1. Myelofibrosis with myeloid metaplasia : Disease overview and non-transplant treatment options Best Practice & Research Clinical Haematology Vol. 19, No. 3, pp. 495–517, 2006 R2 한재준

2. Classification NEJM Vol. 342 Number 17

3. Clinical characteristics anemia multi-organ extramedullary hematopoiesis constitutional symptoms premature death – leukemic transformation or other complications

4. The population-based incidence 1.46/100 000 (Olmsted County,MN, USA)  Median age at diagnosis : 67years 0.4/100 000 (Goteborg, Sweden)

5. Epidemiology : radiation observed at 18 times the expected incidence rate in survivors of Hiroshima exposed to low-level radiation  radioactive contrast material Thorotrast

6. Pathogenesis Stem cell derived clonal myeloproliferation Intense bone marrow stromal reaction  collagen fibrosis  osteosclerosis  angiogenesis

7. Pathogenesis 50% karyotypic abnormalities JAK2  cytoplasmic tyrosine kinase  signal transduction from hematopoietic GFs  acquired activating mutation  Val 617 Phe – point mutation  35% in MMM

8. Pathology NEJM Vol. 342 Number 17

9. Pathogenesis NEJM Vol. 342 Number 17

10. Pathogenesis Cytokines  transforming growth factor beta-1 (TGF-b1),  basic fibroblast growth factor (bFGF),  platelet-derived growth factor (PDGF),  vascular endothelial growth factor (VGEF),  osteocalcin  osteoprotegerin (OPG)

11. Pathogenesis GATA-1  zinc finger  transcription factor  erythroid and megakaryocyte development  release TGF-b1, PDGF from megakaryocyte

12. Clinical manifestations

13. Clinical manifestations : anemia Ineffective hematopoiesis Decreased marrow reserve Splenic sequestration Myelosuppression from cytoreductive therapy Hemolysis GI bleeding-variceal bleeding Iron, Vit B12, Folate deficiencies

14. Diagnosis Reactive myelofibrosis  Exposure to exogenous marrow toxins - benzene  autoimmune diseases – SLE  Disorders of bone matrix – osteopetrosis Non myeloid causes of reactive myelofibrosis  Lymphoma  Hairy cell leukemia  Metastatic cancer

15. Prognosis

16. Management - anemia

17. Management - Epo a response rate of 33% with drug doses of up to 600 units/kg/week. (Rodriguez et al) endogenous serum Epo levels <125 mU/mL highest likelihood of response an overall response rate of 45% in 20 MMM patients treated with 30 000 units/week. (Cervantes et al) Epo treatment should be restricted to patients with anemia and inadequate Epo levels

18. Clinical trials of thalidomide

19. Medical therapy for reduction of myeloproliferation

20. Mayo clinic experience of splenectomy

22. Radiotherapy for palliation