Reviewing Promising Agents in Development for Myelofibrosis

Insights From the SOHO 2022 Annual Meeting

Myelofibrosis (MF) is a rare, aggressive myeloproliferative neoplasm (MPN) with a prevalence of approximately 1.5 cases per 100,000 people in the United States.

In this interview, Dr Srdan Verstovsek shares research presented at the SOHO 2022 Annual Meeting in which he and Dr Helen T Chifotides reviewed therapeutics on the horizon for the treatment of MF.

What are the symptom burden and unmet needs associated with myelofibrosis?

MF is the most aggressive MPN and is characterized by bone marrow fibrosis, anemia, progressive splenomegaly, and several debilitating symptoms, such as fatigue, early satiety, pruritus, bone pain, abnominal discomfort, unintentional weight loss, and others. Progressive bone marrow fibrosis results in decreased production of blood cells and eventually bone marrow failure, leading to anemia and thrombocytopenia (low platelet counts); these cytopenias may be exacerbated by treatment with JAK2 inhibitors, such as ruxolitinib and fedratinib.

Anemia and the requirement for red blood cell transfusions are considered adverse prognostic factors for disease progression and survival in patients with MF. About one-third of patients diagnosed with MF have anemia at diagnosis. Eventually, nearly all patients require red blood cell transfusions, with approximately half requiring transfusions 1 year after diagnosis. Several studies have shown that thrombocytopenia is a negative prognostic factor for patients with MF, and about 25% of patients have moderate to severe thrombocytopenia at diagnosis.

The recent regulatory approval of pacritinib (February 2022) addressed the major unmet needs of severely thrombocytopenic patients with MF who have poor prognosis and lacked effective and safe treatment options until pacritinib was approved. Currently, there is a high unmet need for patients with MF with anemia because no medications have been approved.

However, momelotinib’s (JAK1/2 and ACVR1 inhibitor) high clinical efficacy, particularly regarding anemia benefits, was demonstrated in the recently reported interim results of the MOMENTUM clinical trial and will likely lead to regulatory approval of momelotinib in 2023. Based on the phase 3 clinical trials that have been conducted, momelotinib is poised to improve the quality of patients' lives by significantly improving anemia, splenomegaly, and constitutional symptoms. Momelotinib may also prolong survival in patients with MF.  

Notably, the US Food and Drug Administration (FDA) accepted a new drug application for momelotinib as a treatment for MF in August 2022. Regulatory approval of momelotinib will be a major advancement in the treatment of patients with MF who presently lack efficacious treatments for anemia.

Besides momelotinib, luspatercept (activin receptor IIB ligand trap) is another novel agent that enhances late-stage erythropoiesis and is in advanced clinical development to treat anemia in patients with MF, including ruxolitinib-treated, transfusion-dependent individuals. Currently, luspatercept is being evaluated in the pivotal phase 3 trial INDEPENDENCE and may also be approved as a treatment for patients with MF and anemia (in combination with ruxolitinib) in the near future. Luspatercept was approved to treat anemia in patients with lower-risk myelodysplastic syndromes in 2020.

How have JAK inhibitors impacted treatment considerations?

Ruxolitinib (JAK1/2 inhibitor) has been a transformative medication that dramatically improved the quality of life in patients with MF and markedly extended survival since its approval in 2011. Since that time, ruxolitinib has become the worldwide treatment standard for MF and the backbone of leading combination treatments in advanced clinical development.

In 2019, fedratinib, the second oral JAK2 inhibitor, was approved for treatment of MF. Fedratinib may be considered as a second-line treatment option in patients with MF.

In February 2022, pacritinib received regulatory approval to treat patients with MF with severe thrombocytopenia. In this cohort of patients, treatment with ruxolitinib or fedratinib may not be the best option because these JAK2 inhibitors may exacerbate thrombocytopenia.

Currently, several medications that act through various mechanisms are being considered as treatments for MF in combination with ruxolitinib—for example, pelabresib (BET inhibitor), navitoclax (BcL-2/BcL-xL inhibitor), parsaclisib (PI3Kd inhibitor), and others.

Can you review some agents currently in development for myelofibrosis? Which treatments seem most promising?

