Best of ASH 2007 Myelodysplastic Syndromes Lloyd E. Damon, MD

Hypomethylating Agents in MDS 5-azacitidine and decitabine Incorporate into DNA Block DMT (DNA methyltransferase) Critical DNA moieties are not methylated Reversal of tumor suppressor gene silencing in the MDS clone Restoration of normal hematopoiesis

Cytosine Analogues 5-azanucleoside analogues of cytosine have substitution of C by nitrogen at position 5 of pyrimidine ring C5  N associated with hypomethylating activity NH 2 O O O O N N N N N N N N N N Ribose Deoxyribose CH 3 Cytosine 5-methyl- cytosine 5-aza-2’-deoxy- cytidine 5-aza- cytidine (decitabine)

* BM = Bone Marrow BM ) Supportive Care* RA RARS RAEB RAEB-T CMML StratifyStratify RandomizeRandomize 2) 5-Aza 75mg/m 2 /d x 7 days q28 x 4 Exit Criteria (+) NoContinue until Endpoint (+) Yes ASSESSASSESS Response - Continue Rx No Response - Off Study Day CALGB 9221 A Randomized Phase III Controlled Trial of SQ 5-Azacitidine in MDS Silverman L. The Oncologist (S5): Silverman LR, et al. J Clin Oncol. May 2002;20(10): Kornblith AB, et al. J Clin Oncol : Cycles 1-2Cycles 3-4

CALGB 9221: Response Response Standard of Care (n=92) 5-azacitidine (n=99) Crossover (n=49) CR07 (7%)*5 (10%) PR015 (16%)**2 (4%) Improved5 (5%)38 (37%)**16 (36%) Total Better5 (5%)60 (60%)**23 (47%) Silverman L, et al. J Clin Oncol 2002;20: *p<0.01; **p<0.001

CALGB 9221: Time to AML or Death Probability of Remaining Event-Free Azacitidine Supportive Care Months P = Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGB J Clin Oncol :

CALGB 9221: Overall Survival Probability of Remaining Event-Free Azacitidine Supportive Care P = 0.10 Median 20 months 14 months Months Silverman L, et al. Randomized Controlled Trial of Azacitidine in Patients with MDS: A Study of the CALGB J Clin Oncol 2002; 20:

Azacitidine Prolongs Overall Survival in High-Risk MDS Patients Compared with Conventional Care Regimens: AZA-001 Phase III Study Pierre Fenaux et al ASH 2007 Abstract # 817 The International Vidaza High-Risk MDS Survival Study Group

RAEB, RAEB-T or CMML (FAB) RAEB, RAEB-T or CMML (FAB) IPSS score of INT-2 or High IPSS score of INT-2 or High EligibilityEligibility

ObjectivesObjectives PrimaryPrimary Overall Survival (OS) SecondarySecondary Time to AML or Death Time to AML Hematologic response and improvement Transfusion independence

SchemaSchema AZA 75 mg/m 2 /d x 7 d q28 d CCR Randomization CCR (conventional care regimen) continued until unacceptable toxicity or AML Best Supportive Care (BSC) onlyBest Supportive Care (BSC) only Low Dose Ara-C (LDAC, 20 mg/m 2 /d x 14 d q4-6 weeks )Low Dose Ara-C (LDAC, 20 mg/m 2 /d x 14 d q4-6 weeks ) Std Chemo (7 + 3)Std Chemo (7 + 3) Central Path Review CCR Selection

Patient Features n = 358 AZA N=179 CCR N=179 Age (yrs) Median Pts ≥ 65 (%) FAB (%) RAEB RAEB-TCMML IPSS (%) INT-1 INT-2High

Patient Features by CCR Type AZA N=179 CCR N=179 CCR Regimens BSC Only N=105 LDAC N=49 Std Chemo N=25 Age (yrs) Median Pts ≥ 65 (%) FAB (%) RAEB RAEB-TCMML IPSS (%) INT-1 INT-2High

Treatment Cycles and Duration Cycles (Median #) Duration (Median mos) AZA910.4 BSC only 76.2 LDAC Std Chemo 11.5

Number at risk AZA CCR Overall Survival: Azacitidine vs CCR p = p = HR = 0.58 [ ] Time (months) from Randomization Proportion Surviving CCR AZA F/U = 21 mo

Overall Survival: Azacitidine vs CCR Time (months) from Randomization Proportion Surviving CCR AZA Difference: 9.4 months 24.4 months 15 months 50.8%26.2%

