Lyons RM et al. J Clin Oncol 2009;27(11):

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Lyons RM et al. J Clin Oncol 2009;27(11):1850-56. Hematologic Response to Three Alternative Dosing Schedules of Azacitidine in Patients with Myelodysplastic Syndromes Lyons RM et al. J Clin Oncol 2009;27(11):1850-56.

Introduction Azacitidine has been shown to alter the natural history of myelodysplastic syndromes (MDS) (J Clin Oncol 2002;20:2429; Lancet Oncol 2009;10(3):223; J Clin Oncol 2002;20:2441) Significant prolonged survival in higher-risk MDS and trend toward prolonged survival in all French-American-British (FAB) MDS subtypes; decreased risk of transformation to AML Significant reduction in transfusion dependence in higher- and lower-risk MDS (J Clin Oncol 2002;20:2429; J Clin Oncol 2006;24:3895) The approved AZA regimen is 75 mg/m2/d administered subcutaneously or intravenously for 7 days every 28 days and includes weekend dosing Study Objective: Assess safety and efficacy, based on hematologic improvement and transfusion independence rates, of three azacitidine dosing schedule alternatives that eliminate weekend dosing, in a multicenter, community-based open-label study Source: Lyons RM et al. J Clin Oncol 2009;27:1850-56.

Phase II Trial of Alternative Dosing Schedules of Azacitidine (AZA) in Patients with MDS AZA 5-2-2 (n=50) AZA, 75 mg/m2 SC, d1-5 AZA, 75 mg/m2, d8-9 q28d x 6 Eligibility Diagnosis of MDS: Refractory anemia (RA) or RA with ringed sideroblasts (RARS) requiring a transfusion every 28 days or with thrombocytopenia or neutropenia RA with excess blasts (RAEB) RA with excess blasts in transformation (RAEB-T) Chronic myelomonocytic leukemia (CMML) AZA 5-2-5 (n=51) AZA, 50mg/m2 SC, d1-5  AZA, 50 mg/m2, d8-12 q28d x 6 R AZA 5 (n=50) AZA, 75 mg/m2 SC, d1-5 q28d x 6 SC = subcutaneous Source: Lyons RM et al. J Clin Oncol 2009;27:1850-56.

Hematologic Improvement (HI) AZA 5-2-2 AZA 5-2-5 AZA 5 Major or minor HI1 (Intent-to-treat) (n=50, 51, 50) 44% 45% 56% Onset of HI during first two cycles 82% 90% Major or minor HI, FAB lower-risk patients (n=33, 29, 32) 49% 41% 50% Patients with multilineage cytopenias who experienced multilineage HI (n=32, 24, 30) 34% 21% 33% 1HI evaluated using International Working Group 2000 criteria Source: Lyons RM et al. J Clin Oncol 2009;27:1850-56.

Achievement of RBC Transfusion Independence (TI) Among Baseline RBC Transfusion-Dependent Patients AZA 5-2-2 AZA 5-2-5 AZA 5 Overall (intent-to-treat) (n=24, 22, 25) 50% 55% 64% FAB lower-risk patients (n=17, 12, 18) 53% 61% Onset of TI within first two cycles 92% 75% Absence of baseline neutropenia or thrombocytopenia and lower transfusion requirements were predictive of higher rates of RBC transfusion independence. Source: Lyons RM et al. J Clin Oncol 2009;27:1850-56.

Selected Grade 3 or 4 Adverse Events AZA 5-2-2 (n = 50) AZA 5-2-5 (n = 48) AZA 5 > 1 grade 3 or 4 adverse events 84% 77% 58% Hematologic disorders 66% 50% 34% Anemia Febrile neutropenia Leukopenia Neutropenia Thrombocytopenia 24% 8% 14% 42% 26% 15% 31% 10% 2% 22% 12% Infections 29% Source: Lyons RM et al. J Clin Oncol 2009;27:1850-56.

Summary and Conclusions These three alternate dosing regimens demonstrated good activity and tolerability HI, overall (intent-to-treat): 44%-56% HI, lower-risk MDS: 41%-50% Achievement of TI, overall (intent-to-treat): 50%-64% Achievement of TI, lower-risk MDS: 50%-61% In all dosing arms, the onset of TI and HI was relatively rapid, occurring in the majority of patients within the first two dosing cycles (75%-92% for TI, 56%-90% for HI) Grade III/IV adverse events included hematologic disorders (34%-66%) and infections (10%-29%) The AZA 5 dosing regimen may be a better-tolerated and more convenient dosing schedule than the other two alternative dosing regimens. Source: Lyons RM et al. J Clin Oncol 2009;27:1850-56.