The Myelodepletive Phenotype in Myelofibrosis: Clinical Relevance and Therapeutic Implication |
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| Affiliation: | 1. Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;2. Leukemia Department, MD Anderson Cancer Center, Houston, TX;1. Department of Hematology/Oncology, Columbia New York Presbyterian, New York, NY;2. Mays Cancer Center, UT Health San Antonio MD Anderson, San Antonio, TX;3. Department of Medicine, Division of Hematology, Cancer Institute, Stanford University, Stanford, CA;4. Department of Leukemia, Memorial Sloan Kettering Cancer Center, New York, NY;5. Division of Hematologic Malignancies and Cellular Therapeutics (HMCT), Department of Internal Medicine, University of Kansas Cancer Center, Westwood, KS;6. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD;7. Leukemia and Myeloid Disorders Program, Cleveland Clinic, Cleveland, OH;8. Cancer Center, Massachusetts General Hospital Harvard Medical School, Boston, MA;9. Winship Cancer Institute, Emory University, Atlanta, GA;10. Division of Hematology, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY;11. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;12. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY;1. Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA;2. Center of Research and Innovation of Myeloproliferative Neoplasms, Department of Experimental and Clinical Medicine, AOU Careggi and University of Florence, Florence, Italy;3. Clinical Haematology, NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK;4. Department of Hematology, Somogy County Kaposi Mor Hospital, Kaposvar, Hungary;5. Second Department of Internal Medicine and Cardiology Center, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary;6. First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia;7. Békés Megyei Pándy Kálmán Kórház, Gyula, Hungary;8. ICON Cancer Care, South Brisbane, QLD, Australia;9. Royal Hobart Hospital, Hobart, Australia;10. Department of Internal Medicine, University Hospital Brno, Brno, Czech Republic;11. First Department of Internal Medicine, Semmelweis University, Budapest, Hungary;12. Department of Haematology, Christchurch Hospital, Christchurch, New Zealand;13. CTI BioPharma Corp, Seattle, WA, USA;14. Erasmus Medical Center, Rotterdam, Netherlands;15. Wellcome Trust Sanger Instutite, Hinxton, UK;p. Centre d''Investigations Cliniques, APHP, Hôpital Saint-Louis, INSERM CIC 1427, Paris, France;q. Paris Diderot University, Paris, France;r. Department of Haematology, Guy''s and St Thomas'' NHS Foundation Trust, London, UK;1. Icahn School of Medicine at Mount Sinai;1. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;2. Hematology Unit, Department of Translational Medicine, University of Eastern Piedmont and AOU Maggiore della Carità, Novara, Italy;3. Guy''s and St Thomas'' NHS Foundation Trust, London, United Kingdom;4. The University of Texas MD Anderson Cancer Center, Houston, TX, USA;5. Memorial Sloan-Kettering Cancer Center, New York, NY, USA;6. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy;7. University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium;8. University of Insubria, Varese, Italy;9. Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;10. University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA;11. Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy;12. Hôpital Saint-Louis, Université de Paris, Paris, France;13. Leukemia Department, University of Texas MD Anderson Cancer Center, Houston, TX, USA;14. Sonic Healthcare USA, Austin, TX, USA;15. Mayo Clinic, Rochester, MN, USA;16. Constellation Pharmaceuticals a MorphoSys Company, Boston, MA, USA;17. Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada;1. Guy''s and St Thomas'' National Health Service Foundation Trust, London, UK;2. Azienda Ospedaliera Careggi Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy;3. Medizinische Fakultät Carl Gustav Carus, Technische Universität, Dresden, Germany;4. Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain;5. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada;6. Hadassah-Hebrew University Medical Center, Jerusalem, Israel;7. University of Insubria, ASST Settelaghi, Ospedale di Circolo, Varese, Italy;8. Emory University School of Medicine, Atlanta, GA, USA;9. Gilead Sciences, Inc, Foster City, CA, USA;10. Saint-Louis Hospital (APHP) and Paris Diderot University, Paris, France;11. University of Texas MD Anderson Cancer Center, Houston, TX, USA |
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| Abstract: | Myelofibrosis (MF) is a BCR-ABL1− myeloproliferative neoplasm that arises from hematopoietic stem and progenitor cells frequently harboring a somatic driver mutation in 1 of 3 genes: JAK2, CALR, or MPL. The pathologic features of this hematologic malignancy include myeloproliferation, diffuse bone marrow fibrosis, and overactivation of the JAK-STAT pathway, resulting in enhanced inflammatory cytokine release. The common clinical manifestations of MF include systemic symptoms, abnormal peripheral blood count levels, and splenomegaly. However, it has become increasingly appreciated that significant clinical heterogeneity exists among patients with MF. Two distinct MF clinical phenotypes include the myeloproliferative and myelodepletive phenotype, with peripheral blood counts being the main discerning feature. Patients with the myeloproliferative phenotype will present with elevated peripheral blood counts and often experience significant constitutional symptoms and progressive splenomegaly. In contrast, patients with the myelodepletive phenotype will have low peripheral blood counts and will frequently require transfusion support. Current frontline therapies for MF, include ruxolitinib and fedratinib, which can exacerbate cytopenias and thereby pose an impediment to effective treatment of the myelodepletive patient. The present review discusses the clinical and prognostic implications of the myelodepletive phenotype and the therapeutic options and limitations for this subset of patients, representing an unmet clinical need. |
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| Keywords: | Bone marrow failure Cytopenias JAK inhibitors Myelodepletion, Thrombocytopenia |
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