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The central goal of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms (MPNs) is to develop new and effective therapies for myeloproliferative neoplasms (MPNs) and Systemic Mastocytosis (SM) that will significantly improve the quality of life and the outcomes of our patients, extend survival, and ultimately cure MPNs. The former and present MPN Faculty at the Hanns Pielenz Clinical Research Center for MPNs at UT MD Anderson developed novel MPN medications, such as ruxolitinib and momelotinib, which significantly improved the quality of life and the outcomes of patients with myelofibrosis.

Impact of Approved JAK Inhibitors in the Treatment of Myelofibrosis

Ruxolitinib (JAK1/2 inhibitor) has been a truly transformative medication in the landscape of myeloproliferative neoplasms that dramatically improved the quality of life and extended the survival of patients with myelofibrosis (MF) since its regulatory approval in 2011. Ruxolitinib significantly ameliorates the quality of life of MF patients by substantially improving splenomegaly and the burden of constitutional symptoms, such as fatigue, early satiety, bone pain, low-grade fevers, pruritus, abdominal discomfort, and unintentional weight loss. 

Prior to the clinical development of ruxolitinib, MF treatments were scarce and the quality of life for patients with MF was very poor. Ruxolitinib has become the global standard of care for MF and the backbone of leading novel combination treatments for MF in advanced clinical development. Notably, follow-up analyses of the phase 3 randomized COMFORT-1 and COMFORT-2 studies documented the marked impact of ruxolitinib versus control in prolonging survival of patients with MF (). These findings were confirmed by recent analyses of retrospective and real-world data, for example, and other studies that were conducted at UT MD Anderson (; ;  ). Life extension is now recognized as a full-fledged benefit of ruxolitinib.

Ruxolitinib was the first and sole medication that had received regulatory approval for MF until August 16, 2019, when fedratinib was approved as a treatment for MF. Fedratinib, the second approved oral JAK2 inhibitor, may be considered as a good treatment option in second line patients with MF. Fedratinib reduces the spleen size and improves symptoms similarly to ruxolitinib, but fedratinib has a different toxicity profile, requiring a more attentative approach than ruxolitinib. 

Pacritinib (JAK2/IRAK1/ACVR1 inhibitor) was approved as a treatment for MF patients who have severe thrombocytopenia (low platelet counts), on February 28, 2022. In thrombocytopenic patients, treatment with ruxolitinib or fedratinib is not recommended because these agents may exacerbate thrombocytopenia. About 25% of MF patients have moderate to severe thrombocytopenia at diagnosis. Regulatory approval of pacritinib addressed the major unmet need of severely thrombocytopenic patients with MF; these patients had poor prognosis and lacked effective and safe treatment options until pacritinib was approved.

On September 15, 2023, momelotinib received regulatory approval as a treatment for patients who have intermediate- or high- risk MF (primary or secondary MF) and anemia based on the data acquired in the pivotal phase 3 MOMENTUM trial (NCT04173494) and the data from a cohort of patients who participated in the Phase 3 SIMPLIFY-1 trial (NCT01969838). 

Momelotinib is a unique JAK1/2 inhibitor because it also inhibits ACVR1 and thereby expression of hepcidin (master regulator or iron in the body) in the liver, leading to marked and sustained anemia benefits, including red blood cell transfusion independence. For a comprehensive review on the mechanism of momelotinib, which improves anemia, please review our article, .

The regulatory approval of momelotinib was a major advancement in the treatment of anemic patients with MF. Until momelotinib received regulatory approval, there was a critical unmet need for MF patients with anemia, which is one of the hallmarks of the disease. Prior to momelotinib's regulatory approval, Professor Verstovsek, MD, PhD, presented the interview titled, "".

Data from the phase 3 MOMENTUM trial demonstrated the superior clinical efficacy of momelotinib compared to danazol with respect to anemia measures, and spleen and symptom responses in anemic and symptomatic MF patients. ; our publications on momelotinib's long-term safety and survival benefits in ; and our article on momelotinib's efficacy in improving constitutional symptoms in . The durability of momelotinib's clinical benefits were analyzed in our publication in .

• An expert overview of momelotinib in the treatment of MF can be found in our recent article .

Please review the UT MD Anderson News Release on the clinical benefits that momelotinib elicited in anemic and symptomatic MF patients in the registrational MOMENTUM clinical trial.

Anemia and especially the need of red blood cell transfusions are considered adverse prognostic factors for disease progression and survival of MF patients. About one third of MF patients have anemia at diagnosis and approximately half of the patients require red blood cell transfusions one year after diagnosis; eventually, nearly all MF patients require red blood cell transfusions.

Momelotinib is poised to improve the patients' quality of life by providing significant anemia benefits, including red blood cell transfusion-independence, besides improving splenomegaly and constitutional symptoms. Please review our web page on Current MPN Research and Treatments for an overview of momelotinib¡¯s clinical efficacy in the phase 3 clinical trials and other novel MPN medications in advanced clinical development. 

