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Background: Approximately 40-60% of older patients (pts) with AML achieve complete remission (CR) with IC. Factors influencing the use of consolidation after induction include disease-related considerations, extent of hematopoietic recovery, pt fitness, and physician and pt preference. Most older pts who achieve AML remission will experience disease relapse despite consolidation therapy (Schlenk, Haematologica, 2018). In the phase III, randomized, double-blind QUAZAR AML-001 Maintenance Trial, CC-486, an oral hypomethylating agent, was shown to significantly prolong OS and RFS vs. placebo (PBO) in pts with AML in first remission following induction ± consolidation. Prior to study entry, the use of consolidation chemotherapy and number of consolidation cycles was at the discretion of the treating physician, with study eligibility not contingent on the use of consolidation. Objective: Assess survival outcomes in the QUAZAR AML-001 trial in pt subgroups defined by number of consolidation courses received before study entry. Methods: Eligible pts were aged ≥55 years with newly diagnosed AML, intermediate- or poor-risk cytogenetics, and ECOG PS ≤3. Within 4 months (mo) of attaining first CR or CR with incomplete blood count recovery (CRi), pts were randomized 1:1 to CC-486 300 mg or PBO QD for 14 days per 28-day treatment (Tx) cycle. OS and RFS were compared among pts who received no consolidation ("No Consolidation"), 1 cycle of consolidation ("1 Consolidation"), or ≥2 cycles of consolidation ("≥2 Consolidations"). For these analyses, "induction" and "consolidation" defined regimens received before and after, respectively, the reported date of first CR/CRi. OS was defined as the time from randomization to death, and RFS as time from randomization to relapse or death. Kaplan-Meier OS/RFS estimates were compared for CC-486 vs. PBO using log-rank test. Hazard ratios (HRs) and 95% CIs were generated using a stratified Cox proportional hazards model. These analyses were not powered sufficiently to determine statistical significance. Results: 472 pts were randomized to CC-486 (N=238) or PBO (N=234). Most pts (80%) received consolidation before study entry. The No Consolidation cohort comprised 94 pts (20%; CC-486 52, PBO 42), the 1 Consolidation cohort comprised 212 pts (45%; CC-486 110, PBO 102), and the ≥2 Consolidations cohort comprised 166 pts (35%; CC-486 76, PBO 90), including 19 pts (CC-486 6, PBO 13) who received 3 consolidation cycles. Common agents used for consolidation were cytarabine (377/378 pts), idarubicin (95/378), and daunorubicin (37/378). While most pts received 1 induction, 97 pts received ≥2 induction courses; of them, 21 (CC-486 14, PBO 7) did not receive consolidation and 76 (CC-486 43, PBO 33) received ≥1 consolidation cycle. Baseline characteristics (eg, CR / CRi after IC, ECOG PS, cytogenetic risk at diagnosis) were generally similar among Tx arms and cohorts. Median (range) ages of pts in the 0 / 1 / ≥2 Consolidation cohorts were 71 (58-84), 68 (55-86), and 67 (55-82) years, respectively. In the No Consolidation cohort, median OS from the time of randomization with CC-486 vs. PBO was 23.3 vs. 10.9 mo, respectively (HR 0.55 [95%CI 0.34, 0.89]), and median RFS was 8.4 vs. 3.9 mo (0.55 [0.34, 0.88]) (Figure A). In the 1 Consolidation cohort, median OS was 21.0 vs. 14.3 mo with CC-486 vs. PBO, respectively (HR 0.75 [95%CI 0.55, 1.02]), and median RFS was 10.0 vs. 4.7 mo (0.72 [0.53, 0.99]) (Figure B). In the ≥2 Consolidations cohort, median OS was 28.6 mo with CC-486 vs. 17.6 mo with PBO (HR 0.75 [95%CI 0.50, 1.11]), and median RFS was 13.0 vs. 6.1 mo (0.59 [0.41, 0.87]) (Figure C). Conclusions: CC-486 was associated with consistent survival benefits vs. PBO regardless of number of prior consolidation cycles. Use of consolidation was generally associated with nominal improvements in OS and RFS within each Tx arm; however, in the CC-486 arm, median OS for pts who did not receive consolidation was similar to those who received 1 consolidation cycle (23.3 and 21.0 mo, respectively). Results should be interpreted with caution, as these cohorts were not prospectively defined and the study was not powered to detect significant differences between subgroups. Nevertheless, these data clearly suggest that older pts with AML in first remission after induction can benefit from CC-486, regardless of their fitness to receive consolidation or the number of consolidation cycles received before starting CC-486. Disclosures Wei: AMGEN: Honoraria, Other: Advisory committee, Research Funding; Walter and Eliza Hall Institute: Patents & Royalties; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Genentech: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee; Astellas: Honoraria, Other: Advisory committee; Pfizer: Honoraria, Other: Advisory committee; Macrogenics: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Speakers Bureau; Astra-Zeneca: Honoraria, Other: Advisory committee, Research Funding; Janssen: Honoraria, Other. Roboz:Orsenix: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Jazz: Consultancy; Astex: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Array BioPharma: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Amphivena: Consultancy. Dombret:Sunesis: Consultancy; Abbvie: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Janssen: Consultancy; Menarini: Consultancy; Pfizer: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Astellas: Consultancy; Servier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Cellectis: Consultancy. Döhner:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Sunesis: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ravandi:Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria.

BACKGROUND: Current guidelines for AML ascribe disease-risk partly based on NPM1 and FLT3 mutational status. NPM1 mutations (mut) occur in 25%-30% of patients (pts) with AML and are associated with favorable prognosis in the absence of co-occurring FLT3-ITD. FLT3-ITD alterations are observed in ~15-30% of AML pts and confer poor prognosis, whereas the prognostic implication of FLT3-TKD point mutations (~7% of pts) is less clear. Post-IC, absence of MRD is associated with favorable relapse-free and overall survival (RFS/OS). In the randomized, phase 3 QUAZAR AML-001 trial, Oral-AZA (CC-486) significantly prolonged OS and RFS vs placebo (PBO) in older pts with AML in first remission after IC (Wei, NEJM 2020). It is of high interest to understand the effects of Oral-AZA in pts with NPM1 and/or FLT3 mutations, and whether their outcomes are influenced by post-IC MRD status. OBJECTIVE: Evaluate survival outcomes with Oral-AZA vs PBO in pts with NPM1mut ± FLT3mut at AML diagnosis (Dx), and OS by baseline (BL) MRD status (+/-) in pts with NPM1/FLT3 mutations. METHODS: In QUAZAR AML-001, pts aged ≥55 years with AML and NCCN intermediate or poor-risk cytogenetics at Dx were randomized 1:1 to receive Oral-AZA 300 mg or PBO QD within 4 mo after attaining first CR/CRi with IC (induction ± consolidation). NPM1 and FLT3 statuses (mut or wild-type [wt]) at AML Dx (before IC) were collected from pt diagnostic case report forms. MRD analyses were conducted by MFC (≥0.1% MRD+ cutoff) in bone marrow aspirate samples collected at screening (post-IC; ie, BL). OS and RFS were estimated from the time of randomization using Kaplan-Meier methods. Multivariate (MV) Cox regression analyses of the prognostic effects on OS/RFS were performed, with NPM1 and FLT3 mutational status and cytogenetic risk at Dx; post-IC MRD status (+/-) at BL, and randomized Tx (Oral AZA vs PBO) as variables. RESULTS: Of 472 pts enrolled , 469 (99.4%) had mutational data available at Dx, and the MRD-evaluable cohort comprised 463 pts (98.1%). In all, 137 pts (29%; Oral-AZA n = 66, PBO n = 71) had NPM1mut at AML Dx, and NPM1mut was significantly correlated with MRD- status at BL (post-IC)(P = 0.0178). Among pts with NPM1mut, OS was significantly improved in pts receiving Oral-AZA vs PBO, whether pts were MRD- (median 48.6 vs 26.2 mo, respectively) or MRD+ (median 39.4 vs 10.3 mo) at BL (both P < 0.0001) (Figure). While median OS for NPM1mut pts in the Oral-AZA arm was nominally improved for MRD- pts vs. those MRD+ (48.6 vs. 39.4 mo, respectively), median OS for NPM1mut pts in the PBO arm was substantially influenced by post-IC MRD status (26.2 vs 10.3 mo for MRD- and MRD+ pts, respectively) (Figure). Similarly, median RFS for pts with NPM1mut/MRD- in the Oral-AZA and PBO arms was 24.9 vs 9.9 mo, respectively, and for pts with NPM1mut/MRD+ was 19.4 vs 4.6 mo. In all, 66 pts (14.1%) had FLT3-ITD (n = 46) and/or FLT3-TKD mut (n = 24) at AML Dx; NPM1 and FLT3-ITD status was NPM1mut + FLT3-ITD - in 107 pts, NPM1mut + FLT3-ITD + in 30 pts, and NPM1wt + FLT3-ITD + in 16 pts. In the Oral-AZA arm, median OS in pts with FLT3mut was not meaningfully different from that in pts with FLT3wt (28.2 and 24.7 mo, respectively), but FLT3mut conferred a negative prognosis in the PBO arm (median OS 9.7 mo, vs 15.2 mo for FLT3wt pts). Risk of death was reduced 46% with Oral-AZA vs PBO in pts with FLT3mut (HR 0.54 [95%CI 0.25, 1.14]). When considering MRD status, median OS in FLT3mut/MRD- pts was 28.2 vs. 15.9 mo in the Oral-AZA (n = 14) and PBO (n = 17) arms, respectively, and was 24.0 vs 8.0 mo in FLT3mut/MRD+ pts (Oral-AZA, n = 16; PBO, n = 18). In MV analyses, Oral-AZA significantly improved OS vs PBO when adjusted for other variables (P = 0.035); NPM1 status (P = 0.001), FLT3status (P = 0.035), and cytogenetic risk at Dx (P < 0.001) were each also significantly predictive of OS, as was post-IC MRD status (P < 0.001). All except FLT3 status (P = 0.737) were significantly predictive of RFS. CONCLUSIONS: Oral-AZA prolonged OS and RFS vs PBO in pts with NPM1mut, with improvements beyond the prognostic benefit conferred by MRD-, suggesting that pts with NPM1mut and MRD- can attain substantial OS benefit with Oral-AZA maintenance. An OS benefit was also observed with Oral-AZA vs PBO in pts in FLT3mut at Dx, but outcomes may be confounded by co-occurring NPM1mut, so further investigation is needed. MV analyses confirmed the independent prognostic influence of Oral-AZA, NPM1 and FLT3 mutations at Dx, cytogenetic risk at Dx, and post-IC MRD status on OS. Figure 1 Figure 1. Disclosures Döhner: Janssen: Honoraria; Helsinn: Honoraria; Gilead: Honoraria; GEMoaB: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; AstraZeneca: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding; Roche: Honoraria. Wei: Astellas: Honoraria; Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees. Roboz: Glaxo SmithKline: Consultancy; Helsinn: Consultancy; AbbVie: Consultancy; Jasper Therapeutics: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Actinium: Consultancy; Agios: Consultancy; Blueprint Medicines: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Jazz: Consultancy; Daiichi Sankyo: Consultancy; Astex: Consultancy; Mesoblast: Consultancy; Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Bristol Myers Squibb: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy. Montesinos: Agios: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Ravandi: AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Astex: Honoraria, Research Funding; Prelude: Research Funding; Taiho: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Sandhu: Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Bioverativ: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Gilead: Consultancy. Skikne: Bristol Myers Squibb: Current Employment. See: Bristol Myers Squibb: Current Employment. Ugidos: Bristol Myers Squibb: Current Employment. Risueño: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Chan: Bristol Myers Squibb: Current Employment. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

BACKGROUND: While many older patients (pts) with AML attain complete remission (CR) after treatment (Tx) with IC, ~80% will relapse and overall survival (OS) is poor. The randomized, placebo (PBO)-controlled, phase 3 QUAZAR AML-001 trial assessed Oral-AZA (CC-486), a hypomethylating agent, in pts with AML in remission after IC who were not eligible for stem cell transplant. At the primary data cutoff in July 2019, Oral-AZA was associated with significantly prolonged OS vs. PBO: 24.7 vs. 14.8 months (mo), respectively (P < 0.001) (Wei, 2020), but the tails of the Kaplan-Meier OS curves for Oral-AZA and PBO began to converge during later time-points (after ~48 mo). More than one-quarter of all randomized pts (125/472 [26.5%]) were either still receiving Tx with Oral-AZA (n = 45) or PBO (n = 26) or remained alive in survival follow-up (n = 26 and n = 28) at the primary cutoff. Upon trial unblinding, pts continued to be followed for OS (but not relapse-free survival). We assessed longer-term OS for pts in QUAZAR AML-001 as of September 2020, after > 1 year of additional follow-up. METHODS: Pt eligibility and study design have been reported in detail. Briefly, eligible pts were aged ≥55 years with newly diagnosed AML, intermediate- or poor-risk cytogenetics at AML diagnosis (Dx), and ECOG PS ≤3, and had achieved first CR or CRi after IC (induction ± consolidation) before screening. Within 4 mo after CR/CRi, pts were randomized 1:1 to Oral-AZA 300 mg or PBO QD for 14 days/28-day Tx cycle. After trial unblinding in July 2019, pts in the Oral-AZA arm could continue to receive Tx in an extension phase if they continued to benefit; pts in the PBO arm had Tx discontinued and were followed for OS. Kaplan-Meier estimated OS was calculated from the time of randomization until death, withdrawal of consent, or loss to follow-up, and compared between Tx arms by log-rank test. To determine whether OS was influenced by pt-related factors, we compared baseline (BL) demographic and disease characteristics of pts who were alive (on-Tx and/or in survival follow-up) for ≥ 3 years from randomization ("Long-term [LT] Survivors") vs. those of pts who died or were censored before 3 years. Results: In all, 472 pts were randomized to Oral-AZA (n = 238) or PBO (n = 234). Median age was 68 years (range 55-86), 91% of pts had de novo AML, and 86% had intermediate-risk cytogenetics. Upon trial unblinding, 39 pts (16%) in the Oral-AZA arm continued into the extension phase Overall, 31.4% and 15.5% of pts received > 24 mo of Tx with Oral-AZA or PBO, respectively. At the updated follow-up in September 2020, 54 pts (23%) in the Oral-AZA arm were alive in survival follow-up, including 31 pts (13%) still receiving Oral-AZA in the extension phase; 165 pts (69%) had died and 19 pts (8%) had withdrawn consent or were lost to follow-up. In the PBO arm, 35 pts (15%) remained alive, 176 (75%) had died, and 23 (10%) had withdrawn consent or were lost to follow-up. At a median follow-up of 51.7 mo, median OS in each arm remained unchanged from the primary cutoff date: 24.7 vs. 14.8 mo with Oral-AZA vs. PBO, respectively (P = 0.0008); however, the KM OS curves for Oral-AZA and PBO showed greater separation with additional follow-up, and the two curves did not touch or cross at any time (Figure). KM-estimated 3-year survival rates were 37.4% vs. 27.9% in the Oral-AZA and PBO arms, respectively (∆ +9.5% [95% CI 0.9%, 18.1%]). The LT Survivors cohort comprised 140 pts (29.7%) in the Oral-AZA (n = 83) and PBO (n = 57) arms who were known to be alive for ≥ 3 years. Compared with pts who died or were censored before 3 years, those in the LT Survivors group were more likely to have intermediate-risk cytogenetics (95% vs. 82%) and an NPM1 mutation (45% vs. 9%) at AML Dx, and less likely to be MRD+ at BL (33% vs. 52%). Among pts with post-IC MRD+ at BL, 71% (34/48) in the LT Survivors cohort achieved MRD negativity on-study, compared with 15% (26/172) in the < 3-year cohort (P < 0.0001). Conclusions: With > 1 year of additional survival follow-up, median OS in QUAZAR AML-001 remained unchanged in both Tx arms, but the tails of the Oral-AZA and PBO OS curves showed greater separation at later time-points than in the primary analysis (which may have been confounded by extensive censoring), indicating a sustained, long-term OS benefit with Oral-AZA. Intermediate-risk cytogenetics and NPM1 mutations at AML Dx, and absence of detectable MRD post-IC, were associated with long-term survival in QUAZAR AML-001. Figure 1 Figure 1. Disclosures Wei: Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Walter and Eliza Hall Institute: Ended employment in the past 24 months; Novartis, Astellas, Pfizer, MacroGenics, AbbVie, Genentech, Servier, Celgene, Amgen, AstraZeneca, Janssen: Honoraria. Döhner: Pfizer: Research Funding; Oxford Biomedicals: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Research Funding; Helsinn: Honoraria; GEMoaB: Honoraria; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; AstraZeneca: Honoraria; Berlin-Chemie: Honoraria; Astex: Honoraria; Astellas: Honoraria, Research Funding; Roche: Honoraria; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Sayar: BMS: Honoraria. Ravandi: Taiho: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Selleslag: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Teva: Consultancy, Honoraria. Skikne: Bristol Myers Squibb: Current Employment. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Tian: Bristol Myers Squibb: Current Employment. Roboz: Celgene: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Mesoblast: Consultancy; Agios: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Helsinn: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Actinium: Consultancy; Astex: Consultancy; Glaxo SmithKline: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.

