2. EHA highlights News in MDS JULY31, TYR,LEBANON MARCEL MASSOUD, M.D.

3. MDSs in 2010 EHA 1 education session : 1.THE BIOLOGICAL BASIS OF MYELODYSPLASTIC SYNDROMES 2. EPIGENETIC THERAPY OF MYELODYSPLSATIC SYNDROMES : AN UPDATE 3. MANAGEMENT OF MYELODYSPLASTIC SYNDROMES 3 scientific sessions : (26 Abst)

4. Contents Update on epigenetic abnormalities in MDS Update on prognosis and diagnosis of MDS –emerging prognostic factors –analysis of patient registries Management of MDS Lenalidomide in patients with MDS

6. 6 Myelodysplastic Syndromes FAB (French, American and British) system 1982:

7. 7 2008: -RCUD includes: RA, RN, RT -chromosomal abnormalities confirm MDS in absence of morphology -Merge RCMD-RS and RCMD -RCC: refractory cytopenia of childhood -t-MDS/t-AML -Ring sideroblast not ringed Myelodysplastic Syndromes Classification of MDS 2001 WHO Classification

8. 8 Myelodysplastic Syndromes 1997- International Prognostic Scoring System (IPSS) IPSS assessment criteria: - Percentage of blasts in bone marrow - Chromosomal abnormalities - Number of cytopenias

9. 9 IPSS defects: -cytopenia severity -transfusion dependency -limited number of cytogenetic abnormalities -fibrosis, LDH, beta2 microglobulin, co-morbidities do not account Myelodysplastic Syndromes : Prognosis and survival using IPSS

12. Update on prognosis and diagnosis of MDS and AML: analysis of patient registries

13. Relative % of Various Cytogenetic Abnormalities in De Novo MDS +

14. Analysis of patient registeries: a new cytogenetic scoring system for primary MDS Schanz J, et al. Oral presentation at EHA 2010, Barcelona, Spain. Abstract 0535 New system based on reclassification of double (2 cytogenetic aberrations) and complex (≥3 cytogenetic aberrations) abnormalities Very good GoodIntPoorVery poor Single del(11q) –Y Normal Single der(1;7) del(5q) del(12q) del(20q) Double Double incl. del(5q) Single –7/7q– +8 +19 +21 iso(17q) Any others Double Any other Single der(3)(q21)/ (3)(q26) Double Incl. –7/7q– Complex 3 abnorm. Complex >3 abnorm. A total of 2,901 untreated patients (GA = 1,192, IMRAW = 816, GCECGH = 849, ICWG = 44); median observation time = 19 (0.1–326) months GA = German/Austrian; IMRAW = International MDS Risk Analysis Workshop; GCECGH = Spanish Cytogenetics Working Group; ICWG = International Cytogenetics Working Group Risk category

15. Schanz J, et al. Oral presentation at EHA 2010, Barcelona, Spain. Abstract 0535 0 10 20 30 40 50 60 70 OS (months) Very good Good Int Poor Very poor 60.8 48.5 25.0 15.0 5.7 Analysis of patient registeries: a new cytogenetic scoring system for primary MDS, cont’d New scoring system predicted survival in 2,799 evaluable patients with MDS Risk PrognosisPatients, n (%) Very good80 (2.9) Good1,844 (65.9) Int578 (20.7) Poor101 (3.6) Very poor196 (7.0) OS

16. Update on epigenetic abnormalities in MDS and AML

17. DNA methylation predicts survival in patients with MDS 1,2 1. Santini V. Oral presentation at EHA 2010, Barcelona, Spain 2. Shen L, et al. J Clin Oncol 2009;28:605–13 Methylation analysis of a panel of 10 genes in 317 patients with MDS from three independent studies OSPFS Methylation measured by combined z score

18. Genome-wide methylation analysis of CD34+ cells from patients with MDS Figueroa M. Oral presentation at EHA 2010, Barcelona, Spain Statistical significance Normal CD34+ cells More methylated in MDS Less methylated in MDS Genome-wide methylation was greater in CD34+ cells from BM of patients with MDS versus normal controls  The aberrant methylation pattern in patients with MDS –was transmitted to CD34– progeny cells –occurred preferentially within certain chromosomal regions –strongly affected genes in the WNT, PTEN and PI3K/Akt signalling pathways  Aberrant methylation was more pronounced in patients with MDS than in patients with de novo AML

19. Azacitidine 30–50mg/m 2 /day 2 Genome-wide methylation assessed in patients who completed at least 4 cycles Day 0Day 15Day 29 Entinostat Treatment regimen (28–29-day cycles) Day 10  Treatment significantly reduced genome-wide methylation vs baseline  Demethylation was sustained throughout each cycle  There was a trend towards greater genome-wide demethylation in responders versus non-responders 1. Figueroa M. Oral presentation at EHA 2010, Barcelona, Spain 2. Fandy TE, et al. Blood 2009;114:2764–73 Epigenetic therapy induced profound and sustained hypomethylation in the BM of patients with MDS Genome-wide methylation analysis of CD34+ cells from patients with MDS: response to therapy 1