Besides momelotinib and luspatercept, the following highly promising agents are in advanced clinical development as treatments for MF:

1. Pelabresib (formerly CPI-0610) is a potent and selective bromodomain and extra-terminal protein inhibitor that improved splenomegaly, bone marrow fibrosis, anemia, total symptom score, and transfusion dependence in patients with MF who were enrolled in the phase 2 MANIFEST study. Pelabresib is currently being studied in combination with ruxolitinib in JAK-inhibitor naïve patients in the pivotal phase 3, placebo-controlled trial MANIFEST-2.
2. Navitoclax is a BcL-2/BcL-xL inhibitor that showed promising clinical efficacy in combination with ruxolitinib in the second-line setting for patients with MF (REFINE trial, cohort 1a). Presently, combination navitoclax/ruxolitinib is undergoing investigation in the randomized phase 3 trial TRANSFORM-2 in the second-line setting, as well as in a randomized phase 3 trial in JAK-inhibitor naïve patients (TRANSFORM-1 trial).
3. Imetelstat (telomerase inhibitor) may be the first medication to significantly prolong survival of patients with MF who have failed ruxolitinib. In the phase 2 IMbark study, patients with MF who were treated with the higher dose of imetelstat (9.4 mg/kg) had a median overall survival of 29 months. This is approximately a 2-fold higher survival for patients who fail ruxolitinib; these patients have advanced disease and typically have a median overall survival of 13 to 14 months. The primary endpoint of the pivotal phase 3 trial IMpactMF of imetelstat is prolongation of survival, which is unprecedented in MF trials.
4. Navtemadlin (formerly KRT-232) is an HDM2 inhibitor that showed promising clinical efficacy and tolerability for patients with TP53 wild-type MF who failed ruxolitinib in a phase 2 study. Currently, navtemadlin is being evaluated in the global phase 3 BOREAS trial in patients with TP53 wild-type disease who are refractory or resistant to JAK inhibitors.

Where do you see the future of care headed as more treatment options are studied and approved?

Presently, several promising new agents that may complement or expand the clinical benefits of ruxolitinib are in advanced clinical development. Combination treatments may increase the depth and duration of spleen and symptom responses and improve other aspects of the disease, such as bone marrow fibrosis and driver mutation burden. Certain novel agents may also address critical unmet therapeutic needs, such as anemia and red blood cell transfusion dependence.

Importantly, prolongation of survival beyond that of ruxolitinib is an important endpoint to assess in investigational agents; achieving prolonged survival would be a major advancement for patients with MF, following the transformative improvements of splenomegaly and constitutional symptoms that ruxolitinib confers.

The availability of a suite of approved medications for MF will allow physicians to tailor treatments to the patient’s needs and maximize clinical benefits. For example, imetelstat may be used to treat transfusion-independent patients who are resistant to ruxolitinib, whereas momelotinib may be the best option for transfusion-dependent patients who also have splenomegaly and symptoms.

Drs Verstovsek and Chifotides provide a comprehensive overview of MF agents in clinical development in their recent review.

About Dr Verstovsek

Srdan Verstovsek, MD, PhD, is professor of medicine in the Leukemia Department at the MD Anderson Cancer Center, in Houston, Texas. He is a global leader in myeloproliferative neoplasms and the founder/director of the largest MPN Clinical Research Center worldwide. Dr Verstovsek has achieved international acclaim for his leadership in developing the first ever MPN therapeutics that received regulatory approval, such as ruxolitinib (JAK1/2 inhibitor), which was approved as a treatment for myelofibrosis and polycythemia vera (2011 and 2014, respectively; pacritinib (JAK2/IRAK inhibitor) for patients with myelofibrosis (MF) and severe thrombocytopenia (2022); and pemigatinib for myeloid/lymphoid neoplasms with FGFR1 gene rearrangement (2022).

Dr Verstovsek has led more than 80 clinical trials of novel MPN agents and is leading the clinical development of several other very promising therapeutics that may receive regulatory approval in the near future; these include momelotinib and luspatercept as treatments for anemic patients with MF and rusfertide for patients with polycythemia vera.

Dr Verstovsek has published more than 600 peer-reviewed articles in leading medical journals, including The New England Journal of Medicine, Lancet Haematology, Leukemia, Blood, and many others. To date, his bibliography has acquired more than 35,000 citations and reached an h-index of 97. Dr Verstovsek has received several distinguished awards, including the Waun Ki Hong Faculty Award for Excellence in Team Science from the MD Anderson Cancer Center in 2020. Dr Verstovsek was elected as a member of the the American Society for Clinical Investigation in 2015.

Dr Verstovsek’s contributions in MPNs have been globally recognized with numerous invitations as an expert speaker/educator/chair at the most significant national and international conferences, including the American Society of Hematology, European Hematology Association, Society of Hematology and Oncology, and many others.