BACKGROUND: CC-486, a DNA hypomethylating agent and epigenetic modifier, is an oral formulation of azacitidine (AZA) that is administered at lower exposures for extended durations (300 mg/day [d] for 14 or 21d/28d cycle) compared with the injectable formulation of AZA, which is given in a high exposure, limited duration regimen of 75mg/m2 for 7d/28d cycle. AZA induces DNA damage and cytotoxicity, and promotes changes in gene expression leading to cellular differentiation. As DNA incorporation of AZA is S-phase-dependent, it has been hypothesized that extended dosing with CC-486 prolongs drug exposure and DNA incorporation to enhance epigenetic activity. The mechanism of action imparted by extended dosing schedules of CC-486 is not fully understood. In patients with myeloid malignancies, DNA hypomethylation in blood is sustained throughout the 28d Tx cycle with extended CC-486 dosing regimens (Laille, 2015; Garcia-Manero, 2016). To better understand the mechanism of CC-486, we assessed the kinetics of expression of myeloid markers of cellular differentiation and cytotoxicity with various AZA dosing schedules in in vitro and in vivo models of AML. METHODS: AML cell lines (AML-193, KG1a, and MV4-11) were treated in vitro with AZA (0.05 - 5 µM daily for 5d or 15d), and at cumulative concentrations of 1 or 3 µM administered once or fractionated over 2-5d to experimentally model CC-486 extended exposures: 1 µM cumulative dose (1 µM × 1d, 0.5 µM × 2d, 0.33 µM × 3d, 0.25 µM × 4d, or 0.2 µM × 5d); 3 µM cumulative dose (3 µM × 1d, 1.5 µM × 2d, 1 µM × 3d, 0.75 µM × 4d, or 0.6 µM × 5d). AZA- or vehicle-treated cells were analyzed by flow cytometry, DNA methylation (Illumina Infinium EPIC assay), and RNA-Seq. Temporal expression of CD11b was assessed as a surface marker of myeloid differentiation, and Annexin-V staining was used to determine the extent of apoptosis and cell death. In efficacy studies, mouse models of AML (syngeneic, cell line-derived xenografts) were treated intraperitoneally with AZA regimens at 1 mg/kg/d × 15d (extended) or 3 mg/kg/d x 5d. RESULTS: Tx of AML-193 cells with 0.05 - 5 µM daily AZA led to upregulation of markers of myeloid differentiation (including CD11b) at lower doses, and a dose-dependent increase in apoptosis up to 7d after Tx initiation. Following Tx with 1 µM AZA for 1d, maximal cellular differentiation (ie, CD11b expression) occurred at d3 in 30% of AML-193 cells; conversely, cells treated with 0.2 µM/d AZA for 5d showed greater differentiation (40%) peaking on d7 (Fig A). CD11b expression was increased upon each subsequent cell division; after 5 cell divisions, CD11b upregulation was 4-fold higher in cells treated with multiple, lower AZA doses than with 1 µM AZA administered for 1d (Fig B). CD11b upregulation was not observed in the absence of cell division under serum starvation conditions for 3d (to induce cell cycle arrest), further suggesting that cell division is a requirement for AZA-induced CD11b changes (Fig C). Similarly, AML-193 cells treated with a 3 µM cumulative AZA dose over 1, 2, 3, 4, or 5d showed greater changes in myeloid differentiation marker expression, with peak apoptosis at d7 with extended dosing regimens (Fig D). In KG1a and MV4-11 cells, Tx with 1 µM AZA QD for 5d led to induction of myeloid differentiation by d7, and cell death (followed by recovery of undifferentiated cells) by d28. In contrast, daily Tx with 0.3 µM AZA for 15d led to slower, more robust upregulation of differentiation markers, peaking at d21 and accompanied by a gradual loss of cell viability. Extended AZA exposure to cells led to pronounced changes in gene expression (Fig E) and DNA methylation (Fig F) at both d7 (immune response gene signature) and d28 (cell adhesion gene signature) compared with limited duration exposure AZA. In mice, low exposure, extended regimens of AZA exhibited higher DNA and RNA incorporation into peripheral blood mononuclear cells (PBMCs) and bone marrow cells when compared with higher exposure, limited duration regimens. Extended AZA dosing led to significant efficacy in murine AML models. CONCLUSIONS: In AML cell lines, low exposure, extended duration AZA schedules modeling CC-486 induced robust changes in differentiation. These results suggest that CC-486-mediated effects using extended exposure regimens preferentially promote a differentiation effect and cell death of AML tumor cells. These mechanistic insights may help inform rational CC-486 combination Tx strategies. Disclosures Dunshee: Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Dai:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jang:Bristol Myers Squibb: Ended employment in the past 24 months. Risueño:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Named in BMS (before Celgene) patent filings related to predictive patient response biomarkers in hematological malignancies. Jeyaraju:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hagner:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. See:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. MacBeth:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

INTRODUCTION: About 50% of older patients with AML attain remission with intensive induction chemotherapy (IC) but the majority will eventually relapse. Effective, well tolerated maintenance treatments are needed to reduce the risk of relapse and prolong survival for older patients with AML in remission, who are less likely than younger patients to be candidates for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to sustain therapeutic activity. In the randomized, phase III QUAZAR AML-001 Maintenance Trial, CC-486 significantly prolonged overall survival (OS) and relapse-free survival (RFS) vs. placebo in patients aged ≥55 years with AML in first remission after IC ± consolidation. Gastrointestinal (GI) events were the most common treatment-emergent adverse events (TEAEs) reported in patients who received CC-486. Here we assess the rates of GI TEAEs and associated management strategies over time with CC-486 treatment in QUAZAR AML-001. METHODS: Eligible patients were aged ≥55 years and had AML with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤3. Patients had achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) after IC ± consolidation and were not candidates for HSCT. Within 4 months of achieving CR/CRi, patients were randomized 1:1 to CC-486 300 mg or placebo, administered once-daily on days 1-14 of repeated 28-day treatment cycles. Safety was assessed among patients who received ≥1 dose of study drug, from the date of first dose through 28 days after the last dose. Prophylaxis and treatment of GI TEAEs were allowed but not mandatory. RESULTS: In all, 236 patients received CC-486 and were evaluated for safety. The median age at study entry was 68 years (range 55-86), 202 patients (85.6%) had intermediate-risk cytogenetics at diagnosis, 185 (78.4%) had achieved CR after induction, and 184 (78.0%) received ≥1 course of consolidation before randomization. Overall, nausea, vomiting, and diarrhea (any grade) were reported in 65%, 60%, and 50%, respectively, of patients treated with CC-486. Few patients experienced grade 3 TEAEs (nausea, 3%; vomiting, 3%; diarrhea, 5%) or serious events (0.4%, 0.8%, and 1.3%, respectively), and only 1 grade 4 event (diarrhea) was reported at any time on-study. Rates of GI TEAEs were highest during initial treatment and decreased thereafter. In cycles 1-2, 3-4, and 5-6, respectively, nausea was reported in 53%, 17%, and 15% of patients; vomiting in 49%, 15%, and 10% of patients; and diarrhea in 29%, 16%, and 11% of patients (Figure). The most commonly used concomitant GI medications were 5-HT3 antagonists, metoclopramide, lactulose, and loperamide; use of these agents was also highest during the first 2 treatment cycles and decreased over time (Figure). GI events required CC-486 treatment interruptions for 13% of patients, dose-reductions for 6% of patients, and treatment discontinuation for 5% of patients. DISCUSSION: Most GI-related TEAEs reported by patients treated with CC-486 were low-grade, and events decreased in frequency after initial treatment cycles, indicating these events were well managed. Use of GI medications decreased concurrently, suggesting progressive GI tolerance to CC-486 with continued therapy. Few patients discontinued CC-486 due to GI TEAEs. Prophylaxis and symptomatic intervention of GI events during early CC-486 therapy may facilitate treatment adherence to promote better outcomes. Disclosures Ravandi: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Selleslag:Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Sayar:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Safah:Amgen: Honoraria; Astellas: Speakers Bureau; Verastem: Honoraria; Janssen: Speakers Bureau. Hiwase:Novartis Australia: Research Funding. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dombret:Otsuka: Consultancy; Abbvie: Consultancy; Servier: Consultancy, Research Funding; Sunesis: Consultancy; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy.

BACKGROUND: In newly diagnosed AML, high remission rates are typically achieved with IC, but the response is often transient, and detectable residual disease in the bone marrow post-chemotherapy is predictive of early relapse. Emerging data show that the identification of ≥ 0.1% MRD by multiparameter flow cytometry (MFC) in patients with AML in remission after IC is an important prognostic marker that may help guide treatment (Tx) decisions. CC-486 is an oral hypomethylating agent that allows for extended dosing schedules to prolong drug exposure over the Tx cycle. In the QUAZAR AML-001 Maintenance Trial, Tx with CC-486 300 mg QD for 14 days/28-day Tx cycle was associated with significantly improved overall (OS) and relapse-free survival (RFS) vs. placebo (PBO) in patients (pts) with AML in first remission after induction chemotherapy ± consolidation. Samples for MFC were obtained prior to randomization and serially throughout the study to assess the impact of MRD on OS and RFS, and to evaluate rates of conversion from MRD positivity (+) to negativity (-) in the CC-486 and PBO arms. METHODS: Eligible pts aged ≥ 55 years with AML were randomized 1:1 to CC-486 300 mg or PBO within 4 months of achieving first complete remission (CR) or CR with incomplete blood count recovery (CRi). MFC assessments of bone marrow aspirates were performed centrally at screening; at cycles 3, 6, 9, 12, 15, 18, 21, 24, 30, and 36; and as clinically indicated. Samples were analyzed with a panel of 22 cell surface markers using an MRD+ cutoff of ≥ 0.1% (per ELN MRD guidelines). For pts MRD+ at baseline (BL; ie, at randomization), an MRD response was defined as achievement of MRD- for ≥ 2 consecutive assessments. MRD- duration was calculated from the time of randomization (for pts MRD- at BL) or from the first of ≥ 2 consecutive MRD- tests (for pts MRD+ at BL), until the last MRD- assessment (for pts who became MRD+) or Tx discontinuation. OS, RFS, and MRD- durations were estimated using Kaplan-Meier methods. Multivariate (MV) Cox regression analyses were performed to evaluate the association of BL MRD status (MRD+ vs. MRD-) and randomized Tx arm (CC-486 vs. PBO) with OS and RFS. RESULTS: The MRD-evaluable cohort comprised 463/472 randomized pts (98.1%; CC-486, n=236; PBO, n=227) who had samples available for evaluation at BL and at ≥ 1 post-BL visit. At BL, 43% of pts (n=103) in the CC-486 arm and 50% (n=116) in the PBO arm were MRD+. Overall, BL characteristics were similar between MRD+ and MRD- pts: median ages were 69 (range 55-84) and 68 (55-86) years, respectively; 84% and 88% had intermediate-risk cytogenetics at diagnosis; 52% and 46% of pts had an ECOG PS of 0; and 79% and 82% received ≥ 1 cycle of consolidation after induction. CC-486 Tx resulted in improved OS from time of randomization compared with PBO in pts who were either MRD+ (median 14.6 vs. 10.4 mo, respectively; HR 0.69 [95%CI 0.51, 0.93]) or MRD- (median 30.1 vs. 24.3 mo; HR 0.81 [0.59, 1.12]) at BL. Median RFS was also extended with CC-486 vs. PBO for both MRD+ (7.1 vs. 2.7 mo, respectively; HR 0.58 [95%CI 0.43, 0.78]) and MRD- pts (13.4 vs. 7.8 mo; HR 0.71 [0.52, 0.98]). In MV analyses, BL MRD status (MRD+ vs. MRD-) was significantly associated with OS (HR 1.85; P < 0.0001) and RFS (HR 2.04; P < 0.0001), and CC-486 showed a significant Tx benefit vs. PBO on both OS (HR 0.74; P = 0.0067) and RFS (HR 0.63; P < 0.0001) independent of MRD status at BL (Figure). The median duration of MRD negativity was extended with CC-486 vs. PBO: 11.0 vs. 5.0 mo, respectively (HR 0.62 [95%CI 0.48, 0.78]). Tx with CC-486 also resulted in a higher rate of MRD response (MRD+ to MRD-) vs. PBO: 37% vs. 19%, respectively. Among MRD responders, 9/38 patients (24%) in the CC-486 arm achieved MRD negativity > 6 mo after randomization, compared with only 1/22 patients (5%) in the PBO arm. CONCLUSIONS: The QUAZAR AML-001 Maintenance Trial was the first prospective, randomized trial to include long-term longitudinal assessment of MRD in older patients with AML in remission. In both treatment arms, MRD+ status (≥ 0.1%) after induction ± consolidation was associated with significantly shorter OS and RFS compared with MRD- status. Approximately one-fourth of MRD responders treated with CC-486 achieved MRD negativity > 6 mo after study entry, suggesting that CC-486 could induce MRD negativity after prolonged MRD+ status. Maintenance Tx with CC-486 substantially improved OS and RFS independent of MRD status at BL. Disclosures Roboz: Otsuka: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Astellas: Consultancy; Argenx: Consultancy; Actinium: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Jazz: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; MEI Pharma: Consultancy; Helsinn: Consultancy; Epizyme: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Trovagene: Consultancy; Takeda: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Array BioPharma: Consultancy; Daiichi Sankyo: Consultancy. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Wei:Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Roche: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Research Funding; Macrogenics: Honoraria; Astra Zeneca: Honoraria, Research Funding. Dombret:Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Servier: Consultancy, Research Funding; Sunesis: Consultancy; Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Döhner:Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Sunesis: Research Funding; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Thol:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Voso:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Porkka:Novartis: Consultancy, Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Risueño:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Named in BMS (before Celgene) patent filings related to predictive patient response biomarkers in hematological malignancies. Lopes de Menezes:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ossenkoppele:Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy; J&J: Consultancy, Research Funding; Agios: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Daiichi Sayko: Consultancy; Amgen: Consultancy.

