1. Myelodysplastic syndromes Achievements in understanding and treatment prof. dr hab. med. Krzysztof Lewandowski

2. Classification of Myeloid Neoplasms According to the 2008 World Health Organization Classification Scheme

3. Myelodysplastic syndromes (MDS) The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML)

4. Some of the deregulated pathways for the upregulated and downregulated genes in MDS CD34 + cells Li J. Int. J. Cancer: 000, 000–000 (2012)

5. Deregulated pathways in CD34ţ cells from MDS subtypes RA and RAEB2 compared with in healthy controls Li J. Int. J. Cancer: 000, 000–000 (2012)

6. Proposed mechanisms of miRNA in MDS pathogenesis Genetic and epigenetic abnormalities may occur in both osteoblasts and HSCs, which result in the deregulation of certain miRNAs in those cells. MiRNA deregulation is followed by the subsequent abnormal expression of HSC extrinsic regulators in osteoblasts or HSC intrinsic regulators in HSCs, both leading to HSC dysfunction and MDS development Li J. Int. J. Cancer: 000, 000–000 (2012)

7. Frequency In the US: The actual incidence is unknown. MDS was first considered a separate disease in 1976, and occurrence was estimated at 1500 new cases every year. At that time, only patients with less than 5% blasts were considered to have this disorder Statistics from 1999 show that 13,000 new cases occur per year (approximately 1000 cases each year in children) Internationally: The disease is found worldwide and is similar in characteristics throughout the world

8. Epidemiology Sex: A slight male predominance is noted in all age groups. Age: MDS primarily affects elderly people, with the median onset in the seventh decade of life. The median age of these patients is 65 years, with ages ranging from the early third decade of life to older than 80 years. The syndrome may occur in persons of any age group, including the pediatric population.

9. MDS diagnosis Is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy Information obtained from additional studies such as karyotype, flow cytometry, or molecular genetics is complementary but not diagnostic

10. MDS- diagnosis (2) Aplastic anaemia and some disease accompanied by marrow dysplasia, including wit. B 12 and/or folate deficiency, exposure to heavy metals, recent cytotoxic therapy and ongoing inflammation (including HIV and chronic liver disease/alcohol use) should be ruled out

11. MDS – clinical findings These are non-specific, and are usually the consequences of cytopenias, including: -symptoms of anaemia -infections due to neutropenia, but also to the frequently associated defect in neutrophil function -bleeding due to thrombocytopenia (may also occur in moderately thrombocytopenic patients or even in patients with normal platelets count, because of its abnormal function)

12. Myelodysplastic syndromes: Refractory anemia (RA) With ringed sideroblasts (RARS) Without ringed sideroblasts Refractory cytopenia (MDS) with multilineage dysplasia (RCMD) Refractory anemia with excess blasts (RAEB) 5q - syndrome Myelodysplastic syndrome, unclassifiable Myelodysplastic/Myeloprolipherative diseases Chronic myelomonocytic leukemia (CMML) Atypic chronic myelogenous leukemia (aCML) Myelodysplastic syndromes WHO classification system

13. WHO 2008 MDS classification Garcia-Manero G. Am. J. Hematol. 2011;86:491–498

14. Marrow blast percentage: < 5 0 5-10 0.5 11-20 1.5 21-30 2.0 Cytogenetic features Good prognosis 0 (–Y, 5q -, 20q - ) Intermediate prognosis 0.5 (+8, miscellaneous single abnormality, double abnormalities) Poor prognosis 1.0 (abnor. 7, complex- >3 abnor.) Cytopenias None or one type 0 2 or 3 type 0.5 Myelodysplastic syndromes IPSS risk-based classification system

15. Overall score: Median survival: low 0 5.7 years Intermediate 1 (0.5 or 1) 3.5 years 2 (1.5 or 2) 1.2 years High > 2.5 0.4 years Myelodysplastic syndromes Overall IPSS score and survival

