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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 led by the Clinical Research Center for MPNs at MD Anderson 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 the treatment of 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 , , ,  and  demonstrated the marked improvement in the survival of patients with MF who were treated with ruxolitinib.
• To date, four JAK inhibitors have received regulatory approval for the treatment of myelofibrosis in the United States: 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 from the "How I Treat" Series in the journal Blood, titled,
• With several 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 JAK inhibitors or have a suboptimal response to ruxolitinib. Please read our review titled, for insights about potential disease-modifying MF treatments and endpoints beyond the usual ones used 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 clinical development. For an overview of novel MF medications in clinical development, please read our comprehensive review articles in Clinical Lymphoma Myeloma & Leukemia,  (2021),  (2022) and (2023), and . In the lower panel, Figure 2 depicts the targets of novel MF medications that currently are 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 MF and anemia based on the data acquired in the pivotal Phase III trial MOMENTUM (NCT04173494) and the data from a cohort of patients who participated in the Phase III 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 was evaluated in comparison to danazol in anemic and symptomatic patients with MF who stopped responding to ruxolitinib in the registrational Phase III clinical trial MOMENTUM. 
• The data from the pivotal Phase III 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  and , 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. Publications on the clinical benefits of momelotinib include the following: ; ; ; ; . 
• 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 III SIMPLIFY-1 trial (NCT01969838) in our article "Momelotinib reduces transfusion requirements in patients with myelofibrosis" (). Another article that we co-authored () underscored the association of transfusion independence at 24 weeks with improved overall survival in JAK inhibitor-na?ve 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 III clinical trials, please view the first graphical abstract below (Figure 1) and read our review article,  
• Prior to momelotinib's regulatory approval, Dr. Verstovsek presented the interview 
• Pacritinib (JAK2, ACVR1/ALK2, and IRAK1 inhibitor) received regulatory approval as a treatment for patients with myelofibrosis and a low platelet count (severe thrombocytopenia, baseline platelet count below 50x10⁹/L) on February 28, 2022. 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 III clinical trial PERSIST-2 (NCT02055781); in this study, pacritinib was evaluated versus best available therapy in patients with primary or secondary MF and thrombocytopenia (platelet counts below 100x10⁹/L).  
• The significant anemia benefits that pacritinib conferred in patients with MF and thrombocytopenia in the Phase III PERSIST-2 clinical trial ¡ª arising from pacritinib's potent ACVR1/ALK2 inhibition ¡ª were demonstrated .
• Pacritinib is being further evaluated in comparison to physician's choice medications in the ongoing randomized Phase III 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 .
• 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  and .
• For a comprehensive review on conventional agents and novel therapeutic strategies to treat anemia in MF, please read our article, . 

At MD Anderson, our expert MPN Physicians are currently conducting additional clinical trials to evaluate other novel, promising medications as treatments for MF (please see Figure 2), PV and essential thrombocythemia (ET) at MD Anderson, including the following:

MYELOFIBROSIS

• Selinexor (selective nuclear export inhibitor) is being evaluated in a Phase II study in JAK inhibitor-na?ve patients with myelofibrosis and moderate thrombocytopenia (SENTRY-2 trial; NCT05980806). Initially, patients receive selinexor monotherapy and have the option to add ruxolitinib, momelotinib or pacritinib (depending on the blood counts) to selinexor after 12 or 24 weeks, if the spleen volume reduction is insufficient with selinexor monotherapy. 
• Selinexor in combination with ruxolitinib is also being evaluated in JAK inhibitor-na?ve patients (versus placebo plus ruxolitinib) in the randomized, double-blind Phase III part of the SENTRY trial (NCT04562389). The results from the Phase I part of the SENTRY trial (in 14 JAK-inhibitor na?ve patients) demonstrated that selinexor (60 mg once weekly) in combination with ruxolitinib elicited a 35% or greater reduction in spleen volume (SVR35) in 79% of patients and symptom improvement of at least 50% (TSS50) in 58% of patients at Week 24. The design of the Phase III part of the clinical trial was published in . The promising results from the Phase I part of the SENTRY trial were recently published in .
• Navtemadlin is a human double minute 2 (HDM2) inhibitor that is currently being evaluated as an "add-on" to a stable dose of ruxolitinib in the registrational Phase III clinical trial POIESIS (P53 activation to OptImize responseS in myelofibrosIS) in JAK inhibitor-na?ve patients with MF who have a suboptimal response to ruxolitinib after 18-24 weeks of ruxolitinib monotherapy (NCT06479135). The unique and novel design of the POIESIS trial was recently published in . Navtemadlin's biological mechanism of action was reported in .
  In a Phase II clinical trial (NCT04485260), navtemadlin added to a stable dose of ruxolitinib in suboptimal responders to monotherapy elicited SVR35 and TSS50 rates of 32% (for each) at Week 24. Navtemadlin also demonstrated disease-modifying activity that correlated with the clinical responses in the randomized phase III clinical trial BOREAS in patients with JAK-inhibitor relapsed/refractory MF (NCT03662126); the study was published in .
• Luspatercept (activin receptor type IIB 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^TM trial; NCT04717414). The pivotal Phase III trial INDEPENDENCE^TM evaluated luspatercept in MF patients who were concomitantly treated with a stable dose of a JAK2 inhibitor and required red blood cell transfusions. The results of the Phase II study, which evaluated luspatercept in the treatment of anemia in patients with myelofibrosis (NCT03194542), were recently published in .
• Luspatercept in combination with momelotinib is being studied in MF patients who are transfusion-dependent (or patients with hemoglobin <8 g/dl) in the Phase II clinical trial ODYSSEY (NCT06517875). The preliminary results of the ODYSSEY trial were published in .
• Pelabresib is an inhibitor of bromodomain and extra-terminal (BET) proteins that was studied in combination with ruxolitinib in the randomized Phase III trial MANIFEST-2 (NCT04603495) in JAK-inhibitor na?ve patients with myelofibrosis. This clinical trial demonstrated that SVR35 and TSS50 were achieved by 65.9% and 52.3% of JAK inhibitor-na?ve patients with MF, respectively, in the Arm treated with pelabresib combined with ruxolitinib, at 24 weeks. In the comparator Arm (placebo plus ruxolitinib), SVR35 and TSS50 were achieved in 35.2% and 46.3% of the patients treated with ruxolitinib and placebo, respectively, at 24 weeks. These results of the phase 3 clinical trial MANIFEST-2 at week 24 were published in . The durable efficacy results of pelabresib in combination with ruxolitinib in JAK-inhibitor na?ve patients with myelofibrosis at 96 weeks in the clinical trial MANIFEST-2 were published in .
• Nuvisertib is a selective inhibitor of PIM1 kinase that is being studied in a multi-arm Phase I/II study (NCT04176198). The ¡°add-on¡± arm of this trial is evaluating the addition of nuvisertib to a stable dose of ruxolitinib in patients who had a suboptimal response to nuvisertib monotherapy. The trial also has two other arms: monotherapy with nuvisertib and the combination of nuvisertib with momelotinib in anemic patients with MF who had previously received a JAK inhibitor (other than momelotinib). In this study, patients with baseline platelet counts as low as 25 x 10⁹/L can be enrolled. The preliminary results from the Phase I/II study of nuvisertib in combination with momelotinib in patients with relapsed/refractory MF were published in .
• DISC-0974 is a first-in-class anti-hemojuvelin antibody that is currently being studied in a Phase II study in patients with MF and anemia (RALLY-MF; NCT05320198). In the Phase I part of the study, DISC-0974 showed anemia responses in both transfusion-dependent and non-transfusion-dependent patients (both as a single agent and in combination with stable-dose JAK inhibitor treatment).
• Elritercept is a modified ActRIIA ligand trap that promotes erythropoiesis and is currently under investigation in patients with MF and anemia. Updated results from the ongoing Phase II RESTORE trial (NCT05037760) evaluating elritercept in patients with MF and anemia were reported in .
• 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 III trial (IMpactMF; NCT04576156). Survival benefit is an unprecedented primary endpoint in clinical trials for investigational MF medications. Imetelstat is also being studied in combination with ruxolitinib in an open-label, single-arm Phase I/IB study (IMproveMF; NCT05371964) in patients with intermediate-1, intermediate-2, or high-risk MF.
• AJ1-11095 (first-in-class, orally bioavailable small molecule type II JAK2 inhibitor) is being evaluated in a Phase I clinical trial in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis who failed a type I JAK2 inhibitor (NCT06343805).
• INCA033989 (anti-mutant monoclonal antibody targeting CALR  mutations) is being evaluated in a Phase I clinical trial in patients with CALR-mutated myelofibrosis  (NCT06034002). The latest results regarding the efficacy and safety of INCA033989, as monotherapy or in combination with ruxolitinib, in patients with CALR-mutated myelofibrosis were published in .
• JNJ-88549968 (bispecific antibody targeting CALR mutations) is being evaluated in a first-in-human study regarding safety, pharmacokinetics, and pharmaco-dynamics in patients with CALR-mutated myelofibrosis (NCT06150157).
• INCB160058 (JAK2 V617F-mutant specific agent) is being evaluated in a novel Phase I clinical trial in participants with myeloproliferative neoplasms harboring the JAK2 V617F mutation (NCT06313593).