BACKGROUND: AML is an aggressive malignancy primarily affecting older individuals. Although 40%-60% of patients (pts) aged >60 years attain complete remission (CR) with IC, 80%-90% of them eventually relapse. In the continuum of AML care, the greatest expenditures are associated with relapsed/refractory disease, and hospitalization is the largest component (~70%) of direct AML healthcare costs (Pandya, 2020). In the randomized, phase III QUAZAR AML-001 Maintenance Trial, CC-486, an oral hypomethylating agent, significantly prolonged overall (OS) and relapse-free survival (RFS) vs. placebo (PBO) in pts with newly diagnosed (ND) AML in first remission following IC. OBJECTIVE: Determine rates of hospitalization and days in hospital with CC-486 and PBO in QUAZAR AML-001, and quantify associated costs of hospitalization using unit costs estimated from a US claims database. METHODS: In QUAZAR AML-001, eligible pts were age ≥55 years, with de novo or secondary AML, intermediate- or poor-risk cytogenetics, and ECOG PS ≤3; achieved first CR or CR with incomplete count recovery (CRi) after IC ± consolidation; and were not candidates for hematopoietic stem cell transplant (HSCT). Within 4 months of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO, administered once-daily on days 1-14 of repeated 28-day cycles. Pts who received ≥1 dose of study drug were followed for hospitalizations and durations of stay from date of informed consent through 28 days after last dose. The mean number of days hospitalized per month (30 days) in each treatment arm was computed by dividing the aggregate number of hospitalized days by the number of ongoing pts at each time-point. Rates of hospitalization and days in hospital were also adjusted for duration of CC-486 and PBO exposure. 95% confidence intervals (CI) for relative risk (RR) estimates and associated P values are based on asymptotic methods. Patients with a primary diagnosis of AML, preceded by ≥6 months (baseline) without a claim for AML were identified in the IBM MarketScan Commercial & Medicare database from April 2013 to July 2019. A stepwise procedure was then used to include pts aged ≥55 years at diagnosis, without a diagnosis of another primary cancer or HSCT, and with insurance coverage during the entire 6-month baseline period. Unit cost of hospitalization was derived as the average total AML-related hospitalization costs incurred per day of stay, adjusted for inflation to 2019 US dollars. RESULTS: In all, 469 pts were enrolled in QUAZAR AML-001 and received CC-486 (N=236) or PBO (N=233). Total exposure to CC-486 was 363.8 pt-years (PY) and to PBO was 234.9 PY. In all, 108 pts (45.8%) in the CC-486 arm and 118 (50.6%) in the PBO arm were hospitalized. The total numbers of hospitalizations were 173 in the CC-486 arm and 151 in the PBO arm; however, the exposure-adjusted rate of hospitalization was significantly lower in the CC-486 arm: 0.48/PY vs. 0.64/PY, respectively (RR 0.740 [95%CI 0.595, 0.920]; P = 0.0068) (Table). The total number of days hospitalized was 2872 in the CC-486 arm and 3139 in the PBO arm, and the exposure-adjusted days-in-hospital rate was significantly lower in the CC-486 arm (7.89/PY vs. 13.36/PY in the PBO arm; RR 0.591 [95%CI 0.562, 0.621]; P < 0.0001) (Table). Of the ND-AML cohort identified in the MarketScan database, 3058 pts had ≥ 1 noncapitated hospitalization and provided the basis for estimated hospitalization-related costs. Median age and sex distribution of these pts were generally consistent with those of pts in QUAZAR AML-001. The mean AML-related hospitalization cost incurred in the database was $7,126/day (2019 USD). Thus, based on exposure-adjusted days-in-hospital rates in the CC-486 and PBO arms (7.89/PY and 13.36/PY, respectively), the estimated mean costs of hospitalization in QUAZAR AML-001 were $56,224/PY in the CC-486 arm and $95,201/PY in the PBO arm. Cumulative cost savings in the CC-486 arm compared with PBO ranged from $2,837 in month 2 to $40,909 by month 24 (Figure). CONCLUSION: CC-486 was associated with significantly reduced exposure-adjusted risk of hospitalization and days in hospital compared with PBO, which are estimated to result in substantial cumulative cost savings. Significantly prolonged RFS with CC-486 vs. PBO in this study (10.2 vs. 4.8 months; P = 0.0001) may translate into substantial economic benefits, with lower hospitalization-related costs due to reduced rates of hospitalization and days in hospital. Disclosures Oliva: Alexion: Consultancy; Apellis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Novartis: Consultancy; BMS: Consultancy, Honoraria, Patents & Royalties, Speakers Bureau. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Chen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ranjan:SmartAnalyst India Pvt. Ltd.: Current Employment. Kiendrebeogo:SmartAnalyst, Inc.: Current Employment. Braun:Servier: Research Funding; Daiichy-Sankyo: Honoraria.

Introduction: Standard treatment with intensive induction chemotherapy (IC) for pts with AML can induce remission, but responses are often short-lived, and the majority of pts will relapse (Chen Y, et al. Medicine 2016;95:e4182). Although maintenance therapy with injectable AZA has improved disease-free survival in pts with AML in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after intensive chemotherapy (Huls G, et al. Blood 2019;133:1457; Oliva EN, et al. Blood 2019;134(Supp 1):117), overall survival (OS) benefits have been more difficult to achieve. In the randomized, phase 3 QUAZAR AML-001 study (NCT01757535), maintenance therapy with CC-486, a novel oral formulation of AZA, demonstrated a significant 9.9-month improvement in OS and a 31% reduction in mortality versus placebo (PBO) for pts with AML in first CR/CRi following intensive chemotherapy (Wei AH, et al. Blood 2019;134:LBA-3). In the absence of direct head-to-head clinical studies to guide treatment selection, we used an ITC to evaluate the comparative efficacy of CC-486 versus injectable AZA as maintenance therapy in pts with AML in first remission after intensive chemotherapy. Methods: Relative OS was calculated by using individual patient data (IPD) derived from published Kaplan-Meier (KM) OS curves from the QUAZAR AML-001 (NCT01757535) study of CC-486 versus PBO, and 2 studies of injectable AZA versus control (HOVON 97 [EudraCT 2008-001290-15] and QoLESS [EudraCT 2010-019710-24]) using Engauge digitization software (Guyot P, et al. BMC Med Res Methodol 2012;12:9). Unlike pts from the intervention arm (CC-486, AZA), pts in the PBO/control arm did not receive cancer therapy post-IC. For each study, time-specific relative OS benefit was calculated by dividing the difference in the KM OS estimate between each intervention arm and the respective PBO/control arm by the KM OS estimate for the PBO/control arm (Betts KA, et al. poster presented at EHA 2017:E1300). Treatment effect was measured by fitting parametric survival curves to the IPD from the intervention arm and PBO/control arms, respectively. The restricted mean survival time (RMST) was estimated as the area under the OS curve (AUC) at 1, 2, 3, 4, and 5 years. The incremental AUC (ΔAUC) was determined at selected timepoints by subtracting the RMST of the PBO/control arm from the RMST of the intervention arm for each study. A 95% confidence interval for the incremental mean survival time was estimated via simulation from the variance-covariance matrix of the fitted parametric model using ≥ 10,000 iterations. Results: Follow-up was longest for QUAZAR AML-001 (5 years) with both HOVON 97 and QoLESS limited to 30 months at time of analysis. Overall, CC-486 showed a sustained and numerically higher relative OS benefit through 60 months compared with AZA in HOVON 97 and QoLESS (Figure). The relative benefit of AZA versus control in the initial 18 months appeared to fade, reaching close to or below zero around month 21. Indeed, the relative OS benefit with CC-486 and AZA (HOVON 97, QoLESS) was 30.4%, 20.3%, and 15.5% at 12 months; 35.5%, 17.0%, and 21.8% at 18 months; and 36.4%, −7.7%, and 2.2% at 24 months, respectively. Log-normal survival curves were fitted to IPD from each intervention arm and the respective PBO/control arm. Comparing the RMST, CC-486 showed a statistically meaningful improvement in mean survival time at 1, 2, 3, 4, and 5 years and for the entire extrapolation period, while AZA was not associated with significant OS benefits at any time point in HOVON 97 or QoLESS (Table). The mean incremental survival benefit with CC-486 versus PBO and AZA (HOVON 97 and QoLESS) versus control at 3 years was 4.18 versus 1.18 and 2.35 months, respectively; at 5 years was 6.14 versus 1.11 and 0.99 months, respectively; and for the entire extrapolation period was 10.12 versus −6.58 and −18.32 months, respectively. The improvement in mean OS of 10.12 months with CC-486 was consistent with the median OS improvement (9.9 months) reported in QUAZAR AML-001. Conclusions: In this ITC, CC-486 had a longer duration of follow-up than injectable AZA and an earlier and more durable relative OS benefit, which was maintained beyond 60 months. This analysis demonstrates that CC-486 was associated with a meaningful improvement in mean survival time, and that maintenance treatment with CC-486 provides a long-term survival benefit compared with the relative short-term benefit observed with AZA. Disclosures Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Disher:Eversana: Current Employment. Siddiqui:Eversana: Current Employment. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Suero:Eversana: Current Employment; Bristol Myers Squibb: Consultancy. Cameron:Eversana: Current Employment. Gavanji:Eversana: Current Employment. Cameron:Eversana: Current Employment, Current equity holder in private company.

Introduction: Many older patients (pts) with AML respond to intensive induction chemotherapy (IC), but responses are often short-lived and overall survival (OS) is poor. The benefit of post-remission maintenance treatment (Tx) for pts with AML is unclear, as no therapy has shown to significantly improve OS. CC-486 is an oral hypomethylating agent that allows for prolonged drug exposure during each Tx cycle to sustain therapeutic activity. We hypothesized that prolonged Tx with CC-486 could be effective as post-remission maintenance in AML. Herein, we report the primary results of QUAZAR AML-001 (NCT01757535), a phase III international, randomized, double-blind, placebo (PBO)-controlled study evaluating CC-486 as maintenance therapy in pts aged ≥55 years with AML in first remission following IC. Methods: Eligible pts had de novo or secondary AML, intermediate- or poor-risk cytogenetics, and Eastern Cooperative Oncology Group performance status (ECOG PS) scores of ≤3; had achieved first complete remission (CR) or CR with incomplete count recovery (CRi) after IC, with or without consolidation chemotherapy; and were not candidates for hematopoietic stem-cell transplant (HSCT). Within 4 months of attaining CR/CRi, pts were randomized 1:1 to receive CC-486 300 mg or PBO once-daily on days 1-14 of repeated 28-day Tx cycles. A 21-day dosing schedule was permitted for pts who experienced AML relapse with 5-15% blasts in blood or bone marrow while on-study. Tx could continue indefinitely until the presence of >15% blasts, unacceptable toxicity, or HSCT. The primary endpoint was OS. Secondary endpoints included relapse-free survival (RFS), health-related quality of life (HRQoL), and safety. Samples were collected for exploratory translational endpoints, including measurable residual disease (MRD). Kaplan-Meier estimates of OS and RFS were compared for CC-486 vs. PBO by stratified log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were generated using a stratified Cox proportional hazards model. Results: Between May 2013 and October 2017, 472 pts were randomized to receive CC-486 (n=238) or PBO (n=234). Baseline characteristics were balanced between Tx arms. Median age was 68 years (range 55-86), 91% of pts had de novo AML, and 86% and 14% of pts, respectively, had intermediate-risk or poor-risk cytogenetics. Following induction, 81% of pts achieved a CR and 19% achieved CRi; 80% of pts had received consolidation chemotherapy (45% received 1 consolidation cycle and 31% received 2 consolidation cycles). At a median follow-up of 41.2 months, OS was significantly improved with CC-486 vs. PBO: median OS was 24.7 months vs. 14.8 months from time of randomization, respectively (P=0.0009; HR 0.69 [95%CI 0.55, 0.86]) (FigureA). RFS was also significantly prolonged: median RFS was 10.2 months in the CC-486 arm, compared with 4.8 months in the PBO arm (P=0.0001; HR 0.65 [95%CI 0.52, 0.81]) (Figure B). OS and RFS benefits of CC-486 were demonstrated regardless of baseline cytogenetic risk, the number of prior consolidation cycles received, and CR/CRi status. CC-486 did not adversely impact overall HRQoL vs. PBO, as assessed by mean changes from baseline in HRQoL measures during Tx. CC-486 had a manageable safety profile generally consistent with that of injectable azacitidine. Median exposure to CC-486 was 12 cycles (range 1-80) and to PBO was 6 cycles (1-73). The most frequently reported adverse events (AEs) with CC-486 and PBO were grade 1 or 2 gastrointestinal (GI) events, including nausea (64% and 23%, respectively), vomiting (59% and 10%), and diarrhea (49% and 21%). The most common grade 3-4 AEs were neutropenia (CC-486, 41%; PBO, 24%), thrombocytopenia (23% and 22%), and anemia (14% and 13%). Serious AEs were infrequent, mainly infections, which occurred in 17% of pts in the CC-486 arm and 8% of pts in the PBO arm. Few AEs led to Tx discontinuation, most often GI events (CC-486, 5%; PBO, 0.4%). Conclusions: CC-486 is the first therapy used in the maintenance setting to provide statistically significant and clinically meaningful improvements in both OS and RFS in pts with AML in remission following induction chemotherapy, with or without consolidation. Oral CC-486 has a manageable safety profile and represents a new therapeutic standard for pts with AML in remission. Disclosures Wei: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner:AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding; Celgene, Novartis, Sunesis: Honoraria, Research Funding. Montesinos:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Ravandi:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orsenix: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sayar:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Porkka:Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Selleslag:Celyad: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Daichii Sankyo: Consultancy; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Astex Otsuka: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Sandhu:Takeda: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Bioverativ: Consultancy; Celgene Corporation: Consultancy; Pfizer: Consultancy; Janssen: Consultancy. Giai:BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Beltrami:Ospedale Policlinico San Martino: Employment. Ossenkoppele:Celgene Corporation: Consultancy, Honoraria, Research Funding. La Torre:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Dong:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

