Current MPN Research & Treatments

Clinical MPN Research & Treatments

Ruxolitinib (JAK1/2 inhibitor) has been a truly transformative medication for myelofibrosis (MF) and became the global standard of care. The pivotal clinical trials that the Clinical Research Center for MPNs at MD Anderson Cancer Center led globally resulted in regulatory approval of ruxolitinib as the frontline medication for MF in 2011 and the second line treatment for polycythemia vera (PV) in 2014.

Ruxolitinib was the first and sole medication that was approved for MF until 2019 when fedratinib (JAK2 inhibitor) was approved. There was a dearth of MF treatments prior to the clinical development of ruxolitinib, which dramatically improved the quality of life, reduced very large spleen and liver, and prolonged the survival of patients with MF. The retrospective analyses that we conducted and published in Cancer (2023), Cancer (2022) and Annals of Hematology (2021) demonstrated the marked improvement in the survival of patients with myelofibrosis since the clinical development and regulatory approval of ruxolitinib.

Currently, it is a very exciting time in research of myeloproliferative neoplasms (MPN) because an array of new medications are in advanced clinical development. For a comprehensive overview of novel MF medications in clinical development, please review our comprehensive articles in Clinical Lymphoma Myeloma & Leukemia, "SOHO State of the Art Updates and Next Questions: Novel Therapies in Development for Myelofibrosis" (2022) and "SOHO State of the Art Updates: Novel Therapeutic Strategies in Development for Myelofibrosis" (2023). Please review the figure (lower panel), depicting the cellular targets of novel MF medications in clinical development.

With the new MF agents in clinical development, we aim to enhance the therapeutic potential of ruxolitinib, improve deficiencies that have not been addressed with the approved treatments, or provide options for patients who develop resistance/intolerance to the approved JAK inhibitors.

The MPN Team is currently conducting registrational Phase 3 clinical trials to evaluate other promising novel MF medications, such as luspatercept, imetelstat, pelabresib, and navtemadlin; and medications to treat PV and essential thrombocythemia (ET), such as rusfertide and ropeginterferon alpha-2b, respectively.

• On September 15, 2023, momelotinib (inhibitor of JAK1/2 and ACVR1) 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 trial MOMENTUM (NCT04173494) and the data from a cohort of patients who participated in the phase 3 trial SIMPLIFY-1 (NCT01969838). 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.
• Momelotinib was evaluated in comparison to danazol in anemic and symptomatic MF patients who stopped responding to ruxolitinib (MOMENTUM trial). The registrational phase 3 MOMENTUM clinical trial was described in Future Medicine (Verstovsek S. et al., 2021). 
• The data from the pivotal phase 3 MOMENTUM trial demonstrated the superior clinical efficacy of momelotinib compared to danazol with respect to anemia measures, and spleen and symptom responses- three hallmarks of MF- in anemic and symptomatic MF patients. For the final results of the MOMENTUM trial and an updated analysis of the trial, please review our publications in the leading journals The Lancet (Verstovsek S. et al., 2023) and Lancet Haematology (Gerds AT, Verstovsek S. et al., 2023), respectively. 
• Please review the MD Anderson News Release on the clinical benefits that momelotinib elicited in anemic and symptomatic patients with MF who participated in the MOMENTUM clinical trial.
• In previous clinical trials, momelotinib consistently elicited high rates of red blood cell transfusion independence in MF patients who previously were transfusion-dependent. Recent publications on the clinical benefits of momelotinib, include the following: Verstovsek S. et al., Blood Advances 2023; Verstovsek S. et al., HemaSphere 2022; Verstovsek S. et al., Blood 2022; Gerds A. et al., Blood  2022; Mesa R. et al. Blood 2022. 
• We retrospectively analyzed momelotinib's marked anemia benefits, including achievement of red blood cell transfusion independence, in MF patients who were enrolled in the phase 3 SIMPLIFY-1 trial (NCT01969838) in our article "Momelotinib reduces transfusion requirements in patients with myelofibrosis" (Leukemia & Lymphoma, 2022). Another article that we co-authored (Leukemia, 2022) underscored the association of transfusion independence at 24 weeks with improved overall survival in JAK inhibitor-naïve patients treated with momelotinib.
• For a comprehensive review on momelotinib's mechanism of action regarding anemia (suppression of ACVR1-mediated hepcidin production) and the sustained anemia benefits (including red blood cell transfusion independence) that momelotinib elicited in MF patients in the pivotal phase 3 clinical trials, please view the graphical abstract below and read our review article, "Momelotinib: an emerging treatment for myelofibrosis patients with anemia" (Chifotides HT, Bose P, Verstovsek S. Journal of Hematology & Oncology, 2022). 
• "ASH 2022: Momelotinib long-term safety in myelofibrosis disease - Analysis of SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials"; Content shared with permission from Touch Medical Media.
  
