Presentation: Classic Myeloproliferative Neoplasms
Management of Myelofibrosis; Professor Srdan Verstovsek, M.D., Ph.D.
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.
Other medications that we are investigating in randomized phase 3 clinical trials at MD Anderson for possible regulatory approval include the following:
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 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 MLNFGFR1 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.
Educational videos for patients on Myeloproliferative Neoplasms (myelofibrosis, polycythemia vera and essential thrombocythemia)
Comprehensive educational podcast "A Deep Dive into Myelofibrosis"
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 three MPN medications and the array of other medications in advanced clinical development!
Clinical Research Center for MPN Team
Cellular Targets of Novel Medications in Clinical Development for Myelofibrosis
For example, medication targets include epigenetic regulators, apoptotic and intracellular signaling/proliferation pathways, telomerase, immunogenic antigens, the 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.
Our MPN laboratory houses a large number of bone marrow and blood specimens (~3,500), collected from patients with MPNs. These specimens 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 MPN Research Team, currently comprising Professor Zeev Estrov, MD; 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.
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.