1. Myelodysplastic syndrome overview Razelle Kurzrock Seminars in Haematology, Vol 39, No 3, Suppl 2 (July) 2002, pp 18-25

2. Myelodysplastic syndrome (MDS) It is a term for a heterogeneous collection of haemopoietic stem cell disorders affecting older adults. There is underlying ineffectiveness of haemopoiesis that results in dysplasia of bone marrow precursors and peripheral cytopenias.

3. Moderate anaemia is the most common clinical problem in MDS patients, but complete myeloid bone marrow failure also occurs leading to death from bleeding or infection. Approximately half of the patients transform to AML.

4. Prognosis depends on the individual’s risk factors, with median survival ranging from 5.7 years in lower-risk group to 1.2 years or less in those with higher-risk MDS. MDS is extremely difficult to treat. Most cases are resistant to current therapies, and the most potent anti-MDS treatments (transplantation and dose intensive chemotherapy) are often too toxic for the majority of patients.

5. MDS background Pathobiology –The cardinal features of MDS are Increased marrow proliferation Failure of stem cells to differentiate And increased marrow apoptosis. –The disease is of clonal origin –Chromosomal abnormalities are detectable in 30-70% of patients. The no. of chromosomal abn. may correlate with the risk of progression to AML.

7. FAB classification In 1982 The FAB group classified MDS according to Morphology and the % of myeloblasts in the BM and PB. These included –Refractory anaemia (RA) –Refractory anaemia with ringed sideroblasts (RARS) –Refractory anaemia with excess blast in marrow (RAEB) –CMML –Refractory anaemia with excess blast in transformation (RAEB-t)

8. Morphological characteristics of MDS

10. WHO classification The WHO proposed changes including reclassification of RAEB-t to AML and adding a subgroup called refractory cytopenias with dysplasia (RCD)

11. International Prognostic Scoring System (IPSS) The most practical and validated MDS classification system currently available to clinicians is the IPSS which predicts both survival and risk of transformation to AML based on: –Marrow blast % –Cytogenetics –And number of cytopenias.

13. The scope of MDS MDS is primarily a disease of the elderly, with a median age at diagnosis of between 60-80 years. The incidence is approximately double that of AML. The recent increase in MDS incidence may be related to growing awareness, better diagnosis, and an aging population.

14. Prognosis for most patients is poor. If not cured by BMT, the disease is invariably fatal. The common symptoms at presentation, fatigue or weakness, are attributable to cytopenia. Easy bruising, ecchymosis, epistaxis, gingival bleeding, and bacterial infections may also be encountered.

15. Transformation to acute leukaemia occurs in up to 40% of patients. Although progression to frank AML is a primary concern, 20-40 % or more of patients die of infections and/or haemorrhagic complications.

16. Conventional therapies Supportive care including blood products with deferoxamine, haemopoietic growth factors and antibiotics. EPO increases red blood cells in some patients, GM-CSF may limit infections. Hormone suppressive therapy with danazol has been used to help resolve anaemia and reduce transfusion requirements.

17. Most attempts to induce haemopoietic cell differentiation have failed. For example, interferon alfa-2 transiently improves platelet counts in some MDS patients. However progression is also possible. Clinical studies with differentiation promoters such as retinoids, Vit D3, butyrates have been disappointing. In contrast, the hypomethylating agent 5- azacytidine has produced significant clinical benefit in patients with MDS

18. Low intensity chemotherapy with cytarabine induces response in approximately 30% of MDS patients. However, the relapse rate is high, and there is no improvement in overall survival. Recent studies show that using low dose cytarabine in conjunction with M-CSF, GM-CSF, or ATRA may improve overall response and survival.

19. Bone marrow transplantation is currently the only potentially curative therapy for MDS patients. Overall disease-free survival at 3 years with allogenic procedures ranges approximately from 35-60% depending on IPSS score and other patient’s risk factor especially age. However, the procedure related mortality among these pt is significant, with patients older than 50 years having an approximately 50% chance of dying from the transplant itself.

20. Anti-MDS agents in development ATRA Amifostine –cytoprotective agent Melphalan Azacytidine- blocks DNA methylation and may initiate transcription and differentiation. Thalidomide-antiangiogenic, anti-TNF alpha and immunosuppressive. Immunosuppressive therapy-ATG, cyclosporine A

21. Farnesyltransferase inhibitors- modulate multiple proteins and /or cell signaling pathways that have been implicated in MDS pathophysiology or progression, including Ras, p53.. Antiproliferative, antiangiogeneic and proapoptotic activity

22. Conclusion In the majority of patients with MDS who are not eligible for allogenic transplantation, the disease is fatal. Approximately 2/3 of patients die within 3- 4 years of diagnosis. Patients with high risk MDS generally survive approximately one year.

23. Except for a recent trial of azacytidine, none of the other currently available drugs for MDS extends survival, and many are highly toxic. The FTIs are an example of targeted therapy with potential clinical applicability in MDS-modulating an array of tumour signaling cascades via inhibition of farnesyitransferase.

24. Current treatment options for MDS No MDS-specific therapies are available. Clinicians typically choose the therapy on the basis of risk factors, such as patient age, MDS subtype, IPSS score, and performance status. For example, lower risk patients generally receive supportive care and perhaps low intensity chemotherapy or differentiating agents. While those with higher risk may be candidates for dose intensive chemotherapy or in younger patients, bone marrow transplantation.