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Managing Myelofibrosis
Myelofibrosis: Where We Are and Where We Are Going

Released: October 04, 2023

Jean-Jacques Kiladjian
Jean-Jacques Kiladjian, MD, PhD
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Key Takeaways
  • JAK inhibitors provide clinical benefits for patients with myelofibrosis (MF), and JAK inhibition alone can be the backbone of MF treatment in many patients.
  • Momelotinib is now approved for the treatment of intermediate or high-risk MF, including primary MF or secondary MF (post-polycythemia vera and post-essential thrombocythemia,) in adults with anemia.
  • Ongoing phase III trials are exploring new combination therapies with JAK inhibitors plus agents with other targets and novel monotherapies.
  • Neoepitope-directed vaccines and monoclonal antibodies directed against the calreticulin mutation are currently being investigated in MF with hope for long-term control.

Management of myelofibrosis (MF) continues to expand with drug approvals and the growth of novel agents in clinical trials. There are now mature data with 4 JAK inhibitors (ruxolitinib, fedratinib, pacritinib, momelotinib), including evidence that JAK inhibition alone can be the backbone of MF treatment as first‑line therapy. Momelotinib is now approved for the treatment of intermediate or high-risk MF, including primary MF or secondary MF (post-polycythemia vera and post-essential thrombocythemia,) in adults with anemia. First‑line JAK inhibitors are suitable for most patients, depending on patient clinical needs, the presence of splenomegaly and other symptom burden. You may have a choice between the different first‑line JAK inhibitors based on patient clinical and hematological characteristics. However, there are limitations in JAK inhibitor activity and unmet needs for some patients who still need more than can be achieved with available first‑line therapies. For example, alternatives are limited for optimizing care in a younger patient who is unable to have allogenic stem cell transplantation either because of ineligibility or lack of a suitable donor. We hope to advance first‑line therapy for these patients, or in some cases for those with very high‑risk disease. Here we can also include those patients whose disease has additional high-risk mutations that may worsen the long‑term prognosis. For these subsets of patients, we clearly need more effective approaches, and what can we propose today? There are trials of combination therapy, such as adding an additional agent to the backbone of JAK inhibition. We are eager for the final results of the main phase III trials combining ruxolitinib either with navitoclax, a BCL-2/BCL-XL inhibitor, or with pelabresib, a BET inhibitor, as first‑line therapy. The preliminary results were encouraging in terms of improved clinical response but also achievement of some molecular and histopathologic responses, with diminution of JAK2 mutant allele burden and reduction of fibrosis on bone marrow biopsies. We will see if these findings are confirmed on a larger scale and if the combinations can be administered safely. It is important to keep in mind the benefit–risk balance of having 2 drugs instead of 1. For example, a combination regimen offers more effective treatment with better long‑term disease control, but it also carries a potential increased risk of adverse events. Other agents including interferon and selinexor are being evaluated in combination with ruxolitinib as first-line therapy.

The situation is similar for second‑line therapy, because we know that the response to JAK inhibitors may wane over time. With ruxolitinib, a number of patients stop treatment within 5 years of initiating therapy. I suspect it is probably the same with the other JAK inhibitors, so we need alternatives to switching from one to the other. Although switching JAK inhibitors can be an option, we may be able to add a second drug or switch to a new class of drug to restore the response again. Agents under investigation in this setting include imetelstat and navtemadlin.

There is ongoing research into immunotherapy with neoepitope-directed vaccines and monoclonal antibodies that are directed against the calreticulin mutation. There are trials that are starting using either vaccine or antibodies against mutant CALR. These are completely new strategies in these diseases, although we now have very encouraging results with such strategies in other hematological diseases such as lymphoma, and acute leukemia. With myeloproliferative neoplasms, and particularly MF, these would be the first trials with this type of approach. This prospect is very exciting because we have a potential long‑term control of the disease with completely new pathways.

Upcoming Live In-Person/Virtual Symposium on Personalized Myelofibrosis Care

Want to learn more about myelofibrosis management today and in the future? Register to join me and Abdulraheem Yacoub, MD either in-person or virtually for our upcoming symposium, titled “A Master Class in Personalized Myelofibrosis Care: Applying New Evidence and Novel Therapeutic Strategies to Improve Outcomes” at the American Society of Hematology annual meeting on Friday, December 8, 2023. We will discuss ways to partner with patients to improve outcomes and quality of life, nuances in selecting initial treatment for patients with myelofibrosis, recognizing patterns of suboptimal response to first line myelofibrosis treatment, disease progression or intolerance to initial therapy, and more about what is on the horizon in myelofibrosis treatment. I hope to see you there!

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