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Management of MF
Contemporary Topics in Treating Myelofibrosis: A Conversation Between Experts

Released: April 07, 2023

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Key Takeaways
  • Approved JAK inhibitor options for treating patients with MF now include ruxolitinib, fedratinib, and pacritinib (April 2023).
  • Momelotinib is an investigational JAK inhibitor that was superior to danazol in improving spleen and symptoms and noninferior in improving anemia transfusion independence rate in a phase III study.
  • Ongoing phase III trials are exploring ruxolitinib combination therapies, novel monotherapies, and anemia treatments for patients with MF.

Best practices in the treatment of patients with myelofibrosis (MF) continue to evolve with drug approvals and ongoing late-phase clinical trials. In this commentary, John Mascarenhas, MD, and Ruben A. Mesa, MD, FACP, discuss recent developments and emerging clinical trials and data in this space.

Approach to MF Treatment

Ruben A. Mesa, MD, FACP:
As we think about treating patients with MF in 2023, we still fundamentally have the same key pathway that we have had for many years. We begin by identifying the patient’s prognostic risk using a modern scoring system, of which there are many. I tend to use the MIPSS70 most often, with perhaps some variability for post–essential thrombocythemia or post–polycythemia vera MF. We then assess additional factors, including the patient’s disease burden, symptoms, platelet count, and splenomegaly. With this information, we can formulate a treatment approach with medical therapy or stem cell transplantation. Dr. Mascarenhas, how do you approach medical therapy in 2023?

John Mascarenhas, MD:
For those patients who require a reduction in spleen and symptom burden, the first line of therapy remains a JAK inhibitor, with ruxolitinib, fedratinib, and pacritinib having received FDA approval for specific patient profiles with MF. If a patient has a platelet count of >50 x 109/L, I will typically recommend ruxolitinib up front, although the label for fedratinib would also allow this agent as a first-line option as well. If a patient has a platelet count of <50 x 109/L, by label, pacritinib would be the JAK inhibitor of choice to address spleen and symptom burden. So, we use JAK inhibitors to address these disease aspect burdens, with the understanding that we will not induce pathologic remission or molecular remission with JAK inhibitors, and that we need to have a treatment plan in place in which we are considering second-line options for when a patient experiences loss of response or refractory disease with our initial therapy.

Ruben A. Mesa, MD, FACP:
Wonderful and well put. Ruxolitinib has now been approved for well over a decade, and this agent has been a game changer. The JAK inhibitors and ruxolitinib transformed the face of MF. Patients now live longer and better than before these agents were available. Although we have room to go, how impactful these agents have been should not be minimized. However, we know that JAK inhibitors do not provide a cure and that patients can fail ruxolitinib, although, on average, patients can remain on this therapy and derive benefit for 3-4 years.

For those who have not yet prescribed pacritinib, this agent was approved by the FDA in March 2022 for patients with intermediate-risk or high-risk primary or secondary (post–polycythemia vera or post–essential thrombocythemia) MF with a platelet count <50 × 109 /L. Pacritinib is a JAK2 and FLT3 inhibitor that also inhibits IRAK1 and ACVR1. This is a somewhat unique inhibitory profile. Indeed, pacritinib can be very helpful for cytopenic patients with MF. It can be given at full dose, regardless of platelet count, at 200 mg twice daily. Some patients may also achieve anemia responses. This may be because of the inhibition of ACVR1 by pacritinib. So, this agent has been an important addition to the treatment paradigm for patients with MF.

Dr. Mascarenhas, you mentioned fedratinib. In which patients do you consider the use of fedratinib in 2023?

John Mascarenhas, MD:
I generally consider fedratinib for patients who have been receiving ruxolitinib but perhaps continue to have spleen or symptom burden and a platelet count >50 × 109 /L. Those patients are excellent candidates for fedratinib, which is probably an underused JAK inhibitor today and should certainly be considered as a valuable second-line agent after ruxolitinib.

Ruben A. Mesa, MD, FACP:
You raise an excellent point. Fedratinib is an agent that has likely been underprescribed since its approval. It has very solid data from the JAKARTA and the JAKARTA-2 studies. It can be beneficial in the frontline or second-line setting. I think where healthcare professionals (HCPs) are often missing an opportunity is in the second-line setting when patients have adequate platelet counts. HCPs need to be mindful of a patient’s thiamine levels when using this agent, as there is a black box warning regarding the possibility of Wernicke encephalopathy, although there is a very low risk of this, which is quite manageable with proper tracking of thiamine and/or replacement.

Ruxolitinib Failure

Ruben A. Mesa, MD, FACP:
How do you think treating physicians should be defining ruxolitinib failure at this time? I know, as academic investigators, we sometimes have struggled to define this in a reproducible way.

John Mascarenhas, MD:
Ruxolitinib failure can be hard to define because it is not always black and white. Sometimes there may be a great initial spleen response with ruxolitinib, but spleen size may gradually increase over time at a maximally tolerated dose of ruxolitinib; in this case, something that I would call “symptom creep” can occur. Other times there may be frank progression of disease to acute leukemia or MF in the blast phase. In approximately one quarter of patients, it simply might be toxicity, such as cytopenias or infectious complications. HCPs need to be aware of the patient and the spleen and symptom response or thereafter loss of response, as well as blood counts and the potential for progression of disease despite having spleen and symptom control. As you mentioned, after an average of approximately 3 years, one half of the patients who began first-line ruxolitinib treatment will stop this therapy, and this reinforces the point that one needs to plan and have second-line options ready for that patient.

