Overview. Overview 6/17/2013. New Directions in Myelodysplastic Syndromes: What s on the Horizon? Defining Terms

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1 ew Directions in Myelodysplastic Syndromes: What s on the Horizon? Mikkael A. Sekeres, MD, MS Professor of Medicine Director, Leukemia Program Taussig Cancer nstitute verview verview Defining Terms Approaches For Lower-risk Disease Approaches For Higher-risk Disease Conclusions Defining Terms Approaches For Lower-risk Disease Approaches For Higher-risk Disease Conclusions nternational Prognostic Scoring System Lower Risk Adapted from Vardiman et al. Blood 009;114:937. Lower Risk 5-9% Blasts 10-19% Blasts >0% Blasts = AML! Calculation of prognostic score Score BM Blast % < Cytogenetics Good ntermediate Poor Cytopenias 0/1 /3 Estimation of prognosis verall PSS Subgroup Median Survival Lower Score (Years) Risk 0 Low ntermediate ntermediate- 1. >.5 High 0.4 Cytopenias: AC < 1.5, HGB < 10.0, PLT < 100,000 Good Risk: [-Y,del(5q), del(0q),l]; ntermediate Risk: [8+,other]; Poor Risk: [Chr. 7 abn, >3 abn] Greenberg P, et. al. Blood 1997:89:

2 Revised PSS (PSS-R) points blasts ( %) <% - -4% % >10% Hemoglobin >10 g/dl 8-10 g/dl <8 g/dl AC >0.8 G/l <0.8 G/l Platelet > <50 Cytogenetics Very Good -Y del(11q) Good ormal der(1;7) del(5q) del(0q) del(1p) Double incl del(5q) P. Greenberg et al, Blood 01 [Epub ahead of print] ntermed -7/7q +8 so(17q) other double inclusions Poor: der3q(1) der3q(6) Complex Double inclusion 7q/7 Very Poor Complex >3 4 categories 3 categories categories 3 categories 5 categories 16 subgroups o. pts PSS-R utcomes Very Low Low ntermediate High Very High Patients (%) % 38% 0% 13% 10% Survival, All (Years) Hazard ratio [95% C] 8.8 [ ] 0.5 [ ] 5.3 [ ] 1.0 [ ] 3.0 [.7-3.3].0 [1.8-.1] 1.6 [ ] 3. [.9-3.5] 0.76 [ ] 8.0 [7.-8.8] Patients (%) % 37% 0% 13% 11% AML/5% (Years) Hazard ratio [95% C] R [14.5-R] 0.5 [.4-.6] 10.8 [9.-R] 1.0 [ Lower-risk Greenberg et al. Blood 01 [Epub ahead of print] 3. [.8-4.4] 3.0 [.7-3.5] 1.4 [ ] 6. [5.4-7.] 0.73 [ ] 1.7 [ ] MDS Classification The Ultimate Simplification!!! Lower Risk RA, RARS RCMD, RCUD MDS-U, MDS del (5q) PSS Low, nt-1 (0-1.0); PSS-R V. Low, Low verview Defining Terms Approaches For Lower-risk Disease Approaches For Higher-risk Disease Conclusions Higher Risk RAEB (-1, -) PSS nt-, High (> 1.5); PSS-R High, V. High Treatment with the TP-Receptor Agonist in Thrombocytopenic Patients with Low or nt-1 Risk MDS: Results of a Randomized, Double-Blind, Placebo-Controlled Study Aristoteles Giagounidis 1, Ghulam Mufti, Hagop Kantarjian 3, Pierre Fenaux 4, Mikkael Sekeres 5, Jeffrey Szer 6, Andrea Kuendgen 7, Uwe Platzbecker 8, Gianluca Gaidano 9, Wieslaw Wiktor-Jedrzejczak 10, Kuolung Hu 11, Allen S. Yang 11, Susie Jun 11 1 Duisburg, Germany, London, United Kingdom, 3 Houston, TX, 4 Bobigny, France, 5 Cleveland, H, 6 Melbourne, Australia, 7 Duesseldorf, Germany, 8 Dresden, Germany, 9 ovara, taly, 10 Warsaw, Poland, 11 Thousand aks, CA ASH 011 S C R E E G Study Design R A D M Z A T 6-Week Treatment Period 750 mcg weekly ( = 160) Placebo weekly ( = 80) T E R M B M B P S Y 4-Week Treatment Continuation 750 mcg weekly + standard of care ( = 160) Placebo weekly + standard of care ( = 80) Week 1 Week 6 Week 30 Week 48 Week 5 o P o P Eligible patients were PSS low/int-1 MDS receiving supportive care only, with platelets 1) 0x10 9 /L or ) 50x10 9 /L with a history of bleeding, and stratified by baseline PSS status (low, int-1) and platelet count (<, 0x10 9 /L). The first patient enrolled in July 008 with last end-of-study visit in March 011. P dose was adjusted per platelet count. ASH 011 E T B M B P S Y L T F U A D E S