After failure of DNA methyltransferase inhibition (DNMTi) there is no standard of care therapy for high-risk myelodysplastic syndromes (MDS), and median survival for higher risk disease is less than 6 months (Prebet et al, JCO 2011; Jabbour et al, Cancer 2015). Pevonedistat, a first in human small molecule inhibitor of the NEDD8 activating enzyme (NAE), downregulates Cullin ring ligases (CRL) which interferes with the shuttling and degradation of proteins in the proteasome and leads to accumulation of CRL substrates. Combining pevonedistat (Pev) with azacitidine (AZA) resulted in synergistic cell killing in in vitro and xenograft models of acute myeloid leukemia (AML) (Smith et al, Blood 2011), elicited favorable response rates in treatment naïve elderly or unfit AML patients (Swords et al Blood 2018), and is currently under study in treatment-naïve MDS. The study presented herein (NCT03238248) investigates the utility of adding pevonedistat to azacitidine (PevAz) after DNMTi failure in MDS and MDS/MPN overlap syndromes. Methods: In this on-going single-arm phase II study, MDS and MDS/MPN patients were eligible if they were refractory to DNMTi treatment, progressing after at least 2 cycles of therapy; had failed to achieve a complete remission (CR) after at least 4 cycles of DNMTi therapy; or had relapsed after an initial response to DNMTi therapy. Enrolled subjects received AZA 75mg/m2 sc/iv daily on days 1-5 and Pev 20mg/m2 iv on days 1, 3 and 5 of each 28-day cycle. Survival is the primary endpoint and is assessed at regularly scheduled study visits and every 3 months after ending protocol-directed therapy. Hematologic and bone marrow response rates are secondary endpoints. Responses to treatment are determined by the MDS International Working Group (IWG) response criteria (Cheson et al, Blood 2006) or for MDS/MPN, by the modified MDS/MPN IWG response criteria (Savona et al, Blood 2015). Results: As of the data cutoff on 15 MAR 2019, 23 subjects (21 with MDS, 2 with MDS/MPN) had enrolled and initiated treatment. Subjects had previously been treated with AZA (n=11/23), decitabine (n=11/23), and ASTX727 (n=4/23); some subjects had been treated with more than one DNMTi prior to enrollment. Median number of cycles of any prior DNMTi therapy was 7 (range 2-35). 65% of subjects were female. Median age at enrollment was 67 years (range 51 - 85). 65% had Intermediate-2 or High risk disease by IPSS at time of enrollment. Median number of PevAz cycles completed prior to the data cutoff was 4 (range 1-19). One subject had not reached the first response assessment at the time of the data cutoff and data was unavailable for one subject. The overall response rate including complete and partial remission, hematologic improvement and clinical benefit (CB) was 42.9% (9/21), and CR rate (including 1 CR + 4 marrow CR) was 23.8% (5/21) with a median duration of response (DOR) of 8.7m (range 2.8m-15.7m). An additional 38.1% (8/21) had stable disease as best response (Table 1). The most common Grade >2 adverse events (any attribution) include thrombocytopenia (39%), anemia (35%), leukopenia (26%), neutropenia (22%), infections (17%), and febrile neutropenia (13%). Six subjects experienced Grade ≤ 2 elevations in AST/ALT and 4 had Grade ≤ 2 elevation in bilirubin, whereas only one subject experienced Grade > 2 LFT abnormality (increase in ALT). There was one death on study due to intracerebral hemorrhage related to a previously undiagnosed metastatic carcinoma. PevAz treatment was discontinued in other subjects due to disease progression (n=7), adverse event (n=1), lack of response (n=1), or to pursue allogeneic stem cell transplant after achieving a satisfactory response to PevAz (n=3). Ten subjects were continuing PevAz therapy on study as of the data cutoff. Summary: PevAz was well-tolerated in MDS and MDS/MPN patients who had previously failed DNMTi, with the most common adverse events of cytopenias, which are a common feature of these diseases. 5/21 subjects achieved CR/mCR with meaningful DOR, and the ORR of 42.9% exceeded expectations for MDS patients with previous failure of DNMTi therapy; both MDS/MPN patients responded with CR and CB. For these patients whose treatment options are limited and prognosis very poor, these preliminary data are especially encouraging and warrant further investigation. This therapy combination is being tested in a phase 3 study in treatment naïve high risk MDS, CMML and low-blast AML. Disclosures Watts: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Byrne:Karyopharm: Research Funding. Bradley:AbbVie: Other: Advisory Board. Savona:Sunesis: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties.

Allogeneic stem cell transplantation (SCT) is a potentially curative treatment for MDS. Besides the innate heterogeneity of MDS, intensity of the conditioning regimen (myeloablative (MAC) versus reduced intensity/non-myeloablative (RIC)), specific agents used in conditioning, donor and source of stem cells and GVHD prevention regimens further influence outcomes. We sought to determine how conditioning regimens influenced MDS subgroup cohort outcomes. We retrospectively analyzed outcomes of 107 MDS patients (63 male and 44 females) with median age 61.8 (17-73 years) who underwent allogeneic SCT at our institution between 2008 and 2017. For the purposes of this report, patients were grouped according to WHO classification into non-RAEB (RCMD, RA, RARS RCUD or 5q deletion, n=49) and RAEB (RAEB1 and RAEB2, n=58) categories. Median time from MDS diagnosis to transplantation was 139 days (20-3175). No patients were in complete remission (CR) at time of SCT. Allogeneic donor types were matched related, matched unrelated, haplo-identical and cord blood in 30, 65, 10 and 2 patients, respectively. Stem cell source was peripheral blood (91 patients) and bone marrow in 14. Forty patients (median age 52.2 (17-61) years) underwent MAC and 67 (median age 63.7 (23-73) years) RIC. Twelve patients died within 100 days of transplantation, 3 due to disease progression, 5 to acute GVHD, and 4 to other transplant-related causes. Median overall survival (OS) for all 107 patients was 1.3 years with 54%, 47% and 40% alive at 1, 2 and at 5 years. OS was slightly higher in patients undergoing RIC with OS of 57%, 48% and 40% (median 1.532 years) versus 50%, 40% and 38% with MAC (median 0.92 years) at the same time points (p>0.1). Median OS of the 49 patients with non-RAEB and 58 patients with RAEB MDS was 3.01 years versus 0.92 years (p>0.1). GVHD was the most frequent cause of death (46%), followed by relapse/progression (28%), infection (14%) and other (12%). Of 29 patients undergoing RIC with non-RAEB MDS, median OS was 3.78 years while for 38 RAEB patients it was 1.17 years (p>0.1). See table for OS according to conditioning regimen and WHO classification. For MAC, in 20 non-RAEB patients median OS was 2.2 years while the median OS was 0.69 years for 20 RAEB patients (p>0.1). CR after SCT was achieved in 57 patients (53%), 33 receiving RIC (CR 49.2%) and 24 receiving MAC (CR 60%). Seven patients subsequently relapsed, 4 RIC and 3 MAC. Of the non-RAEB patients achieving CR, median OS in the 16 patients treated with 111 RIC was not reached and in 14 patients receiving MAC, median OS was 3.75 years (p>0.1). For the 27 RAEB patients achieving CR, median OS was 4.4 years in 17 patients treated with RIC versus not reached in 10 patients treated with MAC. Overall, death in non-RAEB patients occurred in 26/49 (53%) compared to 38/58 (66%) RAEB patients and in 40/67 (59%) patients undergoing RIC versus 25/40 (63%) MAC patients (p>0.5). The hematopoietic transplant comorbidity index did not predict OS outcomes in these MDS patients (p>0.1) and the cytogenetic score according to the IPSS-R "very good -very poor" groups indicated no differences in OS in the non-RAEB patients but in RAEB patients significant differences according to the cytogenetic score was evident (P Conclusions: In this retrospective analysis of MDS patients undergoing allogeneic SCT, achieving CR led to improved survival. In non-RAEB MDS patients achieving CR, OS was similar irrespective of conditioning intensity (RIC or MAC). Furthermore, outcomes did not differ in RAEB patients who achieved CR according to intensity of conditioning regimen. However, those receiving MAC had not reached median OS at 5 years. The outcomes in this analysis indicate that improvement in the incidence of deaths due to GVHD would likely have the greatest impact in improving survival in MDS patients undergoing allogeneic transplantation. Table Disclosures Abhyankar: Therakos: Other: Consulting, Speakers Bureau; Incyte: Speakers Bureau. Lin:Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Yacoub:Incyte: Consultancy, Speakers Bureau. Ganguly:Kite Pharma: Honoraria, Other: Advisory Board; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Daiichi Sankyo: Research Funding. McGuirk:Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation.

Current initiatives to reduce the high prevalence of nutritional iron deficiency have highlighted the need for reliable epidemiologic methods to assess iron status. The present report describes a method for estimating body iron based on the ratio of the serum transferrin receptor to serum ferritin. Analysis showed a single normal distribution of body iron stores in US men aged 20 to 65 years (mean ± 1 SD, 9.82 ± 2.82 mg/kg). A single normal distribution was also observed in pregnant Jamaican women (mean ± 1 SD, 0.09 ± 4.48 mg/kg). Distribution analysis in US women aged 20 to 45 years indicated 2 populations; 93% of women had body iron stores averaging 5.5 ± 3.35 mg/kg (mean ± 1 SD), whereas the remaining 7% of women had a mean tissue iron deficit of 3.87 ± 3.23 mg/kg. Calculations of body iron in trials of iron supplementation in Jamaica and iron fortification in Vietnam demonstrated that the method can be used to calculate absorption of the added iron. Quantitative estimates of body iron greatly enhance the evaluation of iron status and the sensitivity of iron intervention trials in populations in which inflammation is uncommon or has been excluded by laboratory screening. The method is useful clinically for monitoring iron status in those who are highly susceptible to iron deficiency.

Background: Karyotype is the strongest independent prognostic factor for survival in AML. The randomized phase 3 AZA-AML-001 study of older patients with AML showed AZA prolonged overall survival (OS) compared with CCR (10.4 vs 6.5 months, respectively; P=0.101) (Dombret et al, Blood, 2015). In a prospective subanalysis of the study, AZA was shown to meaningfully prolong OS by 3.2 months compared with CCR (P=0.0185) in the subgroup of patients with NCCN-defined poor-risk cytogenetics (Döhner et al, Blood, 2014: Abstract 621). Aim: This analysis evaluates treatment effects of AZA vs CCR on OS in subgroups of patients with specific cytogenetic abnormalities as well as in patient subgroups defined by cytogenetic risk per modified European LeukemiaNet (ELN) recommendations (not considering molecular markers) (Döhner et al, Blood, 2010). Methods: Patients aged ≥65 years with newly diagnosed AML (>30% bone marrow [BM] blasts), ECOG performance status score ≤2, intermediate- or poor-risk cytogenetics per NCCN 2009 criteria, and WBC count ≤15x109/L were randomized to receive AZA (75 mg/m2/day [d] x7d/28d) or CCR: intensive chemotherapy (cytarabine 100-200mg/m2IV x7d + anthracycline IV x3d induction), low-dose ara-C (20mg SC BID x10d/28d), or best supportive care only. Karyotypes obtained from BM were reviewed centrally by an independent cytogeneticist. OS was evaluated in subgroups of patients with frequent specific abnormalities, including -5/del(5q), -7, -7/del(7q), abnormal (17p) or complex karyotype (based on specific abnormalities, patients may have been evaluated in more than one category). OS was also assessed for patients in ELN-defined karyotype risk subgroups: Intermediate (Int)-I (normal karyotype), Int-II (all abnormalities not classified as Favorable or Adverse), and Adverse karyotype. OS was assessed using Kaplan-Meier methods and compared using a weighted log-rank test. Results: Centrally reviewed cytogenetic data were available for 485/488 patients (99.4%). In all, 220 patients (45.4%; AZA n=114, CCR n=106) had Int-I karyotype, 111 patients (22.9%; AZA n=53, CCR n=58) had Int-II karyotype, and 154 patients (31.8%, AZA n=73, CCR n=81) had Adverse karyotype (Figure 1). OS was comparable between AZA and CCR in patients with Int-I karyotype (14.1 vs 10.1 months, respectively; hazard ratio [HR] 0.83, 95%CI 0.60, 1.1; P=0.44) and patients with Int-II karyotype (8.9 vs 9.6 months; HR 1.19, 95%CI 0.79, 1.8; P=0.78). There was a significant 2.4-month median OS difference in favor of AZA in patients with Adverse karyotype (5.3 vs 2.9 months with CCR; HR 0.71, 95%CI 0.51, 0.99; P=0.046; Figure 2), with 1-year survival rates of 29.1% vs 14.7% for AZA and CCR, respectively. AZA was associated with longer median OS and higher 1-year survival compared with CCR for all subgroups of patients with the specific cytogenetic abnormalities under study: -5/del(5q), -7, -7/del(7q), abnormal (17p), and complex karyotype, with HRs ranging from 0.54 to 0.69(Table). Median OS in the CCR arm was less than 3 months for each of these subgroups. Similar to what has been reported in MDS (Ravandi et al, Cancer, 2009), AML patients with chromosome 7 abnormalities responded particularly well to AZA, with an improvement in median OS of 4.1 months over CCR. Patients with complex karyotypes also had meaningful improvements in OS, with ~15% more AZA-treated patients alive at 1 year than CCR patients. Conclusions: Prognosis is dismal for older AML patients with adverse karyotypes, and is especially poor for patients with complex karyotypes. Median OS and 1-year survival in patients with ELN-defined Adverse karyotype treated with AZA were almost double those of patients treated with CCR. AZA-treated patients with the specific cytogenetic abnormalities and/or complex karyotype in this analysis had a 31-46% reduction in risk of death vs CCR, and proportions of patients alive at 1 year were 11-22% greater with AZA. These data suggest AZA should be the preferred treatment for older patients with AML and adverse karyotypes. Disclosures Seymour: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Santini:Astex: Consultancy; Amgen: Consultancy; Onconova: Consultancy; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Stone:Celator: Consultancy; Novartis: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Al-Ali:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Morrill:Celgene: Employment, Equity Ownership. Songer:Celgene: Employment, Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Dombret:Agios: Honoraria; Ambit (Daiichi Sankyo): Honoraria; Menarini: Honoraria; Menarini: Honoraria; Servier: Honoraria; Sunesis: Honoraria; Karyopharm: Honoraria; Kite Pharma.: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding.

