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 Dr. Verstovsek led globally resulted in regulatory approval of ruxolitinib as the frontline medication for myelofibrosis (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 (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.
Presently, 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 article in Clinical Lymphoma Myeloma & Leukemia (2022), "SOHO State of the Art Updates and Next Questions: Novel therapies in development for myelofibrosis." Please review the figure depicting the cellular targets of novel MF medications in clinical development in the panel below.
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 (for example, anemia), or provide options for patients who develop resistance/intolerance to the approved JAK inhibitors.
Professor Verstovsek and the MPN Team are currently leading registrational Phase 3 clinical trials evaluating very promising MF medications, including the JAK inhibitors momelotinib and pacritinib, and medications to treat PV and essential thrombocythemia (ET), such as rusfertide and ropeginterferon alpha-2b, respectively.
- Momelotinib (JAK1/2 and ACVR1 inhibitor) is currently being evaluated (in comparison to danazol) in MF patients who stopped responding to ruxolitinib and suffer from anemia (pivotal Phase 3 MOMENTUM trial; NCT04173494). The registrational MOMENTUM clinical trial is described in our article that was published in Future Medicine (Verstovsek S. et al., 2021).
Interim analyses of the MOMENTUM trial data of anemic and symptomatic MF patients demonstrated the superiority of momelotinib compared to danazol with respect to red blood cell transfusion requirements, as well as spleen and symptom responses were reported in our recent publications Verstovsek S. et al., HemaSphere, 2022; Verstovsek S. et al., Blood, 2022; Gerds A. et al., Blood, 2022; and Mesa R. et al. Blood 2022.
In previous clinical trials, momelotinib consistently elicited high rates of red blood cell transfusion independence in MF patients who previously were transfusion-dependent. 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 unique mechanism of action regarding anemia (suppression of ACVR1-mediated hepcidin production) and the sustained anemia benefits that momelotinib elicited in MF patients in previous clinical trials, please read our review article "Momelotinib: an emerging treatment for myelofibrosis patients with anemia" (Chifotides HT, Bose P, Verstovsek S. Journal of Hematology & Oncology, 2022).
- Momelotinib may receive regulatory approval in the near future as a medication to treat MF patients who have anemia. Currently, there is a critical unmet need for patients who have myelofibrosis and anemia (the majority of patients).
- Pacritinib (JAK2 and IRAK1 inhibitor) received accelerated approval from the Food and Drug Administration (FDA), 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). There has been 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 count below 100x109/L). The clinical benefits of pacritinib in the PERSIST-2 study, which Dr. Verstovsek co-led, were published in JAMA Oncology (2018).
- Pacritinib is 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 count below 50x10^9/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).
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, pelabresib as a monotherapy in the second-line setting or pelabresib in combination with ruxolitinib in the frontline setting demonstrated significant clinical benefits in patients with myelofibrosis (reduction of spleen volume, improvement of constitutional symptoms and anemia). Preliminary results of the MANIFEST trial were published in Blood (2022).
- 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, evaluating pelabresib in combination with ruxolitinib in MF patients who were not previously treated with JAK inhibitors, is currently open 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 currrently 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 is evaluated in advanced phase studies, including the pivotal phase 3 trial BOREAS (NCT03662126), in MF patients who have suboptimal response or failed JAK inhibitor treatment. The phase 3 BOREAS clinical trial is currently open at MD Anderson Cancer Center (protocol #2018-0906). Navtemdalin's biological mechanism of action, and the clinical concept and design of the BOREAS trial, evaluating navtemadlin in MF patients, were reported in our article in Future Medicine (2022).
- Ropeginterferon alpha-2b (Besremi): 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 require 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 MLNFGFR1. MLNFGFR1 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 MLNFGFR1, 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. MLNFGFR1 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 MLNFGFR1 (please review our publications Verstovsek S. et al., Ann. Oncol. 2018; Strati P. et al., Leuk. Lymphoma 2018). MLNFGFR1 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 MLNFGFR1 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 Dr. Verstovsek led and supported regulatory approval of the medication (please review our publications 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 MLNFGFR1 because this neoplasm is treatable and even curable at present given the discovery and approval of pemigatinib.
Professor Verstovsek presented 19 educational videos for patients on Myeloproliferative Neoplasms (myelofibrosis, polycythemia vera and essential thrombocythemia)
Professor Verstovsek presented the comprehensive educational podcast "A Deep Dive into Myelofibrosis"
Professor Verstovsek presented a few educational interviews for patients/caregivers on novel MPN treatments in development at "The Patient Story":
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!
