Myelofibrosis

An elderly male myelofibrosis patient outside gardening with his wife

Patient Current State

Myelofibrosis is driven by a complex disease process resulting in bone marrow fibrosis, impaired hematopoiesis, and the appearance of constitutional symptoms.^12,14

Patients with MF often present with¹

Common symptoms in myelofibrosis include anemia, splenomegaly, hepatomegaly, fatigue, night sweats, pruritis, and weight loss

Atypical megakaryocyte proliferation leads to increased proinflammatory cytokine release, resulting in BM fibrosis and development of constitutional symptoms.^5,9,15

A diagram showing that inflammatory cytokines lead to constitutional symptoms, increased fibroblast production and stromal fibers that impact the bone marrow microenvironment in myelofibrosis

Altered BM environment and fibroblasts deposit collagen and reticulin, which causes scarring and leads to impaired hematopoiesis.¹

Myelofibrosis is pathologically characterized by deposition of collagen and reticulin fibers and distortion of bony trabeculae.^1,5

An illustration of 3 bones showing decreasing fibrosis, first with severe bone marrow fibrosis, then bone marrow fibrosis, with healthy bone last

Patient Molecular Level

Multiple pathways contribute to the pathogenesis and progression of MF.^3,4,13,16,18

Click the pathway tabs to expand details.

BCL-2 family proteins

JAK/STAT

TGFβ

Epigenetic regulators

Telomerase

Targeting multiple pathways that contribute to MF pathogenesis may be a future approach to alter the course of MF.^2,12

Restoration of normal bone marrow appearance coupled with reduction in MPN symptom burden and/or splenomegaly may indicate modification to the underlying disease process.¹¹

In addition to measuring bone marrow fibrosis reduction, other clinical trial endpoints are going beyond symptom control and are potentially assessing disease modification in MF.¹¹

Markers for disease modification: spleen size reduction, anemia and symptom improvement, increased overall survival, and reduction in variant allele frequency

Current therapeutic modalities often provide symptom control. Over time, some patients will experience return of symptoms and progression of disease.^2,12

Multiple pathways and key mechanisms leading to disease progression in MF should be further explored.^2,12

An elderly male myelofibrosis patient outside sitting at a table, enjoying a cup of coffee with his wife

Resources

References

1. Agarwal A, et al. Bone marrow fibrosis in primary myelofibrosis. Stem Cell Investig. 2016;3:5.

2. Gerds AT. Beyond JAK-STAT: novel therapeutic targets in Ph-negative MPN. Hematology. 2019;2019(1):407-414.

3. Hajmirza A, et al. BET family protein BRD4: an emerging actor in NFkB signaling in inflammation and cancer. Biomedicines. 2018;6(1):16.

4. Jiang Q, Jamieson C. BET’ing on dual JAK/BET inhibition as a therapeutic strategy for myeloproliferative neoplasms. Cancer Cell. 2018;33(1):3-5.

5. Lu M, et al. Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells. Blood. 2015;126(8):972-982.

6. Melo-Cardenas J, et al. The role of megakaryocytes in myelofibrosis. Hematol Oncol Clin North Am. 2021;35(2):191-203.

7. Mesa RA. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109(1):68-76.

8. Mitra D, et al. Symptom burden and splenomegaly in patients with myelofibrosis in the United States: a retrospective medical record review. Cancer Med. 2013;2(6):889-898.

9. Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89-101.

10. Nasillo V, et al. Inflammatory microenvironment and specific T cells in myeloproliferative neoplasms: immunopathogenesis and novel immunotherapies. Int J Mol Sci. 2021;22:1906.

11. Pemmaraju N, et al. Defining disease modification in myelofibrosis in the era of targeted therapy. Cancer. 2022;128:2420-2432.

12. Pettit K, Odenike O. Novel therapies for myelofibrosis. Curr Hematol Malig Rep. 2017;12(6):611-624.

13. Plati J, et al. Apoptotic cell signaling in cancer progression and therapy. Integr Biol. 2011;3(4):279-296.

14. Reilly JT, et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012;158(4):453-471.

15. Tabarroki A, et al. Molecular genetics of myelofibrosis and its associated disease phenotypes. Transl Med UniSa. 2014;8:53-64.