3 Clinically Significant Bleeding Events (CSBE) and Protocol-defined Transfusions Events (PTE) Placebo ( = 43) Baseline platelets < 0x10 9 /L ( = 87) Placebo ( = 40) ( = 80) CSBE (rate/100 pt-yr) RR = 1.03, p = 0.87 Baseline platelets 0x10 9 /L RR = 0.35, p< PTE (rate/100 pt-yr) RR = 0.71, p< RR = 1.38, p = Progression to AML Placebo Total HR, 95% C Study-defined AML /8 (.4%) 10/168 (6.0%) 1/50 (4.8%).54, RAEB-1/- /9 (%) 6/5 (4%) 8/34 (4%) 1.06, on-raeb 0/73 (0%) 4/143 (.8%) 4/16 (1.9%) A AML Diagnosis by: - BM/perip blast >0% 1/8 (1.%) 5*/168 (3.0%) 6/50 (.4%) - Anti-AML therapy 1/8 (1.%) 3/168 (1.8%) 4/50 (1.6%) ASH 011 ASH 011 Treatment with the Thrombopoietin (TP)- Receptor Agonist in Thrombocytopenic Patients with Low or nt-1 Risk MDS: Follow-up AML and Survival Results of a Randomized, Double-Blind, Placebo (PB)- Controlled Study (# 41) Hagop Kantarjian 1, Ghulam Mufti, Pierre Fenaux 3, Mikkael Sekeres 4, Jeffrey Szer 5, Uwe Platzbecker 6, Andrea Kuendgen 7, Gianluca Gaidano 8, Wieslaw Wiktor-Jedrzejczak 9, John Bennett 10, Anne Meibohm 11, Allen S. Yang 1, Aristoteles Giagounidis 13 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, Kings College London, London, United Kingdom, 3 Service d'hématologie clinique, Hopital Avicenne Universite Paris X, Bobigny, France, 4 Cleveland Clinic, Taussig Cancer nstitute, Cleveland, H, 5 Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia, 6 University Hospital Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik, Germany, 7 Heinrich-Heine-University of Düsseldorf, Medizinische Klinik und Poliklinik A, Germany, 8 Amedeo Avogadro University of Eastern Piedmont, ovara, taly, 9 Medical University of Warsaw, Warsaw, Poland, 10 University of Rochester, Medical Center, Rochester, Y, 11 ckham, Cary, C 1 Amgen nc., Thousand aks, CA, 13 Katholisches Klinikum Duisburg, St. Johannes Hospital, Duisburg, Germany ASH 01 in MDS. 58-week Updated Data Placebo HR 95% C Deaths 17.9% (30) 0.7% (17) , 1.56 AML 6.0% (10) 4.9% (4) , 3.84 AML-free survival 19.6% (33) 3.% (19) , 1.50 (x) = x patients Two AML cases in PB arm occurred within the 58-week study period; not recorded in time for interim analysis in 011. in MDS. Survival Through July 01 LTFU data out to 3 years verall Survival Probability Time (months) Patients at Risk: Placebo (x) = x patients verall Survival HR 1.08 (95% C: 0.70, 1.67) Placebo Time (months) Patients at Risk: Placebo Placebo HR 95% C Deaths 38.1% (64) 37.8% (31) , 1.67 AML 8.9% (15) 8.5% (7) ,.85 AML-free survival 39.3% (66) 39.0% (3) , 1.68 AML-Free Survival Probability AML-Free Survival HR 1.09 (95% C: 0.71, 1.68) Placebo Erythropoietin + G-CSF in MDS: Patient Selection RA, RARS, RAEB Score > +1 Score 1 to +1 Score < 1 Treatment response score s-epo <100 + U/L >500 3 Transf < units/m + U RBC/m = or > units/m Hellström-Lindberg E et al. Br J Haematol. 003;10:1037 Good response (74%, n=34) ntermediate response (3%, n=31) Poor response (7%, n=9) 3