• "Momelotinib as a potential treatment for myelofibrosis patients with anaemia – Findings from the MOMENTUM phase III clinical trial" posted at Touch Haematology.
• Prior to momelotinib's regulatory approval, Dr. Verstovsek presented the interview "Momelotinib may become No. #1 choice for second-line therapy in myelofibrosis."
• Pacritinib (JAK2, ACVR1, and IRAK1 inhibitor) received accelerated regulatory approval in February 2022 as a treatment for patients with intermediate or high-risk myelofibrosis and a low platelet count (severe thrombocytopenia, baseline platelet count below 50x10⁹/L). Until pacritinib received regulatory approval, there was a critical unmet medical need for patients with cytopenic myelofibrosis. Accelerated approval of pacritinib was based on the results of the randomized phase 3 clinical trial PERSIST-2 (NCT02055781), in which pacritinib was evaluated versus best available therapy in patients with primary or secondary MF and thrombocytopenia (platelet counts below 100x10⁹/L). The clinical benefits of pacritinib in the PERSIST-2 study were published in JAMA Oncology (2018). 
• Pacritinib is being further evaluated in comparison to physician's choice medications in another ongoing randomized phase 3 study (PACIFICA trial; NCT03165734) in patients with MF and severe thrombocytopenia (platelet counts below 50x10⁹/L). The results of the PACIFICA trial will further confirm the clinical benefits of pacritinib in MF patients who have severe thrombocytopenia. The design of the PACIFICA trial, evaluating pacritinib in MF patients who have severe thrombocytopenia, was detailed in Blood (2022).
• For retrospective analyses of the clinical benefits that pacritinib elicited in patients with myelofibrosis and severe thrombocytopenia in the PERSIST-1 and PERSIST-2 trials, please review our articles in Haematologica (2021) and Blood Advances (2020).
• Recently, the potent ACVR1 inhibitory activity of pacritinib was reported, leading to anemia benefits in MF patients (Blood Advances, 2023).

Other medications that we are investigating in randomized phase 3 clinical trials at MD Anderson for possible regulatory approval include the following:

• Pelabresib (formerly CPI-0610) is an inhibitor of bromodomain and extra-terminal (BET) proteins that appears to augment the efficacy of ruxolitinib in improving quality of life and splenomegaly. In the phase 2 MANIFEST trial (NCT02158858), pelabresib as a monotherapy or in combination with ruxolitinib demonstrated significant clinical benefits in patients with myelofibrosis (reduction of spleen volume, improvement of constitutional symptoms, bone marrow fibrosis, and anemia). Preliminary results of pelabresib in combination with ruxolitinib administered in MF patients who had suboptimal response to ruxolitinib in the MANIFEST trial (Arm 2) were published in Harrison C. et al., Blood (2022). The final results of treating  JAK inhibitor-naïve MF patients with pelabresib/ruxolitinib of the MANIFEST trial (Arm 3) were published in Mascarenhas J. et al. J. Clin. Oncol. (2023); the combination of pelabresib with ruxolitinib in JAK inhibitor-naïve patients with MF was well tolerated and elicited durable improvements in spleen volume and constitutional symptom burden as well as other biomarkers of the disease.
• The design of the registrational phase 3 MANIFEST-2 trial (NCT04603495), evaluating pelabresib in combination with ruxolitinib in comparison to ruxolitinib monotherapy, in patients with myelofibrosis in the frontline setting was published in Future Oncology (2022). The phase 3 MANIFEST-2 trial enrolled JAK inhibitor-naïve patients at MD Anderson Cancer Center (protocol #2020-0739).
• Luspatercept (ACVR ligand trap) is evaluated for anemia benefits and its potential to eliminate the necessity of red blood cell transfusions in MF patients who are receiving ruxolitinib (INDEPENDENCE trial; NCT04717414). The pivotal phase 3 INDEPENDENCE trial, evaluating luspatercept in MF patients who have anemia, is currently open at MD Anderson Cancer Center (protocol #2020-1010).
• Imetelstat (telomerase inhibitor) is a pioneering medication in treatment of MF because it appears to significantly prolong survival (by a factor of two) of MF patients after ruxolitinib who become resistant/refractory to ruxolitinib. Currently, the possible survival benefit of imetelstat in intermediate-2 and high-risk MF patients who are refractory to JAK inhibitors is being evaluated in a pivotal Phase 3 trial (IMpactMF;  NCT04576156) against best available therapy.  Survival benefit is an unprecedented primary endpoint in clinical trials for investigational MF medications. The design of the IMpactMF trial was reported in our article in Future Oncology (2022). The phase 3 IMpactMF clinical trial, evaluating imetelstat in MF patients who are refractory/resistant to JAK inhibitors, is currently open at MD Anderson Cancer Center (protocol #2020-1141).
• Navitoclax (Bcl-2/Bcl-xL inhibitor) is evaluated in combination with ruxolitinib in two Phase 3 trials in MF patients who relapsed or were refractory to ruxolitinib (TRANSFORM-2 trial; NCT04468984) and in the frontline setting (TRANSFORM-1 trial; NCT04472598). The results of the phase 2 study (NCT03222609) in which navitoclax was added to ruxolitinib in MF patients who progressed or had suboptimal response to ruxolitinib were reported in the Journal of Clinical Oncology (2022) and Lancet Haematology (2022).  In the phase 2 study, the addition of navitoclax to ruxolitinib resulted in reduction of splenomegaly; and improved constitutional symptoms, anemia and bone marrow fibrosis in MF patients who progressed or had suboptimal response to ruxolitinib monotherapy.
• Navtemadlin (formerly KRT-232) is a human double minute 2 (HDM2) inhibitor that has been evaluated in a few clinical trials for MF patients, for example, natemadlin in combination with ruxolitinb is being evaluated in the phase 1/2 clinical trial in MF patients with suboptimal response to ruxolitinib (NCT04485260); and navtemadlin as a monotherapy has been evaluated in the phase 3 trial BOREAS (NCT03662126) in MF patients who were refractory/resistant to JAK inhibitor treatment. Navtemadlin's biological mechanism of action, and the clinical concept and design of the BOREAS trial were reported in Future Medicine (2022).
• Ropeginterferon alpha-2b: novel long-acting interferon formulation (injected subcutaneously) that received FDA approval as a first-line treatment of patients with PV in the US, in November 2021. Ropeginterferon alpha-2b maintained the hematocrit below 45% and eliminated the need for phlebotomies (bloodletting) in the majority of patients with PV. Ropeginterferon alpha-2b also decreased the JAK2V617F mutation allele burden; in 5 years, the JAK2V617F allele burden was below 1% in nearly 20% of the patients who were treated with ropeginterferon alpha-2b in the phase 3 PROUD-PV trial and its extension study CONTINUATION-PV. Maintaining hematocrit levels below 45% decreases the risk of thrombosis. Besides managing symptoms and short-term complications, ropeginterferon alpha-2b may help reduce the risk of disease progression to MF and acute myeloid leukemia over time. 
• Ropeginterferon alpha-2b is currently evaluated against anagrelide in patients who have essential thrombocythemia (ET) and are resistant or intolerant to hydroxyurea (SURPASS ET trial; NCT04285086). The phase 3 SURPASS ET clinical trial evaluating ropeginterferon alpha-2b in ET patients is currently open at MD Anderson Cancer Center (protocol #2020-0108).
• Rusfertide (formerly PTG-300) is a hepcidin-mimetic (hepcidin is secreted by the liver and regulates iron metabolism) that maintained the hematocrit below 45% and eliminated 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 (when added to the ongoing PV treatment) compared to placebo is currently evaluated in PV patients who need frequent phlebotomies (with or without concurrent cytoreductive therapy) to maintain the hematocrit below 45% in a randomized phase 3 clinical trial (VERIFY study; NCT05210790) at MD Anderson Cancer Center (protocol #2022-0005). The design of the registrational phase 3 clinical trial VERIFY on rusfertide in PV patients was published in Verstovsek S. et al., Blood 2022.