16. Tremblay D, Mascarenhas J. Next generation therapeutics for the treatment of myelofibrosis. Cells. 2021;10:1034.

17. Wang X, et al. Imetelstat, a telomerase inhibitor is capable of depleting myelofibrosis stem and progenitor cells. Blood Adv. 2018;2(18):2378-2388.

18. Yanagida M, et al. The role of transforming growth factor-β in PEG-ruHuMGDF-induces reversible myelofibrosis in rats. Br J Haematol. 1997;99:739-745.

19. Zahr AA, et al. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016;101(6):660-671.

Patient Current State

Myelofibrosis is driven by a complex disease process resulting in bone marrow fibrosis, impaired hematopoiesis, and the appearance of constitutional symptoms.^12,14

Myelofibrosis is driven by a complex disease process resulting in bone marrow fibrosis, impaired hematopoiesis, and the appearance of constitutional symptoms.^12,14

Patients with MF often present with¹

Patient Cellular Level

Megakaryocytes play a key role in myelofibrosis through promotion of myeloproliferation and fibrosis.⁶

Megakaryocytes play a key role in myelofibrosis through promotion of myeloproliferation and fibrosis.⁶

Atypical megakaryocyte proliferation leads to increased proinflammatory cytokine release, resulting in BM fibrosis and development of constitutional symptoms.^5,9,15

Atypical megakaryocyte proliferation leads to increased proinflammatory cytokine release, resulting in BM fibrosis and development of constitutional symptoms.^5,9,15

Altered BM environment and fibroblasts deposit collagen and reticulin, which causes scarring and leads to impaired hematopoiesis.¹

Altered BM environment and fibroblasts deposit collagen and reticulin, which causes scarring and leads to impaired hematopoiesis.¹

Myelofibrosis is pathologically characterized by deposition of collagen and reticulin fibers and distortion of bony trabeculae.^1,5

Patient Molecular Level

Multiple pathways contribute to the pathogenesis and progression of MF.^3,4,13,16,18

Multiple pathways contribute to the pathogenesis and progression of MF.^3,4,13,16,18

Click the pathway tabs to expand details.

Targeting multiple pathways that contribute to MF pathogenesis may be a future approach to alter the course of MF.^2,12

Targeting multiple pathways that contribute to MF pathogenesis may be a future approach to alter the course of MF.^2,12

Restoration of normal bone marrow appearance coupled with reduction in MPN symptom burden and/or splenomegaly may indicate modification to the underlying disease process.¹¹

In addition to measuring bone marrow fibrosis reduction, other clinical trial endpoints are going beyond symptom control and are potentially assessing disease modification in MF.¹¹

In addition to measuring bone marrow fibrosis reduction, other clinical trial endpoints are going beyond symptom control and are potentially assessing disease modification in MF.¹¹

Current therapeutic modalities often provide symptom control. Over time, some patients will experience return of symptoms and progression of disease.^2,12

Current therapeutic modalities often provide symptom control. Over time, some patients will experience return of symptoms and progression of disease.^2,12

Multiple pathways and key mechanisms leading to disease progression in MF should be further explored.^2,12

Resources

References

Patient Current State

Myelofibrosis is driven by a complex disease process resulting in bone marrow fibrosis, impaired hematopoiesis, and the appearance of constitutional symptoms.12,14

Myelofibrosis is driven by a complex disease process resulting in bone marrow fibrosis, impaired hematopoiesis, and the appearance of constitutional symptoms.12,14

Patients with MF often present with1

Patient Cellular Level

Megakaryocytes play a key role in myelofibrosis through promotion of myeloproliferation and fibrosis.6

Megakaryocytes play a key role in myelofibrosis through promotion of myeloproliferation and fibrosis.6

Atypical megakaryocyte proliferation leads to increased proinflammatory cytokine release, resulting in BM fibrosis and development of constitutional symptoms.5,9,15

Atypical megakaryocyte proliferation leads to increased proinflammatory cytokine release, resulting in BM fibrosis and development of constitutional symptoms.5,9,15