Srdan Verstovsek, MD, PhD, Professor of Medicine; Director of the Hanns A. Pielenz Clinical Research Center for MPNs
Cellular Targets of Novel Medications in Clinical Development for Myelofibrosis
For example, targets include epigenetic regulators, apoptotic and intracellular signaling/proliferation pathways, telomerase, immunogenic antigens, microenvironment of the bone marrow, and others. Figure from our publication. Chifotides HT, Bose P, Masarova L, Pemmaraju N, Verstovsek S. SOHO State of the Art Updates and Next Questions: Novel Therapies in Development for Myelofibrosis. Clinical Lymphoma Myeloma & Leukemia 2022;22(4):210-223 . Copyright: The University of Texas MD Anderson Cancer Center and Elsevier, 2021.
Basic/Translational MPN Research
Dr. Verstovsek’s laboratory houses a large number of bone marrow and blood specimens, collected from patients with MPNs. These specimans are cataloged in a database that includes information on patient demographics, disease stage and characteristics, responses to treatment, time to progression and other valuable clinical information (e.g., blood counts).
During the past several years, our basic/translational MPN Research Team, currently comprising Professor Zeev Estrov, MD; Professor Srdan Verstovsek, MD, PhD; Taghi Mashouri, PhD, Laboratory Manager; Ivo Veletic, MD, Instructor; and Ying Zhang, MD, Senior Research Scientist, made several notable discoveries in the laboratory. Our findings in basic MPN research are highlighted below and the relevant figures are depicted.
Our basic MPN research studies aim to shed light on how and why MPNs develop. Understanding, at the cellular and molecular levels, how MPNs develop is the key to developing effective and potentially curative therapies. Elucidating the biological mechanism of cancer often takes years of research. However, without understanding the fundamental mechanism by which MPNs develop, we cannot effectively treat or prevent MPNs, and ultimately cure them.
Activation of Pro-fibrotic Pathways in Myelofibrosis
Figure: Model of glioma-associated oncogene-1 (GLI1) signaling cascade in myelofibrosis (MF) fibrocytes. Constitutively activated STAT3 (1) induces expression of GLI1 (2), which in turn transcriptionally activates matrix metalloproteases 2 and 9 (3). These proteins, likely by activating TGF-β (4), induce downstream pro-fibrotic pathways (5), and inhibit apoptotic cell death (6) in MF fibrocytes. Copyright: The University of Texas MD Anderson Cancer Center and Springer Nature.
In our recent study, we demonstrated for the first time that GLI1 is overwhelmingly expressed in fibrocytes of MF patients and that JAK2-activated STAT3 induces expression of the GLI1 gene in MF cells. Our study also showed that GLI1 activates pro-fibrotic signaling pathways in MF fibrocytes and provides neoplastic fibrocytes with a survival advantage. Therefore, the data presented in our study provide a rationale for targeting GLI1 in future clinical trials.
Deciphering the Cause of Bone Marrow Fibrosis
Our clinical research is characterized by a high degree of integration with basic/translational research. A main focus of our research in the laboratory is to understand what causes bone marrow fibrosis, which ultimately leads to failure of the bone marrow to produce blood cells and severe anemia.
In the past few years, we made important strides in understanding the mechanism of bone marrow fibrosis (scarring), which is the hallmark of myelofibrosis. We demonstrated that bone marrow fibrosis in primary myelofibrosis is induced by blood cells named monocytes, which are the precursors of fibrocytes (spindle-shaped cells in the bone marrow).
Our MPN Team showed that neoplastic monocyte-derived fibrocytes play a pivotal role in bone marrow fibrosis and in promotion of osteosclerosis (bone hardening) in myelofibrosis patients. The bone marrow of myelofibrosis patients is rich in neoplastic fibrocytes, which contribute to induction of bone marrow fibrosis by producing collagen and fibronectin proteins. Furthermore, osteosclerosis (bone hardening) appears to also be a consequence of the abnormal activity of cells called osteoclasts; they exhibit impaired activity compared to normal osteoclasts, which results in osteosclerosis. Due to its importance, our study was published in the leading medical journal Blood in 2019 and was featured on the cover of the journal (cover depicted in photo. Authored by Veletic I, Manshouri T, Multani AS, Yin CC, Chen L, Verstovsek S, Estrov Z. Myelofibrosis osteoclasts are clonal and functionally impaired. Blood 2019;133(21):2320-2324.
Contrary to conventional belief, our studies established the clonal neoplastic nature of bone marrow fibrosis in myelofibrosis (fibrocytes harbor the JAK2 V617F driver mutation); these findings constitute important advancements in understanding the mechanism that causes myelofibrosis, and potentially reversing, and halting fibrotic transformation.