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 Hanns Pielenz Center for MPNs is world-renowned for developing novel MPN medications, such as the JAK1/2 inhibitor ruxolitinib, 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 MF patients 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 in prolonging survival of MF patients versus control. These findings were confirmed by recent analyses of retrospective and real-world data (for example, the ERNEST study and others that were conducted at MD Anderson Cancer Center, Verstovsek S. et al., Annals Hematol. 2022; and 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 oral JAK2 inhibitor, may be considered as a good treatment option in second line patients with MF, for example. Fedratinib reduces spleen size and improves symptoms, similar to ruxolitinib but has a different toxicity profile requiring a more attentative approach then ruxolitinib.
Pacritinib (JAK2/IRAK1 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 they 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.
Anemia in Myelofibrosis and JAK Inhibitors
Presently, there is a significant unmet need for anemic MF patients who lack approved efficacious treatments for anemia and red blood cell transfusion dependence. Anemia and especially requiring 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 a unique JAK1/2 inhibitor because it also inhibits production 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. The Federal Drug Administration accepted a new drug application for momelotinib as a treatment for MF in August 2022. Momelotinib is evaluated in the pivotal phase 3 MOMENTUM trial (NCT04173494) and will likely receive regulatory approval in 2023 as a treatment for MF patients with anemia in the second line setting. Regulatory approval of momelotinib will be a major advancement in the treatment of anemic patients with MF. Dr. Verstovsek recently presented an interview titled, "Momelotinib may become No. #1 choice for second-line therapy in myelofibrosis".
The data from the 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.
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.
Based on the phase 3 clinical trials that have been conducted until the present, momelotinib is poised to improve the quality of life by significant anemia benefits (including red blood cell transfusion-independence) besides improving splenomegaly and constitutional symptoms. Please review our web page titled "Current MPN Research and Treatments" for an overview of momelotinib’s clinical efficacy in phase 3 clinical trials and other novel MPN medications in advanced clinical development.
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 MF patients, including ruxolitinib-treated, transfusion-dependent individuals. Currently, luspatercept is being evaluated in the pivotal phase 3 trial INDEPENDENCE (NCT04717414) and may also be approved as a treatment for MF patients with anemia (in combination with ruxolitinib) in the near future. The INDEPENDENCE trial, evaluating luspatercept in MF patients who have anemia, is currently open at MD Anderson Cancer Center (protocol #2020-1010).
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 US 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 titled “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 Clinical Trials at the Clinical Research Center for MPNs
- 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.
- An Open-label, Phase 2a/2b Study of Navtemadlin (formerly KRT-232) in Patients with Primary Myelofibrosis (MF), Post-PV MF or Post-ET MF Who Have Failed prior Treatment with a JAK Inhibitor (BOREAS trial, NCT03662126); MD Anderson Protocol #2018-0906.
- An Open-label, Phase 2a Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GB2064 (LOXL2 Inhibitor) in Participants with Myelofibrosis (NCT04679870); MD Anderson Protocol #2020-1217.
- Phase 2 Open-label, Multicenter Study of TL-895 (second generation 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.
- An Open-label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of Navtemadlin (formerly KRT-232) Combined with Ruxolitinib in Patients with PMF, Post-PV MF, or Post-ET MF Who Have a Suboptimal Response to Ruxolitinib (NCT04485260); MD Anderson Protocol #2020-0279.
- Phase 2b, Open-label, Randomized Study to Assess the Efficacy and Safety of Ilginatinib (formerly NS-018) versus Best Available Therapy (BAT) in Patients with Primary Myelofibrosis (MF), Post-PV MF, or Post-ET MF and Severe Thrombocytopenia (NCT04854096); MD Anderson Protocol #2021-0348.
- Phase 1 Study of Elotuzumab (anti-SLAM7 monoclonal antibody) in the Treatment of JAK2V617F-Mutated Primary Myelofibrosis (MF), Post-PV MF, or Post-ET MF (NCT04517851); MD Anderson Protocol #2020-0522.
- Phase 1, Open-label Study of INCB057643 (BET inhibitor) in Participants with Myelofibrosis and Other Advanced Myeloid Neoplasms (Accelerated MPN); 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 Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of TL-895 (second generation 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.
- 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.
- Phase 1/2a Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 (pan-LOX inhibitor) in Patients with Primary MF, Post-PV MF or Post-ET MF (NCT04676529); MD Anderson Protocol #2021-0753.
Polycythemia Vera and Essential Thrombocythemia
- 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.
- Phase 2 Study to Evaluate Sapablursen (formerly IONIS TMPRSS6-LRx, ISIS 702843) in Patients with Polycythemia Vera (NCT05143957); MD Anderson Protocol #2021-0897.
- 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.
- 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.
For an overview of the MPN clinical trials and the medications, please read our recent MPN Focus newsletters at the web page MPN Awareness and Education.
Contact Information for MPN Clinical Trials
Srdan Verstovsek, M.D., Ph.D., Professor of Medicine, Chief of Section for MPNs
Director of the Hanns A. Pielenz Clinical Research Center for MPNs
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: 8 a.m.-5 p.m., Monday-Friday
It is a very exciting time in the field of MPNs in light of the recent approvals of two MPN medications and the array of other medications in advanced clinical development. We are very optimistic that these novel treatment options will substantially improve the quality of life and the outcomes of MPN patients and transform the field of MPNs in the near future!
Srdan Verstovsek, M.D., Ph.D.
Professor of Medicine; Director of the Hanns A. Pielenz Clinical Research Center for MPNs