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 as 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 following studies that we conducted and published in J. Hematol. Oncol. (2017), Cancer (2023), Cancer (2022), Annals of Hematology (2021), and Cancer (2023) demonstrated the marked improvement in the survival of patients with MF who were treated with ruxolitinib.

• To date, 4 JAK inhibitors have received regulatory approval for the treatment of myelofibrosis in the US: ruxolitinib (November 2011), fedratinib (August 2019), pacritinib (February 2022), and momelotinib (September 2023).

• For a comprehensive overview of the four approved JAK inhibitors and how to select them as treatments for patients with MF, please read our recent article in Blood, titled, "How I individualize selection of  JAK inhibitors for patients with myelofibrosis" Masarova L., Chifotides HT., Blood 2024.

• With new agents in clinical development for MF, we aim to enhance the therapeutic potential of ruxolitinib, or provide options for patients who develop resistance/intolerance to the four approved JAK inhibitors. Please read our review titled, "Disease Modification in Myelofibrosis: An Elusive Goal?" (Vachhani P, Verstovsek S, Bose P. Journal of  Clinical Oncology, 2022) for insights about potential disease-modifying MF treatments and endpoints beyond the usual ones in MF clinical trials.

Currently, it is a very exciting time in the research of myeloproliferative neoplasms (MPN) because an array of new medications are in advanced clinical development. For an overview of novel MF medications in clinical development, please read our comprehensive review articles in Clinical Lymphoma Myeloma & Leukemia, "SOHO State of the Art Updates and Next Questions: Identifying and Treating 'Progression' in Myelofibrosis" (2021), "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). In the lower panel, the second figure depicts the targets of novel MF medications in clinical development.

• On September 15, 2023, momelotinib (inhibitor of JAK1, JAK2 and ACVR1/ALK2) 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 patients with MF and anemia, which is one of the hallmarks of the disease.
• For an expert review on the clinical efficacy of momelotinib, please read our recent Blood Spotlight titled, "Momelotinib for the treatment of myelofibrosis" Bose P., Blood 2024.

• Momelotinib was evaluated in comparison to danazol in anemic and symptomatic patients with MF who stopped responding to ruxolitinib in the registrational phase 3 clinical trial MOMENTUM, which 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 patients with MF. For the final results of the MOMENTUM trial and an updated analysis of the trial, please review our publications in the leading medical 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 patients with MF 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 with MF who were 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 patients with MF in the pivotal phase 3 clinical trials, please view the first 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 the 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/ALK2, and IRAK1 inhibitor) received accelerated regulatory approval on February 28, 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). 
• More recently, the significant anemia benefits that pacritinib conferred in patients with MF and thrombocytopenia in the phase 3 PERSIST-2 clinical trial-- arising from pacritinib's  potent ACVR1/ALK2 inhibition-- were demonstrated (Blood Advances, 2023).
• Pacritinib is being further evaluated in comparison to physician's choice medications in the ongoing randomized phase 3 study PACIFICA (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 patients with MF 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 thrombocytopenia in the PERSIST-1 and PERSIST-2 trials, please review our articles in Haematologica (2021) and Blood Advances (2020).

The MPN Team is currently conducting additional clinical trials to evaluate other promising medications as treatments for MF, PV and essential thrombocythemia (ET). MPN medications that we have been investigating in clinical trials at the MD Anderson Cancer Center include the following:

MYELOFIBROSIS

• Selinexor (selective nuclear export inhibitor) is being evaluated in a phase 1/3 study in combination with ruxolitinib in treatment-naïve patients with myelofibrosis (SENTRY trial; NCT04562389).
  
• Navtemadlin (formerly KRT-232) is a human double minute 2 (HDM2) inhibitor that has been evaluated in a few clinical trials for MF patients. Currently, navtemadlin is being evaluated as an "add-on" to ruxolitinib in the novel phase 3 clinical trial POIESIS in JAK inhibitor-naïve patients with MF and suboptimal response to ruxolitinib (NCT06479135). Navtemadlin's biological mechanism of action was reported in Future Medicine (2022).
  
• 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 conducted at MD Anderson Cancer Center. The results of the phase 2 study that evaluated luspatercept in the treatment of anemia in patients with myelofibrosis (NCT03194542) were recently published in Blood Advances (2024).
• INCB057643 (inhibitor of bromodomain and extra-terminal [BET] proteins) is evaluated as a monotherapy and in combination with ruxolitinib in participants with MF (LIMBER trial, NCT04279847).  Pelabresib (formerly CPI-0610) is another BET inhibitor that appears to augment the efficacy of ruxolitinib regarding splenomegaly. The results from the phase 3 trial MANIFEST-2 demonstrated that SVR35 and TSS50 were achieved by 66% and 52% of the patients with myelofibrosis, respectively, at 24 weeks. In the comparator arm, SVR35 and TSS50 were achieved in 35% and 46% of the patients treated with ruxolitinib and placebo, respectively, at 24 weeks (Blood 2023).
• Imetelstat (telomerase inhibitor) is a pioneering medication in the treatment of MF because it appears to significantly prolong the survival of MF patients 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 against best available therapy in a pivotal Phase 3 trial (IMpactMF; NCT04576156). Survival benefit is an unprecedented primary endpoint in clinical trials for investigational MF medications.
• JNJ88549968 (T-cell redirecting bispecific antibody targeting CALR mutations) is being evaluated in a first-in-human study regarding safety, pharmacokinetics, and pharmacodynamics in patients with CALR-mutated myelofibrosis (NCT06150157).
• INCA033989 (anti-mutant monoclonal antibody targeting CALR mutations) is being evaluated in a phase 1 trial in patients with CALR-mutated myelofibrosis (NCT06034002).

POLYCYTHEMIA VERA AND ESSENTIAL THROMBOCYTHEMIA

• Our recent review on novel therapies in polycythemia vera: Masarova L, Chifotides HT. Clin. Lymphoma Myeloma Leuk. 2023.
• 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 versus 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 enrolling patients at MD Anderson Cancer Center (protocol #2020-0108).
• Rusfertide (formerly PTG-300) mimics hepcidin, a natural hormone-peptide that is secreted by the liver and regulates iron metabolism, and therefore, hemoglobin levels. In the phase 2 clinical trial REVIVE (NCT04057040) in PV patients who required phlebotomies, rusfertide maintained the hematocrit below 45%, eliminated the need for phlebotomies, and improved disease-related symptoms in the vast majority of patients. Phlebotomy is a procedure that removes blood from the patient in order to lower the hematocrit. Elimination of the need for phlebotomies decreases the risk of thromboembolic events and improves iron deficiency. The results of the REVIVE study were published in the leading, prestigious journal New England Journal of Medicine.
• The efficacy of rusfertide (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) and an extension phase 3 clinical trial (THRIVE study; NCT06033586) at the MD Anderson Cancer Center. The design of the registrational phase 3 clinical trial VERIFY on rusfertide in PV patients was published in Verstovsek S. et al., Blood 2022.
• JNJ88549968 (T-cell redirecting bispecific antibody targeting CALR mutations) is being evaluated in a first-in-human study regarding safety, pharmacokinetics, and pharmacodynamics in patients with CALR-mutated essential thrombocythemia (NCT06150157).

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) resulting in 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.