4 Model to Predict Response to in MDS Model in Primary Study MDS patients treated with romiplostim Baseline TP: <500 pg/ml pg/ml -3 Prior platelet transfusion: <6 units +1 6 units -3 Score +3 ( = 69) Score -1, - ( = 71) Score -6 ( = 3) Response rate 65.% 33.8% 17.4% Response is defined here as 50% of weeks with platelet response. A history of prior platelet transfusion (<6 vs. 6 units in the past year) was a better predictor of platelet response than baseline platelet counts. Sekeres et al. ASH 01 (# 801) Phase : Alemtuzumab in PSS nt-1/nt- MDS With High PPR For mmunosuppressive Therapy Key Eligibility (goal n=39): De novo MDS with cytopenias and <5% blasts High likelihood (PPR) of ST response (using 003 formula) o prior ATG/CSA Regimen: Alemtuzumab (anti-cd5) test dose, then 10 mg V/day x 10 days TMP/SMX and valgancyclovir prophylaxis Results: Enrolled patients younger (median ~53 years old) and more hypocellular (45%) than a typical MDS population WG responses in 15/16 (93%) with nt-1 MDS, /5 (40%) with nt- Cytogenetic remission in 5/7 Transient EBV positivity in 4/ Sloand EM et al Abstract #116 - ASH 009 Phase / Study of ntravenous Liposomal TLK199 in MDS Liposome n=54 Responses: Trilineage responses in 4/16 pts (5%) with pancytopenia H-E in 9/38 (4%) anemic pts H- in 11/6 (4%) neutropenic pts H-P in 1/4 (50%) thrombocytopenic pts Adverse events: Most mild & attributable to liposomal preparation (e.g. back pain, chills, nausea, bone pain, and diarrhea) Raza A et al J Hematol ncol :0, 009 Response Type Phase ral Ezatiostat 3000 mg/day wks on/1 wk off (n=30) 000 mg/day 3 wks on/1 wk off (n=31) Total (n=61) H E (%) (95% C) 7 (4) (10 44) 6 (19) (8 38) 13 () (1 34) H (%) (95% C) 1 (10) (0 45) 3 (7) (6 61) 4 (19) (5 4) H P (%) (95% C) 1 (7) (0 34) 0 (0) (0 5) 1 (4) (0 19) Bilineage (H-E and H-) (%) (95% C) 1 (11) (0 48) 3 (7) (6 61) 4 (0) (6 44) Trilineage (H-E, H-, and H-P) (%) (95% C) 1 (17) (0 64) 0 (0) (0 5) 1 (9) (0 41) Median Time (Weeks) to H-E Response (Range) 8 (8 10) 8 (8 11) 8 (8 11) Median Duration (Weeks) of H-E Response (Range) 18 ( 51) 46 ( 63) 34 ( 63) # of RBC Transfusion Dependent Patients (%) 0 (69) 18 (58) 38 (63) RBC Transfusions Reduced by 4U/8wks (%) (95% C) 6 (30) (1 54) 5 (8) (10 54) 11 (9) (15 46) RBC Transfusion ndependence (%) (95% C) 1 (5) (0 5) 3 (17) (4 41) 4 (11) (3 5) Raza et al. Blood 010;116:910a Safety and Efficacy of ral Azacitidine (CC-486) Administered in Extended Treatment Schedules to Patients with Lower-Risk Myelodysplastic Syndromes Guillermo Garcia-Manero, MD 1 Steven D. Gore, MD, Suman Kambhampati, MD 3, Bart L Scott, MD, MS 4, Ayalew Tefferi, MD 5, Christopher R Cogle, MD 6, William Edenfield, MD 7, Joel Hetzer, PhD 8, Keshava Kumar, PhD 8, Tao Shi, PhD 8, Kyle MacBeth, PhD 8 and Barry S. Skikne, MD 8 1 University of Texas, MD Anderson Cancer Center, Houston, TX; The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD; 3 Department of Hematology/ncology, University of Kansas Medical Center, Kansas City, KS; 4 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 5 Division of Hematology, Department of nternal