Recent knowledge gained regarding the relationship between erythropoietin, iron, and erythropoiesis in patients with blood loss anemia, with or without recombinant human erythropoietin therapy, has implications for patient management. Under conditions of significant blood loss, erythropoietin therapy, or both, iron-restricted erythropoiesis is evident, even in the presence of storage iron and iron oral supplementation. Intravenous iron therapy in renal dialysis patients undergoing erythropoietin therapy can produce hematologic responses with serum ferritin levels up to 400 μg/L, indicating that traditional biochemical markers of storage iron in patients with anemia caused by chronic disease are unhelpful in the assessment of iron status. Newer measurements of erythrocyte and reticulocyte indices using automated counters show promise in the evaluation of iron-restricted erythropoiesis. Assays for serum erythropoietin and the transferrin receptor are valuable tools for clinical research, but their roles in routine clinical practice remain undefined. The availability of safer intravenous iron preparations allows for carefully controlled studies of their value in patients undergoing erythropoietin therapy or experiencing blood loss, or both.

The present study was undertaken to assess the feasibility of using ferritin and transferrin receptor measurements on dried capillary blood spots to identify iron deficiency (ID) in public health surveys. Measurements on serum and blood spots prepared from venous blood were performed in 71 healthy subjects, 41 of whom were iron-replete and 30 who had ID, either without (n = 20) or with (n = 10) anemia. Parallel measurements were performed on hemolyzed whole blood and washed hemolyzed red blood cells to assess the erythrocyte contribution of ferritin and transferrin receptor to dried blood samples. The concentration of ferritin in dried blood samples was threefold higher than serum assays due to the release of ferritin from hemolyzed erythrocytes, which diminished the usefulness of ferritin measurements for detecting ID. On the other hand, there was negligible erythrocyte contribution to the measurement of transferrin receptor in dried blood spots. The most sensitive parameter in dried blood spots was the ratio of receptor/ferritin, which was suitable for identifying iron-deficiency anemia (IDA), but less reliable than serum assays for detecting milder ID without anemia. We conclude that tandem measurements of serum ferritin and transferrin receptor in dried blood spots can be used to facilitate the identification of IDA in epidemiologic studies.© 1998 by The American Society of Hematology.

Introduction: Approximately 50% of pts with de novoMDS present with cytogenetic abnormalities at diagnosis (Haase D, et al. Ann Hematol. 1995;70:171); deletion (del)5q occurs in ~15% of pts (Haase D, et al. Blood. 2007;110:4385). Cytogenetic abnormalities in addition to del(5q) may be associated with shorter overall survival (OS) and increased risk of progression to acute myeloid leukemia (AML) versus del(5q) alone (Mallo M, et al. Leukemia. 2011;25:110). In 2 large multicenter studies (MDS-003 and MDS-004), lenalidomide (LEN) was evaluated in red blood cell (RBC) transfusion-dependent pts with IPSS Low- or Intermediate-1-risk MDS and del(5q) (List A, et al. N Engl J Med. 2006;355:1456; Fenaux P, et al. Blood. 2011;118:3765). Here, we examine specific cytogenetic abnormalities and outcomes in pts with MDS and del(5q) plus ≥ 2 additional cytogenetic abnormalities from MDS-003 and MDS-004. Methods: Of 353 pts enrolled, 281 had available cytogenetic data with ≥ 12 evaluable metaphases, and were included. Pts received either LEN 10 mg on days 1-21 of each 28-day cycle, LEN 5 mg or 10 mg continuously, or placebo (PBO). In MDS-004, at week (wk) 16, PBO pts could cross over to LEN 5 mg. Centrally reviewed cytogenetic studies were performed at baseline, and wks 24 and 48 (MDS-003); and at baseline, wks 12 and 24, and every 24 wks thereafter (MDS-004). RBC transfusion independence (TI) ≥ 26 wks, cytogenetic response (CyR), AML progression, OS, and AML-free survival were assessed by baseline cytogenetic complexity in LEN-treated pts with del(5q) plus ≥ 2 additional abnormalities. These patients did not fulfill IPSS lower-risk classification after central pathologic/cytogenetic evaluation. Results: Of 281 pts, 25 (8.9%) had del(5q) plus ≥ 2 additional abnormalities at baseline. In these pts, the most common additional abnormalities at baseline were -7 (20.0%), del(13q) (20.0%), +21 (16.0%), and del(11q) (16.0%). Baseline characteristics were comparable across the 24 LEN-treated pts with 2 (n = 9), 3 (n = 8), or ≥ 4 (n = 7) additional abnormalities. Rates of RBC-TI ≥ 26 wks were 44.4%, 50.0%, and 28.6% in pts with 2, 3, or ≥ 4 additional abnormalities (P = 0.77), respectively. In pts evaluable for CyR (n = 21), rates of CyR were 33.3%, 28.6%, and 20.0% (P = 1.00), respectively; all cytogenetic responders achieved RBC-TI ≥ 26 wks. The other pts who achieved RBC-TI ≥ 26 wks but did not meet the criteria for CyR showed reductions in the del(5q) clone. No PBO pts achieved CyR; however, 1 pt had a partial response (PR) after crossover to LEN 5 mg. Of the pts randomized to LEN, 4 achieved a complete response (CR) (5 mg, n = 1; 10 mg, n = 3) and 2 achieved a PR (5 mg and 10 mg). Median duration of CyR was 282 days (range 168-957). The median number of additional cytogenetic abnormalities in the subset of pts with poor-risk abnormalities (i.e. 17p, 3q, and monosomal abnormalities; n = 7) was 3 versus 2 in pts with good-risk abnormalities (i.e. all other abnormalities; n = 14). Rates of RBC-TI ≥ 26 wks were 28.6% versus 57.1% for the poor-risk versus good-risk groups, respectively. Rates of CyR were 14.3% versus 35.7%, respectively (all CR). In pts with 2, 3, or ≥ 4 additional abnormalities, the 2-year AML progression rates were 56.3% (95% confidence interval [CI] 25.8-89.9), 40.0% (95% CI 14.8-80.5), and 33.3% (95% CI 5.5-94.6), respectively. Median time to AML was 1.8 years (95% CI 0.6-not reached [NR]), 3.1 years (95% CI 0.4-4.8), and NR (95% CI 1.6-NR) (P = 0.75), respectively (Figure 1A). Of 10 pts who developed AML, 6 had involvement of chromosome 7 [del(7q) or -7] at baseline, but presence of -7 did not necessarily portend a poor response in all. Median OS was 1.8 years (95% CI 0.6-3.7), 3.6 years (95% CI 0.5-NR), and 1.6 years (95% CI 0.2-3.3) (P = 0.17) in pts with 2, 3, or ≥ 4 additional abnormalities (Figure 1B). Median AML-free survival was 1.5 years (95% CI 0.6-3.7), 2.5 years (95% CI 0.4-4.8), and 1.6 years (95% CI 0.2-3.3) (P = 0.36), respectively (Figure 1C). Conclusions: Although RBC-TI and CyR with LEN do occur in pts with del(5q) plus ≥ 2 additional abnormalities, the prognosis is generally dismal and less favorable versus isolated del(5q) and del(5q) plus 1 additional abnormality (Giagounidis A, et al. Blood. 2014;124:abstract 3270). Pts with del(5q) and complex karyotypes are generally associated with IPSS Intermediate-2- or High-risk MDS, which require more intensive treatment approaches, including azacitidine and stem cell transplantation, if feasible. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Giagounidis: Celgene Corporation: Honoraria. List:Celgene Corporation: Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morrill:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership. Fenaux:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding.

Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to < 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg. Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia [49.3% vs 73.7% for non-del(5q) vs del(5q), respectively], thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia [45.2% vs 72.0% for non-del(5q) and del(5q), respectively], thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (> 12 months) LEN treatment by time of onset (0 to 6, > 6 to 12, and > 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at > 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At > 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%. Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies. Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at > 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable. Disclosures Almeida: Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.

Background: When administered subcutaneously (SC), the epigenetic modifier, azacitidine (AZA) is shown to improve overall survival in patients (pts) with AML compared with conventional care regimens (Fenaux, JCO, 2010; Dombret, Blood, 2015). CC-486, the oral formulation of AZA, is in clinical development for use in hematologic malignancies. An early dose-finding study of CC-486 administered on a 7-day schedule showed it to be safe and clinically active in pts with AML (Garcia-Manero, JCO, 2011; Gore, Blood, 2011). Extending CC-486 dosing for more than 7 days may increase AZA exposure to leukemic cells over the treatment (Tx) cycle to improve response. Objective: Evaluate the safety and efficacy of CC-486 administered in extended dosing schedules (14 days or 21 days per 28-day cycle) in pts with AML. Methods: Pts with AML from two phase I/II studies were sequentially assigned to receive CC-486 in 1 of 4 extended dosing regimens: 300mg QD x14 days (d)/28d (14-QD), 300mg QD x21d/28d (21-QD), 200mg BID x14d/28d (14-BID), or 200mg BID x21d/28d (21-BID). Hematologic responses (complete remission [CR], partial remission [PR], CR with incomplete hematologic recovery [CRi], marrow CR [mCR]), were assessed using IWG criteria for AML (Cheson, J Clin Oncol, 2003), and hematologic improvement (HI) and transfusion independence (TI) were assessed using IWG criteria for MDS (Cheson, Blood, 2006). Tx-emergent adverse events (TEAEs) were graded by NCI-CTCAE v3.1 or v4.0. Results: In all, 23 pts with AML participated in the studies: 14-QD n=4, 21-QD n=12, 14-BID n=4, 21-BID n=3. Median age was 68 years (range 44 - 93), 48% were male, 22% and 78% had ECOG performance status scores of 0-1 or 2, respectively, median % bone marrow blasts was 25%, and median baseline hematology counts were: Hgb 9.1 g/dL (7.4 - 11.7), platelets 33 x 109/L (3 - 435), and ANC 0.3 x 109/L (0 - 6.4). Median time from diagnosis was 1.1 month (range -0.2 - 82.1). Eleven pts (52%) had prior MDS and 13 pts (57%) had received prior Tx for MDS (n=5) or AML (n=8), including 5 pts (38%) who had received hypomethylating agents (HMAs). The median number of CC-486 Tx cycles for all pts was 4 (1 - 9) (Figure). Overall response (CR, PR, CRi, mCR, HI or TI) rate was 48% (11/23), with generally comparable responses and response rates across the 4 dosing regimens (Table 1). Responses were observed in 4 pts (50%) who were relapsed/refractory to prior AML Tx. Two pts (40%) who had received prior HMA Tx responded, 1 of whom attained CR. HI was achieved by 32% (7/22) of pts, and 20% (3/15) of RBC transfusion-dependent pts attained RBC TI. Six pts with prior MDS (55%) responded during Tx. One pt proceeded to transplant. Febrile neutropenia (30%) and anemia (22%) were the most common grade 3-4 TEAEs (Table 2). Incidences of grade 3-4 TEAEs were generally similar across the 4 CC-486 dosing regimens. Conclusions: CC-486 administered in extended 14- or 21-day per cycle schedules was well tolerated. One-half of these older pts with AML had a hematologic response, including pts who had prior MDS, or AML that failed or lost response to prior Tx. Interestingly, pts who previously received injectable HMA Tx had hematologic responses (including CR) with CC-486, likely due to the alternative methylation pattern obtained with prolonged oral administration (Laille, Plos One, in press). Ease of administration of CC-486 can facilitate long-term Tx for sustained disease modification, provide an additional option for failure of IV/SQ HMA therapy, and may improve outcomes in combination Tx regimens, which warrant investigation. Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Kolibaba:Janssen: Research Funding; Acerta: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Cell therapeutics: Research Funding; GSK: Research Funding; Novartis: Research Funding; Genentech, Inc.: Research Funding; Seattle Genetics: Research Funding. Ukrainskyj:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Dong:Celgene Corporation: Employment, Equity Ownership. Hetzer:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment, Equity Ownership.

The present investigation was undertaken to search for soluble forms of the erythropoietin receptor in human serum using polyclonal antibody against an amino terminal peptide sequence in the extracellular domain. This sequence was located adjacent to the amino terminus at residues 25- 38. When this antibody was used for Western blots of solubilized membranes from nucleated bone marrow cells, a protein consistent with native erythropoietin receptor was seen. Purified soluble ectodomain of the erythropoietin receptor displayed appropriate reactivity with this antibody. When sera from normal subjects and patients with a range of hematologic disorders were examined by Western blotting, a protein with a molecular mass of 34 Kd was detected in sera from patients with enhanced erythropoiesis including sickle cell anemia, thalassemia, and megaloblastic anemia. This protein was rarely detected in normal serum but appeared when normal subjects were treated with recombinant erythropoietin and disappeared after full treatment of patients with megaloblastic anemia due to vitamin B12 deficiency. The protein was not detected after myeloablation for bone marrow transplantation but appeared with marrow engraftment. Reactivity of this protein with the peptide antibody was competitively inhibited by the amino terminal peptide sequence. An additional 48 Kd protein was detected that showed minimal variation in intensity with differing degrees of erythropoietic activity. Detection of this protein could not be inhibited by the addition of synthetic peptide. Our findings indicate the presence of a soluble form of the erythropoietin receptor related to the extracellular domain that is highly correlated with enhanced erythropoiesis.