Hazard Ratios for OS ITT Subgroups Total - Event / N Cytopenias: 0/1 20 / / 53 WHO: RAEB-1 15 / / Favors Azacitidine Favors CCR ≥ / 258 Female 61 / / 107 FAB: RAEB 95 / / 207 RAEB-T 80 / / 123 RAEB-2 RAEB / 193 IPSS: INT-2 71 / / 146 High High 98 / / 167 Cytogenetics: Good 80 / / 167 Intermediate Intermediate 38 / / 76 Poor Poor 67 / / 100 2/3 2/3 167 / 290 Karyotype: -7/del (7q) 42 / / 57 ≥ 21% to < 31% 58 / / 99 AGE: < / / 100 LDH: ≤ 240 U/I 97 / / 208 RAEB & RAEB-T: AGE ≥ / 240 > 240 U/I 94 / / 145 ITT 195 / 358 ≥ / / 87 ≥ 11% to < 21% 98 / / 192 Male 134 / 251 BM Blasts: ≥ 5% to < 11% 34 / / 61

Secondary Endpoints Time to AML or deathTime to AML or death 13 mos AZA vs 7.6 mos, p=0.003 Time to AMLTime to AML 26.1 mos AZA vs 12.4, p=0.004 RBC Transfusion IndependenceRBC Transfusion Independence 45% vs 11%, p<0.0001

Secondary Endpoints: IWG (2000) RR and HI Response AZA N=179 (%) CCR N=179 (%) P Value Overall (CR+PR) CR PR IWG HI Major+Minor4929< HI-E Major 4011< HI-P Major HI-N Major

OS by CCR Treatment Median OS (mo)  OS (mo) Hazard Ratio Log- rank P AZA (N=117) vs BSC (N=105) AZA (N=45) vs LDAC (N=49) AZA (N=17) vs Stand Chemo (N=25)

Conclusions Abstract # 817 AZA prolongs OS compared with CCRAZA prolongs OS compared with CCR Consistent effect across demographic and risk subgroupsConsistent effect across demographic and risk subgroups AZA was well toleratedAZA was well tolerated Azacitidine should now be the standard of care for high-risk MDSAzacitidine should now be the standard of care for high-risk MDS

Results of the initial treatment phase of a study of three alternative dosing schedules of azacitidine (Vidaza®) in patients with myelodysplastic syndromes Lyons RM et al Abstract # 819

5-Azaciditidine5-Azaciditidine FDA label –75 mg/m2 SQ daily X 7 doses Q28 days –75 mg/m2 IV daily X 7 doses Q28 days Investigational formulation –Oral Schedule? –Are there other equally effective dosing schedules for 5-azacitidine?

Alternative Dosing Schedules Daily SQ Doses - Monthly Cycles RA RARS RAEB RAEB-IT CMMoL RANDOMIZERANDOMIZE mg/m2 X 5, 2 days off, X 2 (total = 525 mg/m2) mg/m2 X 5, 2 days off, X 5 (total = 500 mg/m2) mg/m2 X 5 (total = 375 mg/m2)

Hematologic Improvement (IWG) Major HI (%) Erythroid Platelets Neutrophils Major + Minor HI (%) RBC Transfusion Independence (%) No statistical difference between comparisons

Abstract # 819 Conclusions Across monthly 5-azacitidine doses of 375 to 525 mg/m2, HI and RBC Tx- Independence appear equivalent Across monthly 5-azacitidine schedules of 5 to 10 doses per cycle, HI and RBC Tx- Independence appear equivalent The 5-2-2, 5-2-5, and 5 regimens appear equivalent to the FDA-approved dose and schedule

AMG 531 Two identical peptides bound to two human IgG1 Fc fragments Fc prolongs the circulatory half-life MplThe peptides bind to the human thrombopoietin receptor, Mpl Stimulates thrombopoiesis Effective in ITP* Administered SQ *NEJM, 2006; 355:

AMG 531 NEJM, 2006; 355:

Phase 1/2 study of AMG 531 in thrombocytopenic patients with low-risk myelodysplastic syndrome: update including extended treatment. Kantarjian H, et al Abstract # 250

Eligibility - Design Eligible –IPSS Low or Int-1 (not CMML) –Platelets ≤50 –Supportive care only Treatment –Sequential cohorts –300, 700, 1000, and 1500 mcg SQ weekly X 3 –Continue weekly therapy if responding End points –Platelet response at week 4 and duration of response –# platelet transfusions –safety

Outcomes of AMG 531 Platelet response –41% overall (n=40 evaluable) 41% if baseline platelet ≥20 40% if baseline platelet <20 –Median duration of response 23 weeks Transfusions –104 Tx given to 39% of patients –17% of patients with a platelet response needed a TX Safety –17 patients with AE, no deaths –2 cases of AML, 6 cases of increasing blasts

AMG 531 Conclusions Abstract # 250 A substantial proportion of severely thrombocytopenic MDS patients respond to AMG 531 The duration of response is nearly 6 months There is no clear indication that AMG 531 accelerates AML transformation AMG 531 has very few side effects