Approved MPN Treatments & MPN Clinical Trials

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) that will significantly improve the quality of life and the outcomes of our patients, extend survival and ultimately cure MPNs. The MPN Team at the Hanns Pielenz Clinical Research Center for MPNs at MD Anderson developed novel MPN medications, such as ruxolitinib (JAK1/2 inhibitor), which dramatically improved the lives and extended survival 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 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 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 (Verstovsek S. et al., J. Hematol. Oncol. 2017). These findings were confirmed by recent analyses of retrospective analyses and real-world data, for example, the ERNEST study and other studies that were conducted at the MD Anderson Cancer Center (Verstovsek S, et al., Cancer 2023; Masarova L. et al., Cancer 2023; Verstovsek S. et al., Annals Hematol. 2022; Masarova L. et al., Cancer 2022). 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 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 spleen size and improves symptoms, similar to ruxolitinib but 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) in February 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 needs of severely thrombocytopenic patients with MF; these patients have 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 that improves anemia, please review our article, "Momelotinib: an emerging treatment for myelofibrosis patients with anemia" (Chifotides HT, Bose P, Verstovsek S, J. Hematol. Oncol. 2022).

Regulatory approval of momelotinib is 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, an interview titled, "Momelotinib may become No. #1 choice for second-line therapy in myelofibrosis" was presented.

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. Please review our publication in the leading journal The Lancet (Verstovsek S. et al., 2023) where the final results of the MOMENTUM study were published; our publications on momelotinib's long-term safety and survival benefits in Blood Advances (Verstovsek S. et al., 2023); and our article on momelotinib's efficacy in improving constitutional symptoms in Cancer Medicine (Mesa RA. et al., 2023). The durability of momelotinib's clinical benefits were analyzed in our publication in Lancet Haematology (Gerds AT, Verstovsek S. et al., 2023).

• An expert overview of momelotinib in the treatment of MF can be found in our recent article Bose P. Blood 2024;144(7):708-713.

Please review the 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 our comprehensive review was published in Cancers (Basel) 2023, and our review was featured on the cover of Cancers (Volume 15, issue 13; July 2023).

• 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 "How I treat" that was published in Blood, "How I individualize selection of  JAK inhibitors for patients with myelofibrosis", Masarova L., Chifotides HT., Blood 2024.

 

Treatments for Polycythemia Vera and Essential Thrombocythemia

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 and blood cells and platelets), improving constitutional symptoms (e.g., pruritus, splenomegaly, fatigue) and quality of life, and decreasing spleen size. Furthermore, the clinical effects of ruxolitinib in PV 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) is currently evaluated in PV patients who need frequent phlebotomies (with or without concurrent cytoreductive therapy) to maintain the hematocrit below 45% in the pivotal phase 3 clinical trial VERIFY (NCT05210790) at MD Anderson Cancer Center (protocol #2022-0005).

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 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, is currently open at MD Anderson Cancer Center (protocol #2020-0108).

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, for example; 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.

Active MPN and Systemic Mastocytosis (SM) Clinical Trials at the Clinical Research Center for MPNs

Myelofibrosis

• Phase 1/3 Study to Evaluate the Efficacy and Safety of  Selinexor, a Selective Inhibitor of Nuclear Export, in Combination with Ruxolitinib, in Treatment-Naïve Patients with Myelofibrosis (SENTRY trial; NCT04562389); MD Anderson Protocol #2023-0757.

• Phase 3 Clinical Study Evaluating Imetelstat vs. Best Available Therapy (BAT) in Adult Patients with Intermediate-2 or High-Risk Myelofibrosis (MF), Refractory to Janus Kinase (JAK) Inhibitors (IMpactMF trial, NCT04576156); MD Anderson Protocol #2020-1141.

• Phase 3 Study of  Luspatercept vs. Placebo in Patients with Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomitant JAK2 Inhibitor Therapy and Who Require Red Blood Cell Transfusions (INDEPENDENCE trial, NCT04717414); MD Anderson Protocol #2020-1010. 

• Phase 3 Study of  Navtemadlin "Add-on" to Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib (POIESIS trial; NCT06479135; MD Anderson Protocol #2024-0506).

• Open Label Phase 2 Study of  Tasquinimod (as Monotherapy and in Combination with Ruxolitinib) in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), or Post-Essential Thrombocytosis Myelofibrosis (Post-ET MF); NCT06327100; MD Anderson Protocol #2023-0934.

• Phase 2 Open-label, Multicenter Study of  TL-895 (potent, selective inhibitor of Bruton tyrosine kinase) in Patients with Relapsed/Refractory Myelofibrosis, Janus Kinase Inhibitor-Intolerant Myelofibrosis and Janus Kinase Inhibitor Treatment-Ineligible Myelofibrosis; NCT04655118; MD Anderson Protocol #2020-0738.

• Phase 1 Study of  Elotuzumab (anti-SLAM7 monoclonal antibody) in the Treatment of  JAK2^V617F-Mutated Primary Myelofibrosis (MF), Post-PV MF, or Post-ET MF (NCT04517851); MD Anderson Protocol #2020-0522.

• Safety and Tolerability Phase 1 Study of  INCB057643 (BET inhibitor), as a Monotherapy and in Combination with Ruxolitinib, in Participants with Myelofibrosis and other Advanced Myeloid Neoplasms (LIMBER trial, NCT04279847); MD Anderson Protocol #2021-1092.