Unmet Needs in MF Treatment

Ruben A. Mesa, MD, FACP:
We have already discussed several unmet needs in MF treatment, in particular the potential loss of response or failure with ruxolitinib. We also discussed thrombocytopenia and the benefits of pacritinib in that space. What are some other unmet needs?

John Mascarenhas, MD:
I would say that there remain unmet needs in disease remission, prolongation of survival, and managing cytopenias. There is a portion of patients with MF for whom spleen and symptom burden management is not the goal of therapy, but rather anemia management, which may be managed with an erythropoiesis-stimulating agent, danazol, an immunomodulatory drug, or the activin receptor-ligand trap luspatercept, which is approved for specific patients with myelodysplastic syndromes and is being assessed in a phase III trial for patients with MF. With erythropoiesis-stimulating agents, immunomodulatory drugs, or danazol, I have found an approximately 30% response rate with each agent, and it is possible to run through those drugs and still be left with a patient who has ongoing anemia or has anemia in the setting of JAK inhibitor therapy in a situation where you are trying to alleviate anemia in addition to spleen and symptom burden. So there remain significant unmet needs in the form of cytopenia management. Looking forward, I would also say that true disease course modifying drugs that change the natural history of the disease are needed for our patients.

Emerging Strategies: Momelotinib and Ruxolitinib Combinations

Ruben A. Mesa, MD, FACP:
Well said. In discussing cytopenias, I would like to pivot to talking about emerging therapies, beginning with momelotinib. Momelotinib is a JAK1, JAK2, and ACVR1 inhibitor that was shown in earlier studies to improve spleen symptoms and anemia. The recently reported MOMENTUM study was a randomized, double-blind phase III trial assessing momelotinib vs danazol in patients who had previously received a JAK inhibitor and were anemic (hemoglobin <10 g/dL) and symptomatic (total symptom score ≥10) with a platelet level ≥25 x 109/L. Momelotinib was superior to danazol in improving spleen and symptoms and noninferior for improvement in anemia (trending toward statistic superiority). I think, combined with favorable frontline data from the phase III SIMPLIFY 1 study, momelotinib is likely to be approved in the near future.

I recently attended a hematology review meeting, and again seeing the data being presented in lymphoma and chronic lymphocytic leukemia, multiple myeloma, and acute leukemias, it certainly strikes me that there are very few diseases, perhaps except chronic myeloid leukemia, for which we continue to treat with monotherapy. In multiple myeloma, patients may receive 4 drug therapy and, again, these are diseases with complex biology. It seems logical to think that combination therapy may be helpful in MF. Dr. Mascarenhas, how do you view combination therapy in 2023?

John Mascarenhas, MD:
There are currently numerous ongoing randomized phase III studies assessing combination therapy for MF. Pelabresib, a BET inhibitor, is currently being evaluated in combination with ruxolitinib in the phase III MANIFEST-2 study in JAK inhibitor naive patients. Parsaclisib, a PI3 kinase inhibitor, is being evaluated in combination with ruxolitinib in the first-line (LIMBER-313) and second-line (LIMBER-304) settings. Navitoclax, a BCL-2/XL inhibitor, is also being evaluated in the first-line and second-line setting (TRANSFORM-1 and TRANSFORM-2). It is the general hypothesis with these trials that synergism would be attained by adding an agent to ruxolitinib, hopefully avoiding additive toxicity while increasing the durability of spleen and symptom benefit, perhaps even attaining other disease-modifying benefits, such as reduction in bone marrow fibrosis, inflammatory cytokines, or driver mutation burden. It is paramount that these studies correlate disease modification biomarkers with actual disease course modification, whether it is a prolongation of progression-free survival or, ideally, overall survival.

Ruben A. Mesa, MD, FACP:
I think you describe a range of exciting things coming down the pike. Indeed, we probably have more phase III studies at the current time for MF than we have ever had before. There are combination therapies or approaches that may be helpful with specific aspects of disease, such as the addition of luspatercept to ruxolitinib for patients with anemia. And in the setting of the patient with anemia, will we use momelotinib? If they are also thrombocytopenic, do we use pacritinib? Do we use luspatercept particularly if they have an SF3B1 mutation or some other aspect?

How do we use combination therapy? How will emerging non-JAK inhibitors in phase III trials be used? Both imetelstat (a telomerase inhibitor) and navtemadlin (an MDM2 inhibitor) are being assessed in phase III trials in patients who were previously treated with ruxolitinib (IMpactMF and BOREAS, respectively).

I think in the future we will have more options and hopefully better-tailored therapy to meet an individual patient’s needs. I think correlative studies and subgroup analyses from these phase III studies are going to be very important.

Your Thoughts?
How has your clinical practice changed in the past 5 years in terms of treating patients with MF? What emerging therapeutics are you most excited about? Please leave a comment or answer the polling question to join the conversation.

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