In Intermediate-Risk Myelofibrosis, Experts Focus on Symptom Relief

When managing patients with intermediate-risk myelofibrosis (MF), the key focus is symptom relief, reducing spleen size, and improving quality of life through the use of Janus kinase (JAK) inhibitors—ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara). Edward Pearson, MD, a medical oncologist-hematologist at Texas Oncology-Baylor Charles A. Sammons Cancer Center in Dallas, Texas, and participants discussed the management of symptoms and triggers to initiate treatment during a virtual Case-Based Roundtable® event.

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CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue​.

• Physical examination: Spleen was palpable 6 cm to 7 cm below the left costal margin​
• Next-generation sequencing: JAK2 V617F mutation​
• Karyotype: 46XX​
• Bone marrow biopsy: Megakaryocyte proliferation and​ atypia with evidence of reticulin fibrosis​
• Blood smear: Leukoerythroblastosis​
• Diagnosis: Primary MF​
• Risk assessment​
• Dynamic International Prognostic Scoring System: Intermediate-2​
• Mutation-Enhanced International Prognostic Score System: Intermediate risk​

DISCUSSION QUESTIONS

1. In your experience with MF, which symptoms/presentations have the most negative impact on a patient’s quality of life?
2. In your practice, what is the trigger to initiate therapy for a patient with MF?
   1. When is the right time to start JAK inhibitor therapy?
   2. How does symptom burden influence your decision to initiate JAK inhibitor therapy?
   3. How does splenic involvement and/or the presence of cytopenias influence your choice of JAK inhibitor?

Edward Pearson, MD: After undergoing a thorough evaluation and risk assessment, [it is determined that] the patient, a 68-year-old woman who presents to her physician with mild fatigue and no known comorbidities, has intermediate risk. In your experience with treating myelofibrosis, which symptoms or presentations have the most negative impact on a patient’s quality of life?

Andrew Dalovisio, MD: In general, it’s fatigue, irrespective of anemia.

Pearson: Has anyone dealt with other constitutional symptoms, such as night sweats?

Rashad Khan, MD: I’ve had a patient complain of pruritus, which they found very bothersome. I treated it with hydrocortisone cream, but it didn’t quite work. It wasn’t until I started the patient on ruxolitinib, which made a difference. Nothing else seemed to work.

Pearson: I’ve seen that as well for the itching, but I tend to see that in patients with polycythemia vera. Ruxolitinib seems to get the itching under control. In your practice, do you have any trigger for starting treatment?

Nihar Patel, MD: I’m usually looking at any kind of symptom that I can attribute to myelofibrosis, whether it’s early satiety, weight loss, an enlarged spleen, or any constitutional symptoms. It’s very subjective, so that sometimes adds some difficulty.

Pearson: Dr Hammoud, do you have a particular time [where] you consider initiating JAK inhibitor therapy?

Dalia Hammoud, MD: It really is symptom directed, particularly if the patient has constitutional symptoms or if they need to have more transfusions. That’s when I start with ruxolitinib. And we check if the patient is eligible for transplantation or not.

Pearson: I think most people would agree that starting ruxolitinib corresponds to a patient’s enlarged spleen. It’s usually go time at that point. Does anyone have easy enrollment in clinical trials? Is that available at your site?

Lorena de Idiaquez Bakula, MD: They are run by a colleague, but we end up giving up the patient when they enter a trial.

Pearson: I’d consider that a barrier. I know none of us wants to give up our patients.

Idiaquez Bakula: It’s very dependent on the group, so some providers become part of the trial, and this allows you to keep the patient.

Pearson: Thank you. How do you assess whether a patient is a transplant candidate?

Muffaddal Morkas, MD: A good candidate is a young, robust patient who is preferably less than 70 years of age. A patient between 70 and 75 years would require some serious consideration in terms of [their] functionality, comorbidity status, and ECOG [performance] status. I’d also add [that] the risk appetite of transplant candidates comes into play at that point in time.

Pearson: The next step would be to treat with any of the 4 JAK inhibitors, refer to transplant, observation, or enroll the patient in a clinical trial. What if this patient presented with alternative symptoms? What if she presented with constitutional symptoms, a spleen that was palpable 8 cm below the left costal margin, CALR negative on next-generation sequencing, and a hemoglobin [level] of 7.8 g/dL? What would you change and why?

Patel: I’m more familiar with ruxolitinib [than] momelotinib, but I know the data show ruxolitinib having less profound anemia effects, so I would probably feel comfortable prescribing the latter in this second scenario, more so than any of the other JAK inhibitors.

Pearson: I think that’s what they were getting at with that change. Pivoting to the higher-risk patient with myelofibrosis, the National Comprehensive Cancer Network guidelines¹ note that if they’re a transplant candidate, you can send the patient for an allogeneic stem cell transplant. If they’re a nontransplant candidate, or it’s otherwise not feasible for platelets less than 50,000/μL, the guidelines recommend pacritinib or momelotinib.

For patients with a platelet count over 50,000/μL who are symptomatic with splenomegaly with or without constitutional symptoms, then enrolling the patient in a clinical trial is the preference, followed by treatment with ruxolitinib, fedratinib, momelotinib, and then pacritinib.

DISCUSSION QUESTION

• How do you monitor and manage anemia in patients?
• Prior to starting JAK inhibitor therapy​
• While receiving JAK inhibitor therapy

Pearson: Shifting gears, how do you monitor and manage anemia in patients with primary myelofibrosis? So prior to starting JAK inhibitor therapy, what’s your strategy for managing anemia?

Giancarlo Moscol, MD: Well, anemia is a consequence of the myelofibrosis process. I provide supportive care while the patient is taking the JAK inhibitor, and sometimes you need to cut back on the dose of ruxolitinib. The other option is to start momelotinib instead. But I usually lower the dose and provide transfusion support.