Medicine, Mayo Clinic, Rochester, M; 6 Medicine/Hematology & ncology, University of Florida; 7 Cancer Centers of The Carolinas, Greenville, SC; 8 Celgene Corporation, Summit, J Study Design Multicenter, phase 1 study Lower-risk MDS (LR-MDS, PSS Low or T-1) RBC transfusion dependent (TD) or Hgb 9 g/l at baseline; or Platelet TD or thrombocytopenic (mean platelet count 50,000 within 56 days before first dose) Sequential assignment to 300 mg x 14d (n=6) or x 1d (n=7) dosing per 8d cycles Hematologic assessments (WG 006 criteria 1 ) every weeks Whole blood evaluation of global DA methylation (nfinium 7K Array) BL (Screen/C1D1) P D 1. Cheson et al. Blood006;108:419-5 PD Hematologic Assessments ral AZA 300 mg QD x 14 day P D 4 ral AZA 300 mg QD x 1 da PD Hematologic Assessments 4

5 Parameter Hematologic Response Treatment Schedule n Responders/ Evaluable* (%) 14d QD (n=6) 1d QD (n=7) Total (=53) 5 Combinations in lower-risk MDS E1905 LE + ESA (enrollment ongoing) European study with 40% higher response rate verall Response* (CR, PR, any H, T) 11/6 (4.3) 10/7 (37.0) 1/53 (39.6) Any H 7/6 (6.9) 8/7 (9.6) 15/53 (8.3) H E 4/3 (17.4) 6/5 (4.0) 10/48 (0.8) H P 4/17 (3.5) 3/15 (0.0) 7/3 (1.9) H 3/10 (30.0) 0/6 3/16 (18.8) RBC T Sustained 56 days Sustained 84 days *WG 006 criteria 8/15 (53.5) 3/15 (0.0) 6/15 (40.0) 5/15 (33.3) 14/30 (46.7) 8/30 (6.7) LE + TLK199 LE + (ASH 009) 39 patients randomized to R500, R750, Placebo Slightly fewer bleeding events in R arms verview Azacitidine Survival Study Defining Terms Approaches For Lower-risk Disease Approaches For Higher-risk Disease Conclusions Higher-risk MDS nly! nvestigator CCR Tx Selection Randomization BSC was included with each arm. Tx continued until unacceptable toxicity, AML transformation, or disease progression AZA 75 mg/m /d x 7 d q8 d [n=179] Conventional care regimens Best Supportive Care (BSC) [n=105] Low Dose Ara-C (LDAC, 0 mg/m /d x 14 d q8-4 d) [n=49] Std Chemo (7 + 3) [n=5] Fenaux P, et al. Lancet ncology 009;10:3-3. verall Survival: Azacitidine vs CCR TT Population Proportion Surviving months Log-Rank p= HR = 0.58 [95% C: 0.43, 0.77] Deaths: AZA = 8, CCR = 113 Difference: 9.4 months 50.8% 4.4 months CCR AZA Time (months) from Randomization Fenaux P, et al. Lancet ncology 009;10: % Lubbert et al. JC 011;9:1987. EU DAC Phase 5

6 EU DAC Phase Why o Survival Advantage for DAC? umber of treatments courses given Different populations and comparator groups MDS duration Cytogenetic risk groups Performance status How the drug was given Lubbert et al. JC 011;9:1987. Median S 10.1 vs. 8.5 months DAC: Alternative Dosing Combinations in higher-risk MDS Hypomethylating agents + Minimize bleeding, cycle delays Hypomethylating agents + HDAC- HDACs promote cell-cycle arrest and apoptosis of cancer cells through gene expression regulation Hypomethylating agents + LE Attack MDS clones by different MA Steensma et al. JC 009;7:384 Hypomethylating Agents + Phase Study 5-azacitidine and Vorinostat in Patients with ewly Diagnosed MDS or AML ot-eligible for Clinical Trials G Garcia-Manero, E Estey, E Jabbour, G Borthakur, T Kadia, K aqvi, R Levine, Z Estrov, A Quintas-Cardama, M Konopleva, S Faderl, M Tanaka, H Yang, F Ravandi, WG Wierda, J Cortes, PA Boone and HM Kantarjian Kantarjian et al. Blood 010;116: 3163 Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX; Hematology/ncology, Fred Hutchinson Cancer Center, Seattle, WA; Leukemia Service, Memorial Sloan Kettering Cancer Center, Y; Hematology/ncology, Baylor College of Medicine, Houston, TX 6

