median time spent in the “low-risk” category was 4.9 years (range, 0-26.7). Mesa noted that as patients progressed through intermediate 1–risk to high-risk disease stages, time spent in each category decreased. Therefore, patients considered to have early myelofibrosis, whether it be low- or intermediate 1–risk disease, still had progressive disease.2

Molecular phenotypes have also been instrumental in the current era of decision making for treatment of myelofibrosis. Based on an unfavorable molecular marker, patients otherwise considered to have intermediate-risk disease might now have a poorer prognosis and require more aggressive therapy in hopes of extending survival.

“New molecular phenotypes have clearly helped augment and refine prognosis, but they don’t fully give us a sense of disease burden,” said Mesa. Issues can arise in which patients with very high-risk disease don’t have severe symptom burden; conversely, individuals with severe symptoms may actually have lower-risk disease.

“We all know patients are much more complex than just the status of their clone or their molecular phenotype, although that is critically important,” Mesa said.

Patients with intermediate-risk disease are the most heterogenous group who stand to benefit greatly from information obtained by next-generation sequencing. Results obtains from molecular profiling may better inform a patient’s prognosis, and incorporation of this information may upgrade disease risk and suggest benefit of transplant or clinical trial.

Based on the National Comprehensive Cancer Network (NCCN) guidelines for MPNs, patients should first be assessed using either the DIPSS or DIPSS-plus. Patients who are asymptomatic by the MPN-SAF TSS can be observed or referred for clinical trial. Symptomatic patients can be treated with ruxolitinib (Jakafi), another available systemic agent, or be referred for clinical trial.3

For patients considered to have intermediate 1–risk disease by the NCCN guidelines, observation, ruxolitinib, clinical trial, and allogeneic hematopoietic stem cell transplantation are all considered acceptable forms of myelofibrosis management.

Systemic Therapy Benefit in Early Disease

The indication for ruxolitinib was based on the COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies,4 both of which examined the use of the JAK2 inhibitor in patients with intermediate or high-risk disease. Mesa said these patients were included in the trial because they represented the greatest need. However, approval based on this evidence should not be interpreted as meaning that ruxolitinib is unsuitable for use in patients with intermediate 1– or low-risk disease.

In fact, data from the phase 2 ROBUST trial that were released after the FDA issued its frontline approval supported the use of ruxolitinib more broadly in patients with myelofibrosis, including 19 patients with intermediate 1–risk disease.5 Similarly, the global, expanded-access phase 3b JUMP trial included the largest cohort to date of patients with intermediate 1–risk myelofibrosis and supported the safety and efficacy of ruxolitinib in this group.6

Mesa also added that fedratinib (Inrebic) is approved as frontline therapy for myelofibrosis,7 but data are lacking to support its use in patients with low-risk disease. “As that becomes available, it can be considered in this group,” he said.

Revisiting the NCCN Guidelines, Mesa reviewed the Evidence Blocks to determine interventions for low-risk disease, including hydroxyurea (Hydrea), interferon, and ruxolitinib. For intermediate 1–risk disease, he said most evidence at this point supports the use of ruxolitinib but he expects that other agents will be added to the list as more data emerge.4 However, studies of real-world evidence and investigator-initiated trials will likely be needed since trials supporting approval typical involve patients in higher-risk categories.

Concluding the discussion, Mesa said understanding why patients progress will be important in the selection of novel therapies for patients with early myelofibrosis. “Earlier patients all have areas in which they might benefit [from therapy], but as is natural, that evolution occurs as we develop more efficacy and safety data for these medications…Once we understand the mechanism of progression and have suitable markers of progression, then we might be in a better position to have progression-free survival be a viable end point for these individuals.”


1. Mesa R. To JAKi or not to JAKi How I treat ”Early” MF. Presented at: Texas Virtual MPN Workshop; August 27-28, 2020; Virtual.

2. DIPSS-Plus: a refined Dynamic International Prognostic Scoring System (DIPSS) for primary myelofibrosis that incorporates karyotype, platelet count and transfusion status. Blood. 2010;116(21):4104. doi:10.1182/blood.V116.21.4104.4104

3. NCCN. Clinical Practice Guidelines in Oncology (Evidence Blocks). Myeloproliferative neoplasms, version 1.2020. Accessed August 27, 2020.

4. FDA approves Incyte’s Jakafi (ruxolitinib) for patients with myelofibrosis. News release. November 11, 2011. Accessed August 27, 2020.

5. Mead AJ, Milojkovic D, Knapper S, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. Br J Haematol. 2015;170(1):29-39. doi:10.1111/bjh.13379

6. Giraldo P, Palandri F, Palumbo GA, et al. Safety and efficacy of ruxolitinib (Rux) in patients with intermediate-1–risk myelofibrosis (MF) from an open-label, multicenter, single-arm expanded-access study. Presented at: 20th Annual Congress of European Hematology Association; June 11-14, 2015; Vienna, Austria. Abstract P675.

7. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed August 27, 2020.