20. Update on prognosis and diagnosis of MDS and AML

21. Update on prognosis and diagnosis of MDS and AML: emerging prognostic factors

22. Emerging prognostic factors in MDS: severity of anaemia Ambaglio I, et al. Poster presentation at EHA 2010, Barcelona, Spain. Abstract 0310 A single-centre study of 920 patients with MDS* IPSS low/int-1/int-2/high, n = 211/264/122/31; TD, % patients = 31 OS in patients with anaemiaOS according to transfusion dependence Anaemia (<9g/dL in males and <8g/dL in females) was an independent unfavourable prognostic indicator of survival in patients with MDS TI patients TD patients 0.9 1.0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 024487296120 Time (months) 144168192216240 No, mild or moderate anaemia Severe anaemia Cumulative probability of survival 0.9 1.0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 024487296120144168192216240 Time (months) *Patients who received HSCT or chemotherapy were censored at time of procedure Cumulative probability of survival

23. Emerging prognostic factors in MDS: transfusion dependence and iron overload Transfusion independency Transfusion dependency Cumulative survival 1.0 0.8 0.6 0.4 0.2 0.0 05101520 Survival, years RR = 5.8; p < 0.001 Ferritin <1,000 ng/mL Ferritin >1,000 ng/mL Cumulative survival 1.0 0.8 0.6 0.4 0.2 0.0 05101520 Survival, years RR = 2.1; p < 0.025 Arnan M, et al. Poster presentation at EHA 2010 Barcelona, Spain. Abstract 0314 Single-centre retrospective study of 639 patients with de novo MDS TD and iron overload were strongly associated with worse OS OS stratified by RBC transfusion dependence OS stratified by serum ferritin levels (indicative of iron overload) RR = response rate TD at baseline: 43% –median 2.03 (range 0.5–13.2) RBC packs/month

24. Emerging prognostic factors in MDS: TP53 mutations in patients with low-risk del(5q) MDS Saft L, et al. Poster presentation at EHA 2010, Barcelona, Spain. Abstract 0313 Assessment BM samples –stained for p53 protein Mutational analysis of TP53 Study of 56 patients with low-risk del(5q) MDS in two centres TD = 52% Mutation of TP53 in patients with low-risk del(5q) MDS was associated with disease progression in this set of 56 patients Patients with TP53 mutation pre- progression, n (%): 10 (18) TP53 mutations were associated with overexpression of p53 protein Progression to AML Disease progression* OS *to >10% blasts or complex karyotype

25. Management of myelodysplastic syndromes

27. Higher Risk MDS CHEMOTHERAPY Intensive Low dose Ara C Newer chemotherapeutic agents ALLOGENEIC SCT HYPOMETHYLATING AGENTS

28. Higher Risk MDS CHEMOTHERAPY Intensive Low dose Ara C Newer chemotherapeutic agents ALLOGENEIC SCT HYPOMETHYLATING AGENTS

31. Higher Risk MDS CHEMOTHERAPY Intensive Low dose Ara C Newer chemotherapeutic agents ALLOGENEIC SCT HYPOMETHYLATING AGENTS

33. Higher Risk MDS CHEMOTHERAPY Intensive Low dose Ara C Newer chemotherapeutic agents ALLOGENEIC SCT HYPOMETHYLATING AGENTS

35. Higher Risk MDS CHEMOTHERAPY Intensive Low dose Ara C Newer chemotherapeutic agents ALLOGENEIC SCT HYPOMETHYLATING AGENTS

40. Higher Risk MDS CHEMOTHERAPY Intensive Low dose Ara C Newer chemotherapeutic agents ALLOGENEIC SCT HYPOMETHYLATING AGENTS

43. Comparison of Decitabine & Azacitidine Phase 3 Trials ParametersDecitabineAzacitidine CrossoverNA53% Response Criteria IWGCALGB % of IPSS Int-2/High 69NA % of prior therapy 2216 Median duration of MDS (months) 7.32.8 Median number of treatment cycles 39 Kantarjian H, et al. Cancer. 2006;106:1794-803.; Silverman LR, et al. J Clin Oncol. 2002;20:2429-40; Kaminskas E. Clin Cancer Res. 2005;11:3604-8; Cheson BD. Blood. 2000;96:3671-74. NA = Not available.

44. Comparison of Decitabine & Azacitidine Phase 3 Trials Parameters DecitabineAzacitidine Response Rates (CR + PR) 17% (9%+8%) 16.2% (6.1%+10.1%) Overall Survival (DMTi vs BSC) 14 v 14.9 (p=0.636) 20 v 11 (p=0.10) Median Response10 m15 m Treatment-associated Mortality 14% ≤ 1% Kantarjian H, et al. Cancer. 2006;106:1794-1803.; Silverman LR, et al. J Clin Oncol. 2002;20:2429-40; Kaminskas E. Clin Cancer Res. 2005;11:3604-8; Cheson BD. Blood. 2000;96:3671-74. NA = Not available.

45. Treatment of Lower Risk MDS Erythropoiesis stimulating agents Thalidomide Hypomethylating agents Immunosuppressive drug

46. Special case of MDS with del 5q Higher risk MDS with del 5 q Lower risk MDS with del 5q

47. Special case of MDS with del 5q Higher risk MDS with del 5 q Lower risk MDS with del 5q

52. Special case of MDS with del 5q Higher risk MDS with del 5 q Lower risk MDS with del 5q

59. Conclusions MDS classifications and prognosis are in transitional phase : FAB, WHO, IPSS, WPSS, fibrosis, immunophenotyping… Hypomethylating agents are a back stone in the treatment of MDS Lenalidomide shows a very promising result in MDS with del 5q

60. Thank you