7 AZA+Vorinostat: Reasons for Eligibility 4 (13% ) with > 1 criteria AZA+Vorinostat: Response (=30) PATET () CR (%) CRp (%) RR ALL 8 (6) 1 (3) 30 Diploid (7) 3 (4) 0 4-5/-7 (16) 3 (10) 1 (3) (3) (66) 0 66 Stopping rule met by patient #8 Median courses to response= (1-9) Final Results from the Phase Continuation Study of the Lenalidomide and Azacitidine Combination in Patients with Higher-risk Myelodysplastic Syndromes Mikkael A. Sekeres, Rami Komrokji, Jeffrey Lancet, Ramon Tiu, Anjali Advani, Manuel Afable, Ricki Englehaupt, Joyce Juersivich, David Cuthbertson, Jennifer Paleveda, Ronald Paquette, April Smith, Lori Strozniak, Alan F. List, Jaroslaw P. Maciejewski Leukemia Program, Cleveland Clinic Taussig Cancer nstitute, Cleveland, hio; H. Lee Moffitt Cancer Center, Tampa, Fl; University of California, Los Angeles, CA H. Lee Moffitt UCLA Dosing Cohort Len + AZA Phase 1: Go-forward Dose 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. JC 010;8:53 LE Dose 5 mg P days mg P days mg P days mg P days mg P days mg P days 1-1 PSS Risk Group 1 nt-1 nt- nt- 1 High 1 nt- High 1 nt-1 nt- nt- 1 High 1 nt-1 1 nt- 1 High Grade 3/4 non-heme Toxicities 0 5 Maximum Response CR 1 progression 1 CR 1 H 1 stable disease CR, 1 stable disease CR, 1 stable disease 1 H 1 stable disease 1 progression 1 CR 1 H 1 BM CR RR = 67% (44% CR) Len + Aza Phase : Response Results REV-AZA Study Correlation of Mutational Status and Responses 0 Mutant Wild Type CR/ BM CR % 100% 100% 100% umber of Patients % 67% 67% 46% Sekeres et al. Blood 01 [Epub ahead of print] 0 TET DMT3A DH1/ SF3B1 Molecular Status Sekeres et al. Blood 01 [Epub ahead of print] All mutations 7

8 orth American ntergroup Randomized Phase MDS Study S1117 verview Higher-risk MDS (PSS >1.5) AZA =80 AZA + LE =80 AZA + Vorin =80 = 110 as of 6-13 Groups: SWG, ECG, CALGB, CC Total Sample Size: 40 Primary bjective: 0% improvement of RR based on 006 WG Criteria Secondary bjectives: S, RFS, LFS Power 81%, alpha 0.05 for each combo arm vs. AZA Anticipated time:.5 years Defining Terms Approaches For Lower-risk Disease Approaches For Higher-risk Disease Conclusions Conclusions ral Clo for Patients Failing Hypomethylating Agents We need to do better Focusing on patients who fail previous disease-modifying therapies is the next regulatory frontier Sekeres et al. Blood 010;116:1869a a - Multikinase nhibitor a Development History Cell-cycle functions and localizations of Plk a Multikinase inhibitor Polo-like kinase 1 modulator? P3K/Akt/ERK pathway inhibitor nduces Bim, inhibits Mcl-1 activation Reduces cyclin D1 levels Barr F et al ature Reviews Molecular Cell Biology 004; 5: = ngoing MDS/AML study recruiting pts per clinicaltrials.gov Source: 8

