IPSS Modified 7/27/2011. WHO-Based Prognostic Scoring System (WPSS)

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1 Advances in MDS Treatment: What s on the Horizon? New Prognostic Models and Therapies Jason Gotlib, MD, MS Assistant Professor of Medicine (Hematology) Stanford Cancer Center AA&MDSIF July 3, 011 WHO-Based Prognostic Scoring System (WPSS) IPSS Modified Factors affecting prognosis Transfusion dependence BM fibrosis (>+) Cytogenetics Low Risk: 5q, 1p, 0q, +1, -Y, 11q, normal, 5q+1 Int 1: +1q, 3q1, +8, +19, -1, t(7q), any single/double abnl Int: -X, -7, double abnl with -7, complex with 3abnl Unfavorable: complex with >3 abnl 1

2 IPSS Modified Fibrosis and survival RA RAEB Newer Cytogenetic Prognostic Data in MDS Risk Group Favorable Intermediate-1 Karyotypes ( groups) 5q-, 1p-, 0q-, +1, -Y, 11q-, t(11(q3)), normal, any abnormalities including 5q- +1q, 3q1/q6 abnormalities, +8, t(7q), +19, -1, any other single abnormality, any double abnormality not including abnormalities of chromosomes 5q or 7 Median survival, months Time until 5% of patients developed AML, months Intermediate- -X, -7 or 7q-, any double abnormality with -7 or 7q-, complex with 3 abnormalities Unfavorable Complex with >3 abnormalities Haase D et al, MDS Foundation Symposium, Patras, Greece; May 009 IPSS-R Expanded database 4417 patients from 15 international institutions Changes/improvements 5 (rather than 3) cytogenetic groups ANC cutpoint 800 Weighted groups cyto>blasts>>hb>plt=anc 5 (rather than 4) prognostic groups Additional minor variables: age, PS, ferritin, marrow fibrosis Proc International Symposium on MDS, Edinburgh, UK, May 011, Leuk Res 35 (Suppl 1): S6, 011, abstract #14.

3 IPSS-R Survival, median, years Development of AML, median # years 5% of patients, developing AML, median # years 1 Very Low Low 3 Intermediate 4 High 5 Very High NR NR NR Proc International Symposium on MDS, Edinburgh, UK, May 011, Leuk Res 35 (Suppl 1): S6, 011, abstract #14. N Engl J Med 011;364: Mutations found in 18 genes Mutations in 6/439 (51.5%) samples 3

4 Multivariate Model 5 genes were present in 137/439 patients (31.%) and were significantly associated with an increased risk of death Overall Survival IPSS Mutational Status Overall Survival 4

5 Overall Survival Summary 18 genes identified, including previously not described in MDS Mutations common (51%) 5 genes with independent prognostic significance, present in 174/439 (40%) Prognostication improvement from IPSS New Investigational Therapies 5

6 Percent survival 7/7/011 Oral Clofarabine in High-Risk MDS Response Dose (mg/m ) N CR (%) HI (%) CB (%) Total (%) Total Deaths on Study: 3 patients (9%) PO Clofarabine in HR-MDS Response Duration and Survival Outcome Median (range), m Duration of response 5.1 (0.5-0) Survival 9. ( ) Survival (responders) 13.8 ( ) Survival (CR pts) 0.9 ( ) PO Clofarabine in HR-MDS Overall Survival with prior Hypomethylators vs no Hypomethylators N Died Median No hypomethylators Hypomethylators p value Months 6

7 TLK199 (ezatiostat hydrochloride) Responses in all lineages -- Phase II underway studying doses -- Study combining TLK199 + lenalidomide (Revlimid) Raza et al. Blood 009;113:6533 Oral AZA Phase I study of 45 patients 34 MDS, 9 AML, CMML MTD of oral AZA was 480mg/d x 7d q8d DLT Grade 3/4 diarrhea Of 14 subjects receiving >6 cycles: 4 CR 6 SD Garcia-Manero et al. Blood 009;114:117a. Phase I Len + AZA Results Dosing Cohort AZA Dose 75 mg/m SC days mg/m SC days mg/m SC days mg/m SC days 1-5, mg/m SC days 1-5, mg/m SC days 1-5, 8-1 Sekeres et al. JCO 010 LEN Dose 5 mg PO days mg PO days mg PO days mg PO days mg PO days mg PO days 1-1 IPSS Risk Group 1 Int-1 Int- Int- 1 High 1 Int- High 1 Int-1 Int- Int- 1 High 1 Int-1 1 Int- 1 High Grade 3/4 non-heme Toxicities 1 0 Maximum Response CR 1 progression 1 CR 1 PR, 1 HI CR, 1 stable disease CR, 1 stable disease 1 HI 1 stable disease 1 progression 1 HI BM CR 7

8 MDS: AzaC + Lenalidomide Treatment Sekeres et al, J Clin Onc May 010 Phase I trial, minimal prior therapy N=18, IPSS Int1, Int 10, High 6 Age 68y, f/u 7 mo, Cycles 3.5 median (1-7) Dose:AzaC 75/m x5d, lenalidomide 10mg/d d1-1 Overall response 67% (44% CR), duration 7.5 mo, AML Normal cytogenetics associated w/ response Other Selected ASH 010 MDS Abstracts Abstr act # Authors Agents Comments 601 Prebet et al Azacitidine +/- Entinostat (ECOG 1905) 4010 Seetharam et al ONO1910.Na (Onconova) in MDS No significant improvement in responses with addition of Entinostat Polo-1 kinase inhibitor; modest responses Acknowledgements for Slides Dr. Peter Greenberg Dr. Mikkael Sekeres Dr. David Steensma Dr. Guillermo Garcia-Manero Dr. Elaine Sloand Dr. Stefan Faderl Dr. P.K. Epling-Burnette 8

9 MDS Information Resources Aplastic Anemia and MDS Foundation MDS Foundation Leukemia and Lymphoma Society National Comprehensive Cancer Network (NCCN) 9