• Phase 1/2 Study of  Zilurgisertib (formerly INCB000928; ACVR1 inhibitor) as a Monotherapy in Participants with Anemia due to Myeloproliferative Disorders (NCT04455841); MD Anderson Protocol #2020-0409.

• Phase 1b/2a Study of  DISC-0974 (monoclonal atibody against hemojuvelin, positive regulator of hepcidin) in Participants with Myelofibrosis and Anemia (NCT05320198); MD Anderson protocol #2022-0291. DISC-0974 can be administered alone, or added to a stable dose of a JAK inhibitor (other than momelotinib).

• Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of  TL-895 (potent, selective inhibitor of Bruton tyrosine kinase) Combined with Ruxolitinib in Myelofibrosis Patients with JAK Inhibitor-Naïve Patients and Patients Who Have Suboptimal Response to Ruxolitinib (NCT05280509); MD Anderson Protocol #2022-0183.

• Open-Label Phase 1/2 Study of  TP-3654, an Orally-delivered PIM Kinase Inhibitor, in Patients with Primary or Secondary Myelofibrosis (NCT04176198); MD Anderson Protocol #2022-0955.

• Phase 1b, Open-label Study of  CK0804 as an "Add-on" Therapy in Participants with Myelofibrosis and Suboptimal Response to Ruxolitinib (LIMBER-TREG108; NCT05423691); MD Anderson Protocol #2021-0341.

• A first-in-human study of the safety, pharmacokinetics, and pharmacodynamics of  JNJ88549968, a T-cell redirecting bispecific antibody targeting CALR-mutated myelofibrosis (NCT06150157); MD Anderson Protocol #2023-1058.

• Phase 1 Study to evaluate INCA033989 (anti-mutant CALR monoclonal antibody) administered in patients with CALR-mutated myelofibrosis (NCT06034002); MD Anderson Protocol #2023-0647.

Polycythemia Vera and Essential Thrombocythemia

• Phase 2a, Randomized, Open-Label Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of  Sapablursen (formerly IONIS TMPRSS6-LRx, ISIS 702843) Administered to Patients with Phlebotomy-Dependent Polycythemia Vera (NCT05143957); MD Anderson Protocol #2021-0897.

• Phase 3 Study of the Hepcidin Mimetic Rusfertide (formerly PTG-300) in Patients with Phlebotomy-Requiring Polycythemia Vera (VERIFY trial; NCT05210790); MD Anderson Protocol #2022-0005.

• An Extension Phase 3 Study to Evaluate the Long-term Safety of Rusfertide (PTG-300) in Subjects with Polycythemia Vera (THRIVE trial; NCT06033586); MD Anderson Protocol #2023-0950.

• Randomized, Open-label, Multicenter Phase 3 Study to Assess the Efficacy and Safety of  Givinostat versus Hydroxyurea in JAK2 V617F-Positive High-risk Polycythemia Vera Patients (GIV-IN PV trial; NCT06093672); MD Anderson Protocol #2024-0092.

• Phase 3, Open-label, Multicenter, Randomized, Active-Controlled Study to Assess the Pharmacokinetics and Compare the Efficacy, Safety, and Tolerability of  Ropeginterferon alpha-2b (formerly P1101) versus Anagrelide as Second-Line Therapy for Essential Thrombocythemia (SURPASS ET trial; NCT04285086); MD Anderson Protocol #2020-0108.

• A First-in-Human Study of the Safety, Pharmacokinetics, and Pharmacodynamics of  JNJ88549968, a T-Cell Redirecting Bispecific Antibody Targeting CALR-Mutated Essential Thrombocythemia (NCT06150157); MD Anderson Protocol #2023-1058.

• Phase 1 Study to Evaluate INCA033989 (anti-mutant CALR monoclonal antibody) Administered in Patients with CALR-Mutated Essential Thrombocythemia (NCT06034002); MD Anderson Protocol #2023-0647.

Systemic Mastocytosis

• Phase 2 Study of  Bezuclastinib (formerly CGT9486) Safety and Efficacy in Patients with Indolent or Smoldering Systemic Mastocytosis (SUMMIT trial; NCT05186753); MD Anderson Protocol #2021-0880.

• Phase 2 Open-label Clinical Study of the Safety and Efficacy of  Bezuclastinib (formerly CGT9486) in Patients with Advanced Systemic Mastocytosis (APEX trial; NCT04996875); MD Anderson Protocol #2021-0587.

• A Randomized Double-Blind Placebo-Controlled Phase 2/3 Study of Elenestinib (formerly BLU-263) in Indolent Systemic Mastocytosis (HARBOR trial; NCT04910685); MD Anderson Protocol #2022-0072.

• Phase 2 Open-label, Multicenter Study of  TL-895 (potent, selective inhibitor of Bruton tyrosine kinase) in Patients with Symptomatic Indolent Systemic Mastocytosis (NCT04655118); MD Anderson Protocol #2020-0738.

For an overview of the MPN clinical trials and the medications, please read our recent Leukemia Insights newsletters at the web page MPN Awareness and Education.

Contact Information for MPN Clinical Trials

New Patient Referral Line: 1-85-LEUKEMIA/1-855-385-3642 (Toll-Free) or 713-563-2000

Leukemia Clinic Phone: 713-792-8760
Leukemia Department Phone: 713-792-7305
Clinic Fax: 713-792-6191
Department Fax: 713-794-4297

Business hours: Monday through Friday, 8 a.m. to 5 p.m.