16. Refined WHO Classification–Based Prognostic Scoring System (WPSS) of Myelodysplastic Syndromes Cazzola M et al. Semin Oncol 2011;38:627-634

17. Kaplan-Meier survival curves of 943 patients diagnosed with MDS according to the 2008 WHO criteria Cazzola M et al. Semin Oncol 2011;38:627-634

18. Myelodysplastic syndromes: 2011 update on diagnosis, risk stratification, and management American Journal of Hematology 2011; 86, 490-498, 18 MAY 2011 DOI: 10.1002/ajh.22047

19. Bone marrow biopsy Blood examination and bone marrow aspirate are sufficient for a diagnosis of MDS -normal or increased cellularity is seen in 85-90% od cases -abnormal localization of immature precursors (ALIP) -fibrosis (significant in 15-20% of cases)

20. Myelodysplastic features in MDS MDSBone marrow and/or peripheral blood findings Dyserythropoiesis Bone marrow: multinuclearity, nuclear fragments, megaloblastoid changes, cytoplasmic abnormalities, ringed sideroblasts Peripheral blood: poikilocytosis, anisocytosis, nucleated red blood cells

21. Myelodysplastic features in MDS MDSBone marrow and/or peripheral blood findings Dysgranulopoiesis Nuclear abnormalities including: hypolobulation, ring- shaped nuclei, hypogranulation DysmegakariopoiesisMicromegakariocytes Large mononuclear forms Multiple small nuclei

22. RAEB-2. Bone marrow, 100x

23. RAEB-2. Bone marrow, 400x

24. RAEB-2. Bone marrow, 400x (2)

25. RAEB-2. Bone marrow 400x (2)

26. MDS with ring sideroblasts. Bone marrow 400x

27. Frequency of cytogenetic alternations in MDS Garcia-Manero G. Am. J. Hematol. 2011;86:491–498

28. MDS therapy Options for newly diagnosed patients with lower risk MDS Therapy in this subset of patients is based on the transfusion needs of the patients Patients that are transfusion independent are usually observed until they become transfusion dependent Erythroid growth factor and granulocyte growth factor support (ESA, G-CSF) Lenalidomide (is approved in the US for patients with lower risk MDS, anemia, and alteration of chromosome 5)

29. Management of progressive or refractory disease At the present time, there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include cytarabine-based therapy, transplantation, and participation on a clinical trial.

30. Myelodysplastic syndromes: 2011 update on diagnosis, risk stratification, and management American Journal of Hematology Volume 86, Issue 6, pages 490-498, 18 MAY 2011 DOI: 10.1002/ajh.22047 http://onlinelibrary.wiley.com/doi/10.1002/ajh.22047/full#fig2 Volume 86, Issue 6, http://onlinelibrary.wiley.com/doi/10.1002/ajh.22047/full#fig2

31. Years 026 13 45 Probability of survival after allogeneic transplant for MDS, age  20 years, by disease status and donor type, 1998-2008 Early, HLA-matched sibling (N=63) SUM10_39.ppt Early, unrelated (N=145) Advanced, HLA-matched sibling (N=114) Advanced, unrelated (N=190) 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P = 0.002

32. Years 026 13 45 Probability of survival after allogeneic transplant for MDS, age  20 years, by disease status and donor type, 1998-2008 Early, HLA-matched sibling (N=599) SUM10_40.ppt Early, unrelated (N=509) Advanced, HLA-matched sibling (N=1,237) Advanced, unrelated (N=1,142) 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P < 0.0001

33. Years 026 13 45 Probability of survival after allogeneic transplant for MDS with reduced-intensity conditioning, by disease status and donor type, 1998-2008 SUM10_41.ppt 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P < 0.0001 Early, unrelated (N=202) Early, HLA-matched sibling (N=217) Advanced, HLA-matched sibling (N=366) Advanced, unrelated (N=383)