The association of the myelofibrosis phenotypes (myeloproliferative and myelodepletive/cytopenic) with clinical manifestations and molecular profiles noted in the patients and the established/emerging treatments were discussed in , and .

• For a comprehensive overview of the four approved JAK inhibitors (ruxolitinib, fedratinib, pacritinib, momelotinib) and how to select them as treatments for patients with MF, please read our recent article that was published in Blood, 

• Currently, many novel agents (with different biological mechanisms of action) are being evaluated, as monotherapy or combination treatments for MF, in clinical trials.

Treatments for Polycythemia Vera and Essential Thrombocythemia

For a comprehensive review on PV, please review our article in and the relevant .

In 2014, ruxolitinib received regulatory approval as a second-line treatment for patients with polycythemia vera (PV) who are intolerant or resistant to hydroxyurea (frontline cytoreductive treatment in PV). The primary goal of PV treatment is mitigation of thrombotic and hemorrhagic events by strictly controlling the hematocrit below 45%. It was demonstrated in two randomized clinical studies that ruxolitinib provided significant clinical benefit in normalizing blood cell counts (red blood cells and platelets), improving constitutional symptoms (e.g., pruritus, splenomegaly, fatigue) and quality of life, and decreasing spleen size. Furthermore, the clinical responses to ruxolitinib in PV patients were durable.

Ropeginterferon alfa-2b is a long-acting interferon that has improved tolerability and reduced dosing frequency (injected subcutaneously once biweekly or less) compared to other interferons, such as pegylated interferon alfa-2a, which is the preferred front-line cytoreductive treatment in young female patients. Ropeginterferon alfa-2b was approved as a front-line treatment for PV patients in the United States in November 2021 and in the European Union in 2019.

Rusfertide (hepcidin-mimetic) is a novel investigational agent that demonstrated remarkable ability to eliminate the need for phlebotomies in the phase 2 clinical trial REVIVE that was conducted in PV patients who required phlebotomies (NCT04057040). The efficacy of rusfertide (concurrently with the ongoing PV treatment) was recently evaluated in PV patients who required frequent phlebotomies (with or without concurrent cytoreductive therapy) to maintain the hematocrit below 45% in the pivotal Phase 3 clinical trial VERIFY (NCT05210790) at UT MD Anderson (protocol #2022-0005). Rusfertide met the primary and all four key secondary endpoints in the VERIFY trial. The results of the VERIFY trial were published in .

In essential thrombocythemia (ET), patients can be treated with cytoreductive agents, such as hydroxyurea and pegylated interferon or anagrelide to reduce high platelet counts, which increase the risk of bleeding. Ropeginterferon alpha-2b is currently being evaluated in a randomized phase 3 trial in ET patients who are resistant or intolerant to hydroxyurea (SURPASS ET trial; NCT04285086). The phase 3 SURPASS ET clinical trial, evaluating ropeginterferon alpha-2b in ET patients versus anagrelide, enrolled patients at UT MD Anderson (Protocol #2020-0108). The results of the Phase 3 SURPASS ET study were published in .

Furthermore, INCA033989, a novel first-in-class mutant CALR monoclonal antibody, is currently evaluated in patients with CALR-mutated ET in a Phase 1 study (UT MD Anderson Protocol #2023-0647). The preliminary results of the study were published in . 

Perspective and Outlook Regarding Novel Promising Medications in MPNs

Presently, a flurry of other promising new agents that may complement or enhance the clinical benefits of ruxolitinib are in advanced clinical development for MF. Please review our web page on Current MPN Research and Treatments for an overview on novel MPN treatments in clinical development. Combination treatments, in which the medications act synergistically, may enhance the depth and duration of spleen and symptom responses of ruxolitinib and improve other aspects of the disease, such as bone marrow fibrosis and driver mutation burden (for example, JAK2 V617F). Deeper spleen responses (elicited with higher doses of ruxolitinib, for example) and achievement of red blood cell transfusion independence (elicited with momelotinib, for example) have been correlated with increased overall survival. Importantly, prolongation of survival is an important endpoint to assess in new investigational agents (for example, imetelstat); achieving prolongation of survival would be a major advancement for MF patients following the transformative improvements of splenomegaly and constitutional symptoms that ruxolitinib conferred.

Besides the aforementioned responses in treating MPNs, we are aiming to develop medications that will elicit complete or partial molecular responses, namely elimination or considerable decrease in the burden of driver mutations, such as JAK2 V617F in PV and MF and CALR in ET; such effects would indicate elimination of the malignant clones and possibly elimination of the disease. Availability of a suite of approved medications for MPNs will allow physicians to tailor and optimize treatments according to the patient¡¯s needs and maximize clinical benefits.

Currently, many promising, novel agents (with different biological mechanisms of action) are being evaluated in clinical trials as treatments for MF, PV, ET, and SM.