POLYCYTHEMIA VERA

• For comprehensive overviews on polycythemia vera and novel treatments, please read our article , together with the , and our article .
• 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 III 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. The results of the randomized Phase IIIb clinical trial ECLIPSE-PV, assessing two dosing regimens of ropeginterferon alpha-2b in PV patients, were published in .
• 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 II 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 to lower the hematocrit. Elimination of the need for phlebotomies decreases the risk of thromboembolic events and improves iron deficiency and the quality of life. The results of the REVIVE study were published in .
• 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 the registrational, randomized Phase III clinical trial VERIFY (NCT05210790) and an extension Phase III clinical trial THRIVE (NCT06033586) at MD Anderson. The results of the randomized Phase III study VERIFY on rusfertide for the treatment of PV were recently published in . On August 25, 2025, the FDA granted breakthrough therapy designation to rusfertide for treating erythrocytosis in PV, based on the results of the Phase III study VERIFY. The efficacy and safety results of rusfertide plus the standard of care through week 52 in patients with PV who enrolled in the VERIFY study were published in . In the VERIFY trial, rusfertide met the primary and all four key secondary endpoints.
• Sapablursen (formerly IONIS-TMPRSS6) is a liver-targeted, anti-sense oligonucleotide against TMPRSS6, a negative regulator of hepcidin, which is a hormone that is produced in the liver. Sapablursen increases hepcidin levels, which in turn limit the amount of available iron and thereby, the excessive production of red blood cells. Sapablursen is given subcutaneously once every 4 weeks. The phase 2 IMPRSSION trial (NCT05143957) is studying sapablursen, alone or in combination with standard cytoreductive therapy, in phlebotomy-dependent patients with PV. The results of sapablursen in patients with PV who were enrolled in the IMPRSSION trial were published in .
• Givinostat (histone deacetylase inhibitor) is being studied in the Phase III clinical trial GIV-IN PV (NCT06093672) in PV patients at MD Anderson. For a comprehensive review on givinostat in PV, please read our article that was published in 2020, ".

ESSENTIAL THROMBOCYTHEMIA

• Ropeginterferon alpha-2b is currently being evaluated versus anagrelide in patients who have essential thrombocythemia (ET) and are resistant or intolerant to hydroxyurea (SURPASS ET trial; NCT04285086). The randomized Phase III clinical trial SURPASS ET evaluated ropeginterferon alpha-2b versus anagrelide in patients with high-risk, hydroxyurea-resistant or hydroxyurea-intolerant ET and white blood cell counts greater than 10x10⁹/L. In the SURPASS ET study, ropeginterferon alpha-2b showed superior efficacy versus anagrelide; the results of the SURPASS ET study were recently published in .
• Bomedemstat (inhibitor of lysine demethylase-1) is being evaluated versus hydroxyurea in cytoreductive therapy-na?ve patients with ET in a Phase III clinical trial (NCT06456346) at MD Anderson.
  
• INCA033989 (monoclonal antibody directed against mutant CALR) is being evaluated in a first-in-human Phase I study in previously treated patients with CALR-mutated ET (NCT05936359) and is showing promising single agent activity. Rapid and durable reduction in platelet counts was noted, and the majority of patients achieved a complete hematologic response and a reduction in the mutant CALR variant allele frequency (). The latest results regarding the efficacy and safety of INCA033989 in patients with CALR-mutated ET were published in .
• JNJ-88549968 (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 ET (NCT06150157) at MD Anderson.

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 ; ). 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 overall complete response (overall rate 74%; the rate was 96% in the chronic phase and 44% in the blast phase) and complete cytogenetic response (overall rate 73%; the rate was 88% in the chronic phase and 50% in the blast phase) in the multicenter, open-label Phase II FIGHT-203 clinical trial (NCT03011372), which enrolled patients at the Clinical Research Center for MPNs. The median duration of complete response was not reached (27.9 months to not reached) , and . The phase II FIGHT-203 trial supported the regulatory approval of the medication. The regulatory approval of pemigatinib was 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.