9 Bone Marrow Transplant for MDS n an evidence-based review sponsored by ASBMT, the panel recommended: Early SCT for higher-risk and poor-risk lower-risk o rec for pre-sct induction chemo o rec for related vs. unrelated donor o rec for RC vs. high-dose conditioning PBSCT from related donor with possible advantage in lower-risk. o rec from unrelated donors. liansky et al. BBMT 009;15:137. Stem Cell Transplantation: Approximation of Life Expectancy (Years) Low nt-1 nt- High mmediate Transplant Cutler C, et al. Blood 004- Prepublished online March 3, 004; D01.118/Blood Transplant at Progression A Decision Analysis of RC Allogeneic HSCT for lder Patients with De-ovo MDS: Early Transplantation ffers Survival Benefit in Higher-Risk MDS John Koreth, MBBS DPhil; Joseph Pidala, MD MS; Waleska S. Perez, MPH; H. Joachim Deeg, MD; Guillermo Garcia-Manero, MD; Luca Malcovati, MD; Mario Cazzola, MD; Sophie Park, MD PhD; Raphael tzykson, MD; Lionel Ades, MD; Pierre Fenaux, MD; Martin Jadersten, MD PhD; Eva Hellstrom-Lindberg, MD PhD; Robert Peter Gale, MD PhD; C. L. Beach, PharmD; Peter L. Greenberg, MD; Martin S. Tallman, MD; John F. DiPersio, MD PhD; Donald Bunjes, MD; Daniel J. Weisdorf, MD; Corey Cutler, MD MPH FRCP(C) Monte Carlo Low/int-1 PSS Survival Estimates Test Test of Equality over Strata p Log-Rank <.0001 Wilcoxon < Log(LR) <.0001 Koreth et al. JC 013 LK _15.ppt Monte Carlo nt-/high PSS Survival Estimates Clinical Trials Why participate? Test Test of Equality over Strata p Log-Rank <.0001 Wilcoxon < Log(LR) <.0001 Patients play an active role in their own health care, they become engaged Patients can gain access to new treatments that may not be otherwise available, before formal governmental (FDA) approval Koreth et al. JC 013 LK _16.ppt Patients can help others by contributing to medical research and helping establish new and better treatments for future patients 9

10 Clinical Trials Who can or should participate? Patients with a disease where treatment is not curative Clinical trials have inclusion and exclusion criteria to Protect the safety of the patient from the new treatment being tested Help produce reliable results which will make sure the trial really determines if the new treatment is effective nclusion/exclusion criteria include age, type and stage of disease, prior treatment history, organ function (heart, lung, kidneys) to make sure the treatment is safe Clinical Trials Phases Phase -designed to determine the best and safest dose and identify side effects Phase -designed to determine the effectiveness of the new treatment Phase -designed to compare the effectiveness of the new treatment to the commonly used treatment Phase V-postmarketing (after FDA approval) trial to further refine the risks and benefits and identify new side effects once the new treatment is widely used Thanks! Cleveland Clinic Leukemia/MDS Program Jaroslaw Maciejewski, MD, PhD Yogen Saunthararajah, MD Anjali Advani, MD Matt Kalaycio, MD Ramon Tiu, MD Ronald Sobecks, MD Hien Duong, MD Brian Hill, MD, PhD Sudipto Mukherjee, MD, PhD Michael Keng, MD Manuel Afable, MD Beth Brien, BA Tracy Cinalli, R Katarina Paulic, BA Kristen Dodd, R Randy Davis, BA Joy Juersivich, R Parisa Talea, BA Barb Tripp, R, P Cassandra Kendleigh, BA Mary Lynn Rush, R Madeline Schaub, BA Monique Biggins, R Laura Bailey, BA Cheryl Redmond, R Tiffany Justi, P Amanda Hooda, P Sean Hobson, BA Ziad Chartouni, BA Marc Earl, PharmD Candice Wenzell, PharmD And ur Patients!!! 10