This study was undertaken to evaluate the role of serum transferrin receptor measurements in the assessment of iron status. Repeated phlebotomies were performed in 14 normal volunteer subjects to obtain varying degrees of iron deficiency. Serial measurements of serum iron, total iron-binding capacity, mean cell volume (MCV), free erythrocyte protoporphyrin (FEP), red cell mean index, serum ferritin, and serum transferrin receptor were performed throughout the phlebotomy program. There was no change in receptor levels during the phase of storage iron depletion. When the serum ferritin level reached subnormal values there was an increase in serum receptor levels, which continued throughout the phlebotomy program. Functional iron deficiency was defined as a reduction in body iron beyond the point of depleted iron stores. The serum receptor level was a more sensitive and reliable guide to the degree of functional iron deficiency than either the FEP or MCV. Our studies indicate that the serum receptor measurement is of particular value in identifying mild iron deficiency of recent onset. The iron status of a population can be fully assessed by using serum ferritin as a measure of iron stores, serum receptor as a measure of mild tissue iron deficiency, and hemoglobin concentration as a measure of advanced iron deficiency.

Background: CC-486 is an oral formulation of the epigenetic modifier, azacitidine, in clinical development for treatment (Tx) of hematological cancers. Part 1 of this phase I, multicenter study showed no effect on pharmacokinetics (PK) of CC-486 when taken with food or with a proton-pump inhibitor (Laille, 2014). A prospective extension phase of this study is ongoing to assess the safety and efficacy of CC-486. Objectives: To assess safety, tolerability, and hematological response associated with an extended CC-486 dosing schedule in patients (pts) with MDS, AML, or CMML. Methods: Eligible pts were age ≥18 years, had confirmed WHO-defined MDS, CMML, or AML based on bone marrow (BM) aspirate and biopsy, and an ECOG performance status score 0-2. In the PK phase, pts received 2 to 3 single CC-486 doses and in the extension phase, pts received CC-486 300 mg QD for the first 21 days of repeated 28-day cycles. Tx-emergent adverse events (TEAEs) were coded by MedDRA v15.0 and graded using NCI-CTCAE v4.0. In addition to TEAEs for all pts, because PK-phase exposure was quite limited, TEAEs of interest are reported for the subset of pts who entered the extension phase (21-day dosing). Responses (complete or partial remission [CR, PR], CR with incomplete blood count recovery [CRi], marrow CR [mCR], hematologic improvement [HI], and transfusion independence [TI]) were defined by IWG 2006 (MDS) or IWG 2003 (AML) criteria. Baseline transfusion dependence (TD) was defined as ≥4 red blood cell (RBC) units or ≥2 platelet transfusions, in the 56 days before first dose. TI was defined as no transfusion for 56 consecutive days. The safety-evaluable cohort included all pts who received ≥1 CC-486 dose. Efficacy-evaluable pts had ≥1 post-baseline efficacy measurement during the extension phase as of data cut-off (June 6, 2014). Efficacy results are reported for the combined MDS and CMML pt population and separately for pts with AML. Results: A total of 32 pts (MDS n=19 [59%], CMML n=4 [13%], and AML n=9 [28%]) received ≥1 CC-486 dose and are evaluated for safety. Median (range) age of all pts was 72 (53-93) years, with 44% of pts age ≥75 years. Most pts were male (69%) and all were Caucasian. Median number of CC-486 Tx cycles for all pts was 4 (range 1-18), and within the MDS, CMML, and AML groups was 5 (1-18), 4 (2-17), and 1 (1-9), respectively. The mean ±SD Tx cycle length was 30 ±9.0 days overall (by group: 33 ±8.3 days in MDS, 25 ±5.4 in CMML, and 27 ±10.7 in AML pts). The most frequent types of TEAE were gastrointestinal (GI) and hematological (Table 1). CC-486 dose was adjusted due to GI TEAEs for 5 pts (16%), and due to hematological TEAEs for 8 pts (25%). Of all 32 pts, 30 pts (94%) entered the 21-day dosing extension phase. Of these pts, GI TEAEs (grade ≥2) were reported for 23 pts (77%). Of these, only 4 grade 3 (vomiting and diarrhea, 2 each) and no grade 4 TEAEs were observed. Hematological TEAEs (grade ≥3) were reported for 19 pts (63%). Neutropenic grade ≥2 TEAEs occurred in 12 (40%) of 30 pts, of which 29% were grade 2, 38% grade 3, and 32% grade 4. Febrile neutropenia occurred in 3 pts and grade 4 thrombocytopenia in 3. Most TEAEs occurred during the first 2 Tx cycles: GI, 73% and hematological, 55%. The efficacy-evaluable population at data cut-off included 27 pts (84%): 20 pts with MDS or CMML, and 7 pts with AML (Table 2). One pt with MDS achieved CR, 1 pt with AML achieved CRi, and 1 pt with AML achieved PR (pt was to proceed to transplant). Of HI-evaluable pts in the MDS+CMML and AML groups, respectively, 6/18 (33%) and 2/7 (29%) attained an HI response. Few pts were TD at baseline. Of pts who were RBC TD at baseline, 1/5 pts (20%) in the MDS+CMML group and 1/5 pts (20%) in the AML group attained RBC TI. Of 3 pts who were platelet TD at baseline, 1 pt with AML attained platelet TI. Conclusions: CC-486 can provide the flexibility to adjust dose or dosing regimen to improve tolerability or efficacy as needed. The safety and tolerability of CC-486 300 mg QD taken for the first 21 days of repeated 28-day cycles were consistent with the known safety profile of injectable azacitidine in these pts with MDS, CMML, and AML. Grade 3-4 gastrointestinal TEAEs were infrequent ( Disclosures Savona: Karyopharm: Consultancy, Equity Ownership; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy. Kolibaba:Celgene: Research Funding. Conkling:Celgene: Research Funding. Rifkin:Celgene: Scientific Advisory Board Other; Millennium/Takeda: Scientific Advisory Board, Scientific Advisory Board Other; Onyx/Amgen: Scientific Advisory Board, Scientific Advisory Board Other. Laille:Celgene: Employment, Equity Ownership. Kellerman:Celgene: Employment. Ukrainskyj:Celgene: Employment, Equity Ownership. Dong:Celgene: Employment. Skikne:Celgene: Employment, Equity Ownership.

Introduction: Around 50% of pts with de novo MDS present with chromosomal abnormalities at diagnosis. One of the most common cytogenetic abnormalities in MDS, deletion 5q [del(5q)], occurs in ~15% of pts (Haase et al. Blood 2007;110:4385-95). The presence of cytogenetic abnormalities in addition to del(5q) may be associated with shorter overall survival (OS) and increased risk of progression to acute myeloid leukemia (AML) versus del(5q) alone (Mallo et al. Leukemia 2011;25:110-20). In 2 large multicenter studies (MDS-003 and MDS-004), lenalidomide (LEN) was evaluated in RBC transfusion-dependent pts with IPSS Low/Intermediate (Int)-1-risk MDS and del(5q) (List et al. N Engl J Med 2006;355:1456-65; Fenaux et al. Blood 2011;118:3765-76). This analysis describes the prevalence and clinical impact of the most common cytogenetic abnormalities in pts with del(5q) from MDS-003 and MDS-004. Methods: Of 353 pts enrolled in MDS-003 and MDS-004, 281 pts had available cytogenetic data with ≥ 16 metaphases evaluable, and were included in the analysis. Pts received 10 mg LEN on days 1–21 of each 28-day cycle; LEN 5 mg or 10 mg continuously; or placebo. In MDS-004, placebo pts could crossover to LEN 5 mg by Week (Wk) 16. Centrally reviewed cytogenetic studies were performed at baseline, and wks 24 and 48 (MDS-003); or baseline, Wk 24, and every 24 wks thereafter (MDS-004). RBC-transfusion independence (RBC-TI) ≥ 26 wks, cytogenetic response (CyR), AML progression, and OS were assessed by most common cytogenetic abnormalities in LEN-treated pts with del(5q) plus 1 additional abnormality. Some pts did not fulfill the IPSS lower-risk classification after central pathologic/cytogenetic evaluation. For this analysis outcomes in the del(5q) plus ≥ 2 additional abnormalities group were not evaluated. Results: Of the 281 pts, 70.8% had isolated del(5q), 19.9% del(5q) plus 1 additional abnormality, and 9.3% had del(5q) plus ≥ 2 additional abnormalities. Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, and platelet and absolute neutrophil counts were comparable across the cytogenetic groups. In pts with del(5q) plus 1 additional abnormality at baseline, the most common numerical abnormalities were +8 (17.9%; n = 10), +21 (14.3%; n = 8), and −7 (3.6%; n = 2); the most common balanced structural rearrangements were translocation 2;11 [t(2;11)] (5.4%; n = 3) and isochromosome 21q [i(21q)] (3.6%; n = 2); and the most common unbalanced structural rearrangements were del(11q) (7.1%; n = 4), del(20q) (5.4%; n = 3), del(9q) (3.6%; n = 2), and del(12p) (3.6%; n = 2) (Figure). In the del(5q) plus 1 additional abnormality group, baseline characteristics were comparable across pts with +8, +21, or other abnormalities (i.e. excluding those with +21 and +8), with the exception of age (P = 0.023). Rates of RBC-TI ≥ 26 wks and CyR did not significantly differ among LEN-treated pts with +8 (n = 9), +21 (n = 8), or other abnormalities (n = 37). Rates of RBC-TI ≥ 26 wks were 66.7%, 50.0%, and 54.1% (P = 0.839), respectively. In pts evaluable for CyR (n = 40), CyR rates were 42.9%, 42.9%, and 65.4% (P = 0.407), respectively. Median time to AML progression was shorter in LEN-treated pts with +21 (2.6 years [yrs]; 95% CI 1.2–4.8) versus +8 (4.8 yrs; 95% CI 1.6–not estimable) or other abnormalities (7.5 yrs; 95% CI 4.1–7.5) (P = 0.0143). The 5-year AML progression rates were 68.8% (95% CI 26.6–98.7), 85.7% (95% CI 53.5–99.3), and 36.3% (95% CI 19.2–61.3) in pts with +8, +21, or other abnormalities, respectively. Median OS was 4.1 yrs (95% CI 0.9–5.3), 3.0 yrs (95% CI 1.1–4.9), and 3.4 yrs (95% CI 2.6–6.5) (P = 0.423), respectively. Of the 2 pts with −7: 1 pt with Int-1-risk MDS had a 92% to 8% reduction of −7-positive metaphases at Day 84 on treatment, but no RBC-TI ≥ 26 wks, and died at Day 709 without AML; the other Int-2-risk pt progressed to AML on Day 147 with clearance of −7 from 8%, and development of new +8 and del(16q) abnormalities. Conclusions:In MDS pts with del(5q) plus 1 additional abnormality from MDS-003 and MDS-004, the most common cytogenetic abnormalities were +8, +21, del(11q), del(20q), and t(2;11), which accounted for 50% of the additional abnormalities at baseline. In the del(5q) plus 1 additional abnormality population, median time to AML progression was shorter in pts with +21 versus either +8 or other abnormalities. Due to small pt numbers, larger prospective analyses are needed to confirm these observations. Figure 1 Figure 1. Disclosures Giagounidis: Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy. Hellstrom-Lindberg:Celgene: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene Corporation: Consultancy. Morrill:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding.

Background: Disease relapse and graft vs host disease (GvHD) following alloHSCT are major causes of treatment (Tx) failure in patients (pts) with MDS and AML (Paietta, 2012). Studies of parenteral azacitidine, an epigenetic modifier, have shown efficacy in preventing post-transplant relapse in MDS and AML pts, and possibly reducing GvHD severity (Platzbecker, 2012; de Lima, 2010). Azacitidine maintenance after alloHSCT may enhance graft vs leukemia (GvL) effects and reduce GvHD by expansion of regulatory T cells (Goodyear, 2010, 2012). CC-486 is a novel oral formulation of azacitidine which, as well as potentially allowing easier administration over extended schedules, could increase the duration of drug exposure to residual malignant cells. We now report preliminary results from a prospective phase I/II dose-finding study of CC-486 as maintenance Tx after alloHSCT in pts with MDS or AML. Objective: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and safety outcomes of CC-486 following alloHSCT in pts with MDS or AML. Methods: Pts with WHO-defined MDS or AML who have undergone alloHSCT with myeloablative (MAC) or reduced-intensity conditioning (RIC) regimens and who had sibling or unrelated donors with ≤1 antigen mismatch at the HLA-A, -B, -C, -DRB1 or -DQB1 locus, are enrolled. CC-486 Tx is initiated between days (d) 42 and 84 after alloHSCT. Pts receive prophylactic Tx for GvHD and infections per institutional standard. A standard 3x3 MTD design is being used to evaluate 4 dosing schedules: CC-486 200 mg or 300 mg QD, administered for 7 d (Cohorts 1 and 2) or 14 d (Cohorts 3 and 4) of repeated 28d Tx cycles. MTD determination is based on DLT that occur during the first 2 Tx cycles (pts are not evaluable if unable to complete 2 Tx cycles for reasons other than a DLT). Adverse events (AEs) are graded using NCI-CTCAE v4.0. Pts are followed for safety, incidence of acute and chronic GvHD, and relapse. PK of azacitidine after CC-486 administration, alone or with standard concomitant medications, are evaluated on d 1 of CC-486 Tx cycles 1 and 2. Results: At data cut-off (7/17/2014), outcome data were available for 7 pts enrolled in the first 2 cohorts (Table): 1 pt had IPSS Int-2 MDS and 6 had AML with high-risk features. Stem cell source was from bone marrow (n=2) or peripheral blood (n=5) from unrelated (n=5) or sibling (n=2) donors. Two pts had 1 antigen mismatch and 5 had a full match.Conditioning included MAC (n=3) and RIC (n=4) regimens. One pt in Cohort 2 was not evaluable for DLT or PK assessments due to early discontinuation (AML relapse) during the first CC-486 Tx cycle. Of the 6 evaluable pts, 4 completed ≥6 CC-486 Tx cycles and 2 ongoing pts had not reached 6 cycles on-study at data cut-off (Table). One pt who had GvHD before CC-486 Tx subsequently withdrew from the study after developing febrile neutropenia and diarrhea related to GvHD of the bowel; 1 pt withdrew for personal reasons; and 1 pt discontinued after 6 Tx cycles due to relapse. At data cut-off, 3 pts remained on-study, all with continued CR (Table). No pt in Cohort 2 developed GvHD. For all pts, most AEs were grade 1-2. Grade 3-4 AEs were reported for 2 pts: both had nausea and vomiting, which were controlled with antiemetic agents upon onset; 1 also had device-related infection and dyspnea, and 1 also had febrile neutropenia and rash. No DLT emerged with these CC-486 regimens and no pt experienced secondary graft failure. Overall azacitidine plasma concentration profiles (Figure) and PK parameters were similar following CC-486 given alone or with concomitant medications, and were within range of values observed following similar CC-486 doses in pts with MDS, CMML, and AML (Garcia-Manero, 2011). The AUC range for oral CC-486 is ~10% of that seen with subcutaneous azacitidine administered at 75 mg/m2 (Garcia-Manero, 2011). Conclusion: Preliminary data from this analysis suggest that CC-486 administered at doses of 200 or 300 mg QD for 7 days every 4 weeks is safe and well tolerated in the post-transplant setting. Overall, azacitidine plasma concentration profiles and PK parameters were not affected by use of concomitant medications. No DLT and a low rate of GvHD support the ongoing evaluation of 14d extended CC-486 dosing regimens in this ongoing study, as a preliminary to a prospective, randomized trial of this new agent post-transplant. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures de Lima: Celgene: Consultancy. Champlin:Celgene: Consultancy. Giralt:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Scott:Celgene: Consultancy, Honoraria, Research Funding. Hetzer:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Craddock:Celgene: Honoraria, Research Funding.