Myeloid/Lymphoid Neoplasms (MLN) with rearrangement of FGFR1

On August 26, 2022, the FDA approved pemigatinib as a treatment for relapsed or refractory myeloid/lymphoid neoplasms (MLN) with rearrangement of the gene Fibroblast Growth Factor Receptor 1 (FGFR1) or MLN^FGFR1. MLN^FGFR1 is a rare yet aggressive hematological malignancy involving myeloid (like myeloproliferative neoplasms) and/or lymphoid proliferation, marked eosinophilia (abnormal counts of eosinophils, a type of disease-fighting white blood cells) in many cases, and activation of the gene FGFR1. In MLN^FGFR1, abnormal cell growth can involve the myeloid type of cells (for example, neutrophils, myelocytes, blasts) resulting in a myeloproliferative neoplasm (MPN) or acute myeloid leukemia. In other cases, it may involve the lymphoid type of cells (for example, lymphocytes, lymphoblasts) resultingin acute lymphoblastic leukemia or lymphoma. A number of patients have a mixture of both types of cells. MLN^FGFR1 is suspected when analysis of chromosomes (karyotype or cytogenetic testing) in cells obtained from the bone marrow shows chromosomal translocation (abnormality) involving the gene FGFR1 in chromosome 8 (specifically at the 8p11 locus). Abnormality in the FGFR1 gene, which is a hallmark of the disease, is detected by a sensitive method named fluorescence in situ hybridization (FISH) and supports diagnosis of MLN^FGFR1 (please review our publications Verstovsek S. et al., Ann. Oncol. 2018; Strati P. et al., Leuk. Lymphoma 2018).  MLN^FGFR1 had very poor prognosis even after chemotherapy and allogeneic stem cell transplant, and effective treatments were lacking until pemigatinib was approved.

Pemigatinib is a highly selective inhibitor of the protein tyrosine kinase FGFR1, which is produced at abnormal levels in MLN^FGFR1 and drives the disease. Pemigatinib demonstrated high rates of complete responses and complete cytogenetic responses (nearly 80%) in the multicenter, open-label phase 2 FIGHT-203 clinical trial (NCT03011372), which were conducted at the Clinical Research Center for MPNs and supported regulatory approval of the medication (Verstovsek S. et al., Blood 2018; Gotlib J. et al., Blood 2021; Verstovsek S. et al., Blood 2022). Regulatory approval of pemigatinib is a major advancement with transformative impact for patients diagnosed with MLN^FGFR1 because this neoplasm is treatable and even curable at present given the discovery and approval of pemigatinib.

Momelotinib's mechanism of action: Momelotinib supresses hepcidin expression in the liver through its activity on the hepcidin (master regulator of iron metabolism)-ferroportin axis, leading to restoration of iron homeostasis and stimulation of erythropoiesis, and thus, marked anemia benefits (including red blood cell transfusion independence) in MF patients who have anemia. On September 15, 2023, momelotinib received regulatory approval as a treatment for MF patients who have anemia, a hallmark of MF. Graphical abstract was published with our article, Chifotides HT, Bose P, Verstovsek S. Momelotinib: An emerging treatment for myelofibrosis patients with anemia. Journal of Hematology & Oncology 2022;15(1):7.