Pearson: Have you ever used ESAs [erythropoiesis-stimulating agents] or luspatercept-aamt [Reblozyl]?

Moscol: No, I haven’t used those agents.

Morkas: The JAK inhibitors were approved for this, and I’m impressed that they work quite well and serve to manage hemoglobin.

Pearson: At what hemoglobin level would you not be comfortable initiating ruxolitinib in your patients with myelofibrosis?

No one chose the range of hemoglobin 8 g/dL to 9 g/dL, and patients who were bordering on transfusion independence gave participants pause as well. There’s definitely a dip [in hemoglobin] when you start patients on ruxolitinib, but patients tend to come back up and often settle in on 1 or 2 points lower than where they were at baseline. That can be tough, but we do have other agents to help us now.

Pearson: Switching agents, let’s discuss the JAKARTA trial [NCT01437787] evaluating fedratinib.² In patients with intermediate-2 or high-risk primary or secondary myelofibrosis and a platelet count less than 50,000/μL, how does the safety and efficacy of fedratinib influence its selection as a frontline therapy compared with the COMFORT trial standards?

Most of the safety and adverse events were straightforward. Anemia and thrombocytopenia were observed with fedratinib, with some grade 3 or higher instances, but not particularly bad. These are adverse events that we’re used to dealing with. But what was unusual was Wernicke encephalopathy.

The investigators found 8 cases of Wernicke encephalopathy, with 7 cases among patients who received the 500-mg dose and 1 case in the 400-mg dose.

ALTERNATE SCENARIO

A 68-year-old woman presented to her physician with fatigue, abdominal pain lasting 4 months, and increased bruising.​

• Physical examination: Spleen was palpable 8 cm below the left costal margin​
• Next-generation sequencing: JAK2 V617F mutation​
• Bone marrow biopsy: Megakaryocyte proliferation and​ atypia with evidence of reticulin fibrosis​
• Blood smear: Leukoerythroblastosis
• Laboratory findings: Hemoglobin level of 13.2 g/dL; platelet count of 35,000/μL

DISCUSSION QUESTION

• How does severe thrombocytopenia impact your choice of frontline therapy?

Pearson: Looking at the alternate case scenario, the patient’s hemoglobin was at 13.2 g/dL, but the platelets were 35,000/μL. She still has fatigue and abdominal pain, with increased bruising. Her spleen is 8 cm below the costal margin. How does this severe thrombocytopenia impact your choice of frontline therapy?

Patel: I think you had mentioned pacritinib earlier for those patients with severe thrombocytopenia.

Pearson: Moving on, PERSIST-2 [NCT02055781] was a pivotal phase 3 trial evaluating the JAK2/IRAK1 inhibitor pacritinib in patients with intermediate or high-risk primary or secondary myelofibrosis, specifically focusing on the challenging subset with significant thrombocytopenia, defined as a platelet count below 100,000/μL.³ Eligible patients also required palpable splenomegaly. Unlike earlier studies, this trial permitted prior treatment with 1 or 2 other JAK inhibitors, resulting in a more heavily pretreated patient population. Participants were randomly assigned 1:1:1 to receive pacritinib at a dose of 400 mg once daily, 200 mg twice daily, or best available therapy.

The best available therapy arm was broadly defined and included ruxolitinib, danazol, hydroxyurea, immunomodulatory agents, hypomethylating agents, corticosteroids, interferon, or watchful waiting, which accounted for 19% of patients in that control group. The co–primary end points of the study were the proportion of patients achieving a 35% or greater reduction in spleen volume and a 50% or greater reduction in total symptom score at 24 weeks. A key secondary end point evaluated rates of red blood cell transfusion independence over time.

Patients who received pacritinib did a little better than patients on best available therapy, keeping in mind that this was a heavily pretreated population. These patients had been on a previous JAK inhibitor.

Looking at the total symptom score end point, 32% of all patients treated with pacritinib achieved a 50% or greater reduction compared with just 14% in the best available therapy group. This benefit was preserved even in the most challenging subset of patients. For those with a baseline platelet count below 50,000/μL, the clinical responses were similarly favorable compared [with] the control arm, demonstrating a significant and durable treatment effect in this high-risk population.³ Secondary anemia data did show patients with an improvement in their hemoglobin [levels] and reduction in transfusion requirements.

The NCCN guidelines recommend pacritinib or momelotinib in patients with platelets less than 50,000/μL and all 4 of the JAK inhibitors in [those with] platelets greater than 50,000/μL. Does this affect your choice of JAK inhibitor?

Khan: I feel like momelotinib is the easiest to go with because it has many applications; it has certain targets that I know that if my patient has any of those, they are going to benefit. It helps with anemia, it addresses low platelet counts. It’s almost a no-brainer, a default choice to go with. It fits more cases, basically.

Hammoud: I think momelotinib has good interaction between different cytopenias. What [are] your criteria, Dr Pearson?

Pearson: If I’m deciding between pacritinib vs momelotinib in patients with thrombocytopenia, I agree with the point about anemia. If the patient has significant anemia, I lean toward momelotinib. If the platelets are under 50,000/μL, I go with pacritinib. If patients are between 50,000/μL and 100,000/μL [platelet count] and they have significant anemia, I’m going to look more at momelotinib, although pacritinib is not a wrong choice.

DISCLOSURES:

Dr Pearson previously disclosed consultancy with AbbVie, Genmab, and Sanofi; and speakers’ bureau with AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, GSK, Incyte, PharmaEssentia, Rigel, Sanofi, and Servier.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2026. Accessed February 3, 2026. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf

2. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. doi:10.1001/jamaoncol.2015.1590

3. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4;(5):652-659. doi:10.1001/jamaoncol.2017.5818