Altered BM environment and fibroblasts deposit collagen and reticulin, which causes scarring and leads to impaired hematopoiesis.1

Altered BM environment and fibroblasts deposit collagen and reticulin, which causes scarring and leads to impaired hematopoiesis.1

Myelofibrosis is pathologically characterized by deposition of collagen and reticulin fibers and distortion of bony trabeculae.1,5

Patient Molecular Level

Multiple pathways contribute to the pathogenesis and progression of MF.3,4,13,16,18

Multiple pathways contribute to the pathogenesis and progression of MF.3,4,13,16,18

Click the pathway tabs to expand details.

Targeting multiple pathways that contribute to MF pathogenesis may be a future approach to alter the course of MF.2,12

Targeting multiple pathways that contribute to MF pathogenesis may be a future approach to alter the course of MF.2,12

Restoration of normal bone marrow appearance coupled with reduction in MPN symptom burden and/or splenomegaly may indicate modification to the underlying disease process.11

In addition to measuring bone marrow fibrosis reduction, other clinical trial endpoints are going beyond symptom control and are potentially assessing disease modification in MF.11

In addition to measuring bone marrow fibrosis reduction, other clinical trial endpoints are going beyond symptom control and are potentially assessing disease modification in MF.11

Current therapeutic modalities often provide symptom control. Over time, some patients will experience return of symptoms and progression of disease.2,12

Current therapeutic modalities often provide symptom control. Over time, some patients will experience return of symptoms and progression of disease.2,12

Multiple pathways and key mechanisms leading to disease progression in MF should be further explored.2,12

Resources

References

Myelofibrosis is driven by a complex disease process resulting in bone marrow fibrosis, impaired hematopoiesis, and the appearance of constitutional symptoms.^12,14

Myelofibrosis is driven by a complex disease process resulting in bone marrow fibrosis, impaired hematopoiesis, and the appearance of constitutional symptoms.^12,14

Patients with MF often present with¹

Megakaryocytes play a key role in myelofibrosis through promotion of myeloproliferation and fibrosis.⁶

Megakaryocytes play a key role in myelofibrosis through promotion of myeloproliferation and fibrosis.⁶

Atypical megakaryocyte proliferation leads to increased proinflammatory cytokine release, resulting in BM fibrosis and development of constitutional symptoms.^5,9,15

Atypical megakaryocyte proliferation leads to increased proinflammatory cytokine release, resulting in BM fibrosis and development of constitutional symptoms.^5,9,15

Altered BM environment and fibroblasts deposit collagen and reticulin, which causes scarring and leads to impaired hematopoiesis.¹

Altered BM environment and fibroblasts deposit collagen and reticulin, which causes scarring and leads to impaired hematopoiesis.¹

Myelofibrosis is pathologically characterized by deposition of collagen and reticulin fibers and distortion of bony trabeculae.^1,5

Multiple pathways contribute to the pathogenesis and progression of MF.^3,4,13,16,18

Multiple pathways contribute to the pathogenesis and progression of MF.^3,4,13,16,18

Targeting multiple pathways that contribute to MF pathogenesis may be a future approach to alter the course of MF.^2,12

Targeting multiple pathways that contribute to MF pathogenesis may be a future approach to alter the course of MF.^2,12

Restoration of normal bone marrow appearance coupled with reduction in MPN symptom burden and/or splenomegaly may indicate modification to the underlying disease process.¹¹

In addition to measuring bone marrow fibrosis reduction, other clinical trial endpoints are going beyond symptom control and are potentially assessing disease modification in MF.¹¹

In addition to measuring bone marrow fibrosis reduction, other clinical trial endpoints are going beyond symptom control and are potentially assessing disease modification in MF.¹¹

Current therapeutic modalities often provide symptom control. Over time, some patients will experience return of symptoms and progression of disease.^2,12

Current therapeutic modalities often provide symptom control. Over time, some patients will experience return of symptoms and progression of disease.^2,12

Multiple pathways and key mechanisms leading to disease progression in MF should be further explored.^2,12