Approaches Abound for Managing Symptoms Associated With Myelofibrosis

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Srdan Verstovsek, MD, PhD, shares recommendation updates for myelofibrosis treatment and emerging options under exploration to effectively manage disease-related symptoms.

Srdan Verstovsek, MD, PhD

Srdan Verstovsek, MD, PhD

Although JAK inhibitors such as ruxolitinib (Jakafi) have helped to manage splenic symptoms associated with myelofibrosis, no FDA-approved approaches are available to manage anemia in patients who are transfusion dependent, according to Srdan Verstovsek, MD, PhD. However, luspatercept-aamt (Reblozyl) may present a potential option.

The agent was approved by the FDA in April 2020 for use in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm (MPN) with ring sideroblasts and thrombocytosis based on the results of the phase 3 MEDALIST study (NCT02631070). Although the drug does not currently have an indication in myelofibrosis, Verstovsek explained why it could fit into the treatment paradigm.

“The 3 main problems [faced in myelofibrosis] are [that patients have a] big spleen, poor quality of life, and anemia. For the splenic symptoms, we have JAK inhibitors such as ruxolitinib and fedratinib [Inrebic]. For anemia, we do not have any approved therapies,” said Verstovsek. “Luspatercept is the anemia drug [we need]. It was approved last year as a therapy for patients with MDS and is being studied as a therapy for myelofibrosis, [which] is a cousin to MDS. Some differences exist [among] chronic myeloid diseases of the bone marrow, but in general, one would expect [to see] activity [with] 1 drug in both [of these] entities, and this appears to be the case.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on hematologic malignancies, Verstovsek shared recommendation updates for myelofibrosis treatment and emerging options under exploration to effectively manage disease-related symptoms. He is a professor of medicine and a hematologist/oncologist in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center.

OncLive®: How do the National Comprehensive Cancer Network (NCCN) guidelines help guide treatment for patients with myelofibrosis?

Verstovsek: The NCCN guidelines are a very valuable tool for every practice in the community setting for physicians and patients with MPNs and they are relatively easy to understand. Until a few years ago, there were [no guidelines] for patients with any type of MPN. Of course, as they are made by experts in the field, [guidance] evolves over time. The last modified version of the guidelines for the management of patients with myelofibrosis in the United States was [published] about 6 months ago by experts in the field. [They made] a few adjustments [pertaining to] prognostication and therapy.

After diagnosis, the question [becomes]: What is the patient’s prognosis? The reason to prognosticate is primarily to refer patients who have a life expectancy of less than 5 years to a bone marrow transplant doctor, [who can] do the transplant and save the patient’s life. [To that end], a new set of prognostic scoring systems has been introduced. These [systems] include not only standard [factors, such as] age, symptoms, and blood cell count, but also genetic information. In academic centers and in the community setting, we are able to test to identify molecular abnormalities in the bone marrow cells or blood cells, giving us additional [insight into] patient [outcomes] because genetic complexity matters. A combination of new prognostic scoring systems has been put together to identify patients for transplant.

[With regard to] therapy, it is relatively [simple] these days. [If] we have a patient with lower-risk disease who presents, [as they] usually [do], with a high blood cell count, [we treat them] with hydroxyurea [Hydrea] or interferon. In those who have a big spleen or systemic myelofibrosis symptoms, JAK inhibitors are routinely used; that is standard practice. Ruxolitinib has been around for 10 years and fedratinib was approved in 2019 as another option.

Could you explain how luspatercept has affected the treatment of patients with myelofibrosis who have anemia?

When we ask doctors about the main problem [they face] with patients who have myelofibrosis, the answer [is] not [just] that [some] have a shorter life expectancy; we [know we] should prognosticate and transplant those with a life expectancy of less than 5 years. Doctors also say that a limited number of medications [are available] to treat these patients for their clinical problems.

Luspatercept is a transforming growth factor β [TGF-β] modifier; it is a trap protein for ligands to specific receptors that are active in receptor α, which is a present antibody [that modulates] the signaling of cytokines, particularly TGF-β or TGβ modifier. That is why we say that luspatercept modifies TGF-β signaling, and that allows for terminal differentiation of red blood cells, [meaning] more red blood cells [develop] in the patient’s blood.

The agent is administered subcutaneously every 3 weeks. In an ongoing study [being done] in [patients with] myelofibrosis—particularly those who have anemia, are transfusion dependent, and are on a stable dose of ruxolitinib JAK inhibitor—[the agent has demonstrated] good results. [Specifically, it has been shown to] eliminate the need for transfusions in one-third of those patients. That appears to be the group [for whom luspatercept may receive a] possible approval [for use]. The announcement has been made that a placebo-controlled, randomized study [will be done] with luspatercept in this group of patients in the near future.

What are some of the combination regimens with ruxolitinib that are currently under investigation?

Several combination therapies with ruxolitinib are [in development in] different clinical settings. In JAK inhibitor– naïve patients for whom you need to control splenic symptoms, you can combine an agent with ruxolitinib to enhance its effect. An example of that is CPI-0610, which is a small molecule BET inhibitor that has been studied in combination from the very beginning with ruxolitinib in an open-label, phase 2 study. In that setting, we have seen quite interesting results, [including] a 67% spleen response and a 57% improvement in symptoms; that appears to be much better than what you would expect with ruxolitinib alone [in the frontline setting].

This is going to be studied [further] in the very near future; I think [the trial] is about to open. In the frontline setting, patients will be randomized between starting ruxolitinib and placebo or ruxolitinib and CPI-0610 with the hope that spleen and symptom response over the first 6 months will be much better [with the combination] than with ruxolitinib alone. The alternative is to add an agent to ruxolitinib in patients who are on [ruxolitinib monotherapy] but are suboptimal responders. There are [always areas for improvement].

In that setting, the [oral] BCL-XL inhibitor navitoclax has shown very good results; I call this the add-on approach. An announcement has been made that 2 phase 3 studies will be done to further evaluate navitoclax in patients with myelofibrosis. The first will be in the frontline setting: Patients will be randomized to receive navitoclax and ruxolitinib from day 1, and that will be compared with ruxolitinib and placebo, again, from day 1. The second study will [examine the agent] in the second-line setting, as an add-on approach, or in the second-line setting after ruxolitinib. There is a little distinction between the plans and what has happened so far, but we are excited to have those opportunities to develop new drugs in combination with ruxolitinib.


  1. US Food and Drug Administration (FDA) approves Reblozyl (luspatercept-aamt), the first and only erythroid maturation agent, to treat anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb. April 3, 2020. Accessed February 23, 2020.
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