Background Subcutaneous (SC) azacitidine prolongs overall survival in subjects with higher-risk MDS (Fenaux, JCO, 2009). Previous Phase I and II studies have shown extended oral azacitidine dosing schedules to be safe and effective in subjects with IPSS-defined lower-risk MDS (Garcia-Manero et al, ASH 2010 and ASH 2012). Objective To assess the efficacy and safety of extended oral azacitidine dosing schedules in subjects with WHO-defined RAEB-1 or RAEB-2 MDS. Methods The subset of subjects with WHO-defined RAEB-1 or RAEB-2 MDS from two ongoing Phase I/II studies was included in this ad hoc analysis. Subjects received oral azacitidine 300mg QD or 200mg BID for 14 or 21 days of repeated 28-day cycles. For purposes of this analysis, subject data were analyzed collectively. Hematologic responses were defined by International Working Group (IWG) 2006 criteria. Overall Response was calculated as any response of complete or partial remission (CR or PR), RBC or platelet transfusion independence (TI), and/or any hematologic improvement (HI). Marrow complete remission (mCR) was not included in Overall Response. Serious treatment-emergent adverse events (STEAEs) that occurred in 2 or more subjects are reported. Results Of 23 subjects in all, 20 received 300mg QD oral azacitidine x 14 or 21 days/28-day cycle and 3 received oral azacitidine 200mg BID x 14 days/28-day cycle. Subjects had median age of 71 (range: 36 - 90) years and were predominantly male (61%). Fourteen subjects (61%) had a diagnosis of RAEB-1 and 9 (39%) had RAEB-2, median time from diagnosis was 2.1 (0.1 - 33.2) months, and ECOG performance status scores were 0 (n=4, 17%), 1 (n=15, 65%), or 2 (n=4, 17%). Five subjects had received prior MDS treatments (azacitidine injection; erythropoiesis stimulating agent [ESA]; thalidomide; azacitidine injection and decitabine; G-CSF, anti-thymocyte globulin, methylprednisolone, cyclosporine, and ESA). Median number of oral azacitidine treatment cycles was 3 (1 - 29). Overall Response was achieved by 11/22 subjects (50%) (Table). Four subjects achieved mCR only and are not included in the Overall Response category. RBC TI was achieved by 5/12 subjects (42%) and platelet TI was achieved by 2/5 subjects (40%). Two subjects were able to consolidate remission and proceed to allogeneic stem cell transplant and 1 subject progressed to AML on-study. Oral azacitidine was generally well tolerated. Three subjects discontinued treatment due to an AE. STEAEs were consistent with the known safety profile of SC azacitidine. Of 8 subjects who had an STEAE of febrile neutropenia, pneumonia, and/or septic shock, 3 were severely neutropenic (ANC Conclusions This analysis in subjects with RAEB-1 and RAEB-2 is the first to assess extended oral azacitidine dosing schedules in higher-risk MDS. One-half of treated subjects achieved a hematologic response to oral azacitidine, which is easy to administer and was generally well-tolerated. Two Phase III studies of extended oral azacitidine dosing (in lower-risk MDS and as maintenance therapy in older patients with AML) are ongoing. Results of these large studies will better elucidate the use of extended oral azacitidine dosing schedules in treating hematologic malignancies. Disclosures: Gore: Celgene Corporation: Consultancy. Cogle:Celgene Corporation: Honoraria, Research Funding. Conkling:US Oncology: Research Funding. Beach:Celgene Corporation: Employment. Hetzer:Celgene Corporation: Employment. Dong:Celgene Corporation: Employment. Skikne:Celgene Corporation: Employment.

Introduction The proportion of aberrant metaphases is prognostic for overall survival (OS) in MDS patients with trisomy 8 (Mallo M, et al. Leuk Res. 2011;35:834-6). The impact of the proportion of metaphases with del(5q) on clinical outcomes, including OS, disease progression and response to therapy with LEN in MDS remains undefined. In two large multicenter studies of LEN (MDS-003 and MDS-004) in RBC transfusion-dependent patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk del(5q) MDS, RBC transfusion independence (TI) ≥ 8 weeks was achieved in 51–67% of patients (List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). This retrospective analysis evaluated response to treatment, progression to acute myeloid leukemia (AML) and OS by proportion of del(5q) metaphases in patients with isolated del(5q) from the MDS-003 and 004 studies. Methods In order to allow sufficient patient numbers for analysis, ≥ 16 metaphases were evaluated for del(5q) by standard karyotyping (MDS-003 and MDS-004) and 200 interphase nuclei were evaluated by fluorescence in situ hybridization (FISH; MDS-004 only) using a probe for the commonly deleted region 5q31 (LSI EGR1/D5S721, Abbott, Wiesbaden, Germany). Patients received LEN on days 1–21 of each 28-day cycle (10 mg) or continuously (5 mg or 10 mg), or placebo. In MDS-004, patients randomized to placebo could cross over to LEN 5 mg by week 16. RBC-TI ≥ 26 weeks, time to AML progression and OS were analyzed by the proportion of del(5q) metaphases or interphases (≤ 60% vs > 60%) using standard karyotyping and FISH, respectively. Results Of the 353 patients from MDS-003 and MDS-004, 194 had isolated del(5q) by standard karyotyping; median proportion of del(5q) metaphases was 96% (range 4–100). Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, platelet and absolute neutrophil counts were comparable among patients with ≤ 60% (n = 21) and > 60% (n = 173) del(5q) metaphases. Rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 0.6515). Time to AML progression was comparable for patients in the ≤ 60% group versus the > 60% group (log-rank test P = 0.9802); 2-year rates were 22.2% (95% confidence interval [CI]: 7.7–54.5%) and 14.6% (95% CI: 9.9–21.2%), respectively. Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.5514). OS was longer in the > 60% versus the ≤ 60% group (log-rank test P = 0.0436); median OS was 3.7 years (95% CI: 3.0–4.2) and 2.4 years (95% CI: 1.5–4.9), respectively. In MDS-004, the proportion of del(5q) interphases was analyzed using FISH in 106 patients, including 46 with ≤ 60% and 60 with > 60%. When analyzed by FISH, rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 1.000). Time to AML progression and OS were similar across these groups (log-rank test P = 0.7311 and P = 0.8639, respectively) when analyzed by FISH. In the ≤ 60% and > 60% groups respectively, 2-year AML progression rates were 14.8% (95% CI: 6.9–30.1%) and 18.6% (95% CI: 10.4–32.0%), and median OS was 3.1 years (95% CI: 2.3–4.8) and 2.9 years (95% CI: 2.3–4.4). Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.8631). Conclusions In IPSS Low- or Int-1-risk MDS patients with isolated del(5q) treated with LEN in MDS-003 and MDS-004 studies, baseline characteristics, RBC-TI ≥ 26 weeks and AML progression were comparable in patients with > 60% versus ≤ 60% del(5q) metaphases. Although similar across groups when analyzed by FISH in a subset of patients, surprisingly, OS was longer in patients with > 60% del(5q) metaphases than in those with ≤ 60% del(5q) metaphases by standard karyotyping. However, the number of patients with ≤ 60% del(5q) metaphases was limited and no adjustment was made for multiple testing. These findings suggest that the number of cells with the isolated del(5q) abnormality measured by FISH does not impact clinical outcome in this RBC transfusion-dependent study population, but this finding could not be confirmed for OS by standard karyotyping. Disclosures: Giagounidis: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Hellström-Lindberg:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene: Consultancy. Morrill:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Celgene: Honoraria.

Abstract 3808 Background: Approximately 10–15% of patients with myelodysplastic syndromes (MDS) have a hypocellular bone marrow (BM) at diagnosis. Some studies have suggested hypocellular MDS may have an adverse prognostic impact, but this is controversial. In the Phase 3 randomized AZA-001 study, AZA prolonged overall survival (OS) in patients with higher-risk MDS compared with conventional care regimens (CCR) (Lancet Oncol, 2009). However, the efficacy and tolerability of AZA in the subset of patients with hypocellular MDS has not been determined. Purpose: This post hoc analysis was conducted to determine whether the prolongation of OS observed with AZA compared with CCR in the AZA-001 study is influenced by baseline BM cellularity. We also sought to explore the tolerability of AZA treatment in patients with higher-risk MDS and hypocellular BM. Methods: Study design of AZA-001 is reported elsewhere (Lancet Oncol, 2009). Briefly, patients with higher-risk MDS (FAB: RAEB, RAEB-t, or CMML, and IPSS Int-2 or High risk disease) were randomized to AZA (75 mg/m2/d SC × 7d q 28d) or to CCR (supportive care, low-dose Ara-C [LDAC], or intensive chemotherapy [IC]). In the current analysis, patients were divided into 2 groups based on centrally reviewed baseline BM biopsy samples which confirmed the diagnosis of MDS (J. Bennett): a hypocellular (≤30%) group and a non-hypocellular (>30%) group. OS was assessed using Kaplan-Meier methods and treatments were compared by log-rank analysis. Results: Of 358 patients in AZA-001 (AZA n=179, CCR n=179), BM cellularity data were available for 299 patients (AZA n=154, CCR n=145). At baseline, 87% of patients (n=260) had non-hypocellular BM and 13% of patients (n=39) had hypocellular BM. Of patients with hypocellular BM in the CCR group (n=18), 7 patients (39%) received supportive care, 9 (50%) LDAC, and 2 (11%) IC. In general, baseline characteristics were similar between the hypocellular and non-hypocellular BM groups. Similarly, age, % BM blasts, cytogenetics, cytopenias, and transfusion dependence, were generally balanced across treatments within the 2 cellularity groups (Table). Median (range) duration of AZA treatment cycles in hypocellular patients was 35.5 (28–54) days and in non-hypocellular patients was 33.0 (15–75) days. Response (complete or partial response [CR+PR]) rates in hypocellular patients treated with AZA were 0% and with CCR were 5.6% (p=0.4615); and hematologic improvement (HI) rates were 52% and 41%, respectively (p=0.532). In non-hypocellular patients treated with AZA or CCR, rates of CR+PR were 7.5% and 0.8%, respectively (p=0.010); and HI rates were 48% and 28% (p=0.001), respectively. The improvement in OS in AZA-treated patients was more pronounced in the hypocellular group than the non-hypocellular group, whereas OS in CCR-treated patients was similar regardless of BM cellularity (Figure). Median OS was significantly prolonged with AZA vs. CCR in both the hypocellular and non-hypocellular groups. In patients with hypocellular BM, at 33 months median OS was not reached (NR; 95% CI: 19.2, NR) in the AZA arm vs. 16.9 months (95% CI: 11.1, 19.3) in the CCR arm (p=0.001). In patients with non-hypocellular BM, median OS in the AZA arm was 21.1 months (95% CI: 16.2, 34.7) vs. 15.3 months (95% CI: 9.3, 17.6) in the CCR arm (p=0.012). Safety and tolerability in the two BM cellularity groups were similar to that seen in the overall AZA-001 study (Lancet Oncol, 2009). Frequencies of grade 3–4 hematologic AEs in AZA-treated patients in the hypocellular and non-hypocellular groups were similar: anemia (9.5% vs 14.7%, respectively), febrile neutropenia (9.5% vs 11.6%), leukopenia (14.3% vs 13.2%), neutropenia (61.9% vs 60.5%), and thrombocytopenia (61.9% vs 58.1%). Conclusions: In this post hoc analysis, the prevalence of patients with hypocellular MDS was 13%, consistent with the reported prevalence in the general MDS population (Bennett, 2009). The survival advantage with AZA vs. CCR in both baseline BM cellularity groups observed in this analysis was consistent with the overall OS advantage with AZA shown in AZA-001. These findings suggest AZA is a safe and effective treatment option for patients with BM hypocellularity. Disclosures: Seymour: Celgene Corporation: Consultancy, Honoraria, Speakers Bureau, Travel support Other. Bennett:Celgene Corporation: Consultancy. List:Celgene Corporation: Consultancy. Mufti:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Gore:Celgene Corporation: Consultancy, Research Funding. Fenaux:Celgene: Honoraria, Research Funding. Hetzer:Celgene Corporation: Employment, Equity Ownership. Songer:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

Abstract 424 Background: Azacitidine for injection has been shown to prolong overall survival in patients (pts) with higher-risk myelodysplastic syndromes (MDS) compared with conventional care regimens (CCR) (Lancet Oncol, 2009). An oral formulation of azacitidine (CC-486) is in development. Oral azacitidine may maximize convenience, eliminate injection-site reactions, and if administered in extended dosing schedules, may enhance and prolong the therapeutic effects of azacitidine. Oral azacitidine administered once-daily (QD) for 7 days (d) of repeated 28d cycles has been shown to be bioavailable, biologically and clinically active, and well-tolerated in pts with MDS and acute myeloid leukemia (Garcia-Manero, J Clin Oncol, 2011). Preliminary evidence suggests that extending oral azacitidine dosing to 14d or 21d of the 28d cycle may enhance pharmacodynamic and epigenetic activity (Laille, Leuk Res, 2011). Purpose: To evaluate hematologic response and safety associated with extended dosing regimens of oral azacitidine in pts with lower-risk MDS. Methods: This ongoing, multicenter, phase 1 study, enrolled pts with lower-risk (IPSS Low or INT-1) MDS who were RBC transfusion dependent (TD) and/or thrombocytopenic (average platelet count ≤50,000 within 56d prior to the first dose) at baseline. Pts were sequentially assigned to receive oral azacitidine 300mg QD for either 14d or 21d of repeated 28d cycles. Hematologic assessments were made every 2 weeks. Hematologic response was assessed using IWG 2006 criteria (Cheson, Blood, 2006). Adverse events (AEs) were graded using NCI-CTCAE version 3.0. Results: At data cut-off (May 18, 2012), 53 pts with lower-risk MDS had enrolled (300mg oral azacitidine QDx14d, n=26; QDx21d, n=27). Demographic and disease characteristics at baseline were similar in the 14d and 21d treatment cohorts (Table 1). Median (range) hematology counts at baseline were Hgb 8.7 g/L (6.0–13.0), ANC 1.6×109/L (0–30.3), and platelets 56.0×109/L (6.0–564.0). At study entry, 40% of pts had received no prior MDS treatment (except transfusions), 45% had received erythropoiesis-stimulating agents, and 15% had received WBC growth factors. The number of oral azacitidine treatment cycles received ranged from 1 to 12 (median numbers of oral azacitidine cycles were 6 in the QDx14d and 4 in the QDx21d cohorts). Four pts in the 21d cohort and 1 pt in the 14d cohort received reduced oral azacitidine doses (200mg QD). Overall, 10 pts discontinued the study, including 6 pts (3 pts in each cohort) who discontinued due to AEs that may have been treatment-related (gastrointestinal [n=2] or intracranial [n=1] hemorrhage, febrile neutropenia [n=1], pneumonia [n=1], thrombocytopenia [n=1]). Overall response rates (ORR), which included complete (CR) and partial remission (PR), any hematologic improvement (HI), and transfusion independence (TI), ranged from 38.5% in the QDx14d cohort to 29.6% in the QDx21d cohort, and RBC TI was achieved by 47% and 33%, respectively, of pts who were RBC TD at baseline (Table 2). For pts who received at least 4 cycles of oral azacitidine (14d, n=19; 21d, n=14), ORR was 47.4% in the 14d and 50.0% in the 21d cohorts, and RBC TI rates in RBC TD pts (n=16) were 67% in the 14d and 57% in the 21d cohorts. The most frequent (≥5%) grade 3/4 hematologic AEs in the QDx14d cohort were anemia (11.5%), thrombocytopenia (11.5%), and neutropenia (7.7%); and in the QDx21d cohort were neutropenia (14.8%), anemia (7.4%), and febrile neutropenia (7.4%). Most frequent grade 3/4 non-hematologic AEs were gastrointestinal, including vomiting (7.7%) in the QDx14d cohort, and diarrhea (11.1%) and vomiting (7.4%) in the QDx21d cohort. Conclusions: Oral azacitidine 300mg QD administered in extended dosing schedules of 14d or 21d of repeated 28d cycles was effective and well-tolerated in these pts with lower-risk MDS. Beside hematologic AEs, the most frequently observed AEs with oral azacitidine were gastrointestinal and were manageable. Efficacy and safety outcomes with 300mg QD oral azacitidine were generally comparable between the 14d and 21d extended dosing regimens. Based on these data, oral azacitidine administered once-daily in extended dosing schedules is active and well-tolerated and warrants further investigation in randomized, controlled trials. Disclosures: Garcia-Manero: Celgene: Research Funding, Speakers Bureau. Gore:Celgene Corporation: Consultancy, Research Funding. Scott:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Hetzer:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership.

Abstract 1337 Background: Oral azacitidine (CC-486) is bioavailable, biologically and clinically active, and well tolerated in patients (pts) with myelodysplastic syndromes (MDS) and acute myeloid leukemia (Garcia-Manero, J Clin Oncol, 2011). Because DNA methyltransferase (DNMT) inhibitors require active cell cycling to effect methylation reversal, prolonged administration of lower doses of azacitidine may provide more extensive reversal of DNA methylation compared with shorter administration. Purpose: We conducted analyses 1) to determine the pharmacokinetic (PK) and pharmacodynamic (PD; ie, DNA demethylating activity) profiles following subcutaneous (SC) AZA and various dosing schedules of oral azacitidine; 2) to assess the correlation between the PK and PD profiles of oral azacitidine administered in extended dosing schedules; and 3) to compare PD effects observed at different time points in the 28-day (d) treatment cycle with SC AZA or oral azacitidine administered for 7 days vs. the PD effects of 300mg QD oral azacitidine administered in extended dosing schedules in pts with MDS. Methods: This multicenter, phase 1 study had 2 parts. In Part 1, 41 pts with MDS, CMML, or AML received SC AZA (75mg/m2 QDx7d of a 28d cycle) for 1 cycle, then oral azacitidine doses ranging from 120 to 600mg (QDx7d of a 28d cycle) in subsequent cycles. In Part 2, 86 pts received oral azacitidine in 1 of 4 extended dosing schedules: 300mg QD or 200mg BID, each for 14d or 21d of repeated 28d cycles. PK parameters were derived from plasma concentrations. The correlation between PK and PD was determined using data from pts who had received oral azacitidine 200mg BID or 300mg QD for 14d or 21d for whom PD data were available at day 15 of the first 28d cycle (C1D15). The PD endpoint was reduction in percentage of highly methylated (≥70%) loci of DNA in whole blood, assessed using Illumina's Infinium Methylation27 Bead Array. Results: SC AZA or oral azacitidine were rapidly absorbed and reached Tmax (median [min, max]) within 0.5 hr [0.2, 1.1] and 1.0 hr [0.3, 3.6] post-dose, respectively. Mean elimination half-life was 1.5 +/− 0.7 hr and 0.6 +/− 0.2 hr for SC and oral azacitidine, respectively. No drug accumulation was noted following multiple dose administration. Compared with SC AZA, 300mg oral azacitidine QDx14d and QDx21d provided mean cumulative exposures (AUC) per cycle of 38% and 56%, respectively. A PK/PD correlation (AUC C1D1 vs. change in methylation on C1D15 compared with baseline) was observed with oral azacitidine 300mg QD or 200mg BID administered for 14d or 21d (r2=0.659, p Conclusions: Methylation reversal was correlated with plasma AUC following oral azacitidine dosing. Consistent with the hypothesis that prolonged exposure to lower doses of DNMT inhibitors leads to improved methylation reversal, extended dosing schedules led to significantly more demethylation compared with the 7-day oral azacitidine schedule. Additionally, DNA hypomethylation was maintained at cycle end with extended oral azacitidine dosing. The oral azacitidine 300mg QDx21d dosing schedule provided the greatest level of sustained hypomethylation at cycle end of all tested dose regimens, including SC AZA. Extended dosing schedules provide the ability to achieve the PD and epigenetic activity of oral azacitidine over a longer period of time. Disclosures: Laille: Celgene: Employment, Equity Ownership. Shi:Celgene: Employment, Equity Ownership. Garcia-Manero:Celgene: Research Funding, Speakers Bureau. Gore:Celgene: Consultancy, Research Funding. Kumar:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership.

Abstract 3828 Background: The identification of appropriate target antigens is critical to the success of cancer immunotherapies. Cancer-testis antigens (CTAs) are ectopically expressed immunoprivileged antigens transcriptionally controlled by DNA methylation which have utility as immunotherapeutic targets. 5-azacytidine (AZA), an analogue of cytidine, has been shown to induce expression of CTAs in cancer. We analyzed matched samples from 42 myelodysplastic syndrome patients receiving an oral AZA to determine if an anti-CTA immune response was generated. Methods: Immunoglobulin G (IgG) responses to CTAs were analyzed by High Throughput Immunoblot assay (HTI), 29 CTAs were bound in a concise pattern to nitrocellulose filters and developed in the following methodology. Patient sera were incubated with the HTI filters and any CTA specific antibodies bound to respective antigens and reactive antibodies were detected by secondary anti-human antibodies in a colorimetric assay. Filters were read by 5 blinded individuals, spots were scored positive or negative against control antigens. These results were compared to the paired post-therapy sample, a score of 5 was maximal change of pre to post. Those CTAs with strong antibody presence post-therapy were then confirmed via ELISA resulting in an antibody titer reflected as ug/mL. A standardization of human IgG, as well as a healthy donor control was used to determine the validity of identified responses. Results: When HTI was examined thoroughly several CTAs, MAGEs, SSX2, NY-ESO1 and MAD-CTs were of particular interest. All patients regardless of pre- or post- therapy exhibited SSX2 expression at high levels this was further confirmed with ELISA exhibiting little to no change from pre- to post-therapy. HTI examination of MAD-CT antigens revealed that pre-treatment, MAD-CT-1 and MAD-CT-2 antibody presence, responses were nearly identical, and thirty-four had the exact same response levels. PRAME, a CTA absent from our HTI filter, was evaluated only through ELISA. We determined that eighteen patients presented with an increased anti-PRAME antibody titers at post-treatment when compared to pre-treatment. Of the cancer testis antigens analyzed patients had the highest average changes in antibody titer to PRAME at post-treatment, with a 0.128 ug/mL average increases. Conclusions: Our findings suggest that CTAs could be further pursued as an immunotherapeutic target in myelodysplastic syndrome and that treatment with AZA could be exploited to modulate antigen expression in combination with immunotherapeutic approaches. Although responses were variable throughout the patients in total, some patients had robust responses at post-treatment. The CTAs, MAGEs, SSX2, NY-ESO1 and PRAME, are of particular interest, due to prior and new findings, as well as, on-going clinical trials. Five patients had a robust antibody response according to HTI to at least six antigens. Eight patients were of further interest according to ELISA examination. Further data on the relation with clinical response and possible prognostic factors of response to therapy will be presented. Disclosures: Skikne: Celgene: Employment, Equity Ownership. MacBeth:Celgene: Employment.

Abstract 3614 Background: Acute Myeloid Leukemia (AML) is a common form of leukemia in adults and often requires high resource use. About 84% of the total cost is attributed to hospital payments (Menzin 2002). The aggregate disease burden is difficult to estimate due to multiple complications and treatment courses. The standard treatment modality for AML is intensive chemotherapy with complete remission (CR) achieved in up to 60% of adults with de novo AML who are less than 70 years old (Tallman, 2005), while in the older adults CR rates occur in approximately 45% (Jabbour, 2006). For patients who relapse after CR there are a limited number of efficacious therapeutic options. These include best supportive care (BSC), additional cycles of chemotherapy and stem cell transplantation (SCT) in a minority of patients. Aim: To estimate the economic burden of the total treatment costs of AML in patients receiving therapy in the US and UK. Treatment costs are specifically assessed for induction therapy (IT), consolidation therapy (CT), for follow up during CR, and salvage therapy for relapsed or refractory disease. Methods: To identify the total costs of AML therapy, a systematic literature review was conducted of standard treatments employed during the past 5 years. Economic costs were estimated per course of treatment which included IT, CT, supportive treatment during CR, and salvage therapy including use of SCT. The total economic burden was calculated combining cost per patient with epidemiology data. Incidence rates for the US and UK and treatment outcome probabilities were calculated from the Surveillance Epidemiology and End Results (SEER), Eurostat and peer reviewed literature. Unit costs were identified using publicly available databases. Calculations were conducted for younger (65) patients given differences in incidence rates identified between these groups. Costs of treatment were calculated individually for each of the following treatment stages: 1) IT (standard dose chemotherapy (SDC) 1 cycle), 2) CT- 2 cycles of chemotherapy 3) follow up after CR (costs of BSC – 6 cycles), and 4) salvage therapy for relapse refractory disease. Results: The costs associated with hospitalization are the main component in all treatment stages (induction, consolidation, and relapse) ranging from 66% to 92% of the total costs. IT plus CT accounted for 19%-91% of the total cost per patient. When combining costs per patient with incidence data, it is estimated that the total economic burden of AML treatment ranges from £13 mln for population >65 and £38 mln for the Summary/Conclusions: The economic burden of AML treatment is very high. In both the UK and US, hospitalization costs are the key drivers. Findings suggest that savings to the healthcare system could be achieved by sustaining CR status for longer periods. When relapse occurs, high costs are incurred again, particularly when another round of chemotherapy is given. Therefore, besides the fact that achieving and staying in CR is important from the clinical point of view, it has an essential justification from the economic perspective when considering the costs that patients incur after relapse. It is critical to focus on developing new therapies that can prevent relapse and maintain AML patients' CR status to maximize their survival. Disclosures: Mahmoud: celgene: Employment. Skikne:Celgene: Employment, Equity Ownership. Kucmin-Bemelmans:Pharmerit BV: Employment. Alleman:Pharmerit BV: Employment. Hensen:Pharmerit BV: Employment.

Abstract 1546 Background: When administered subcutaneously (SC), the cytidine nucleoside analog azacitidine (AZA) has been shown to significantly improve overall survival in patients (pts) with low-blast count (20%–30%) AML compared with conventional care regimens (Fenaux, JCO, 2010). An oral AZA formulation would be more convenient for pts, increase access to treatment, allow extended dosing schedules, and may improve efficacy. An initial study of oral AZA administered once daily on a 7-day schedule demonstrated it to be bioavailable, safe, and clinically active in pts with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) (Garcia-Manero, JCO, 2011). Purpose: To present results of a multicenter phase I study of the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and preliminary hematologic response rates in pts with AML receiving varying dose regimens of oral AZA. Methods: Pts aged ≥ 18 years with AML who were not candidates for other therapies (but who may have failed prior treatment) were included. In Part 1, pts received an initial cycle of SC AZA 75 mg/m2 QD x 7 days of a 28-day cycle. Thereafter, oral AZA (120–600 mg QD) was given for 7 days of repeated 28-day cycles. In Part 2, pts received only oral AZA, in 1 of 4 extended dosing schedules: 300 mg QD or 200 mg BID, each for 14 or 21 days of 28-day cycles. Oral AZA was continued until disease progression or withdrawal for other reasons. PK was assessed during the first cycle of oral AZA treatment and DNA methylation was assessed during cycles 1 and 2 of oral AZA (Infinium Methylation27 BeadArray). Pts were monitored continuously for adverse events (AEs) and assessed for treatment response (Cheson, JCO, 2003; Cheson, JCO, 2006) at the end of every second cycle. Results: In all, 23 pts (median age 68 years [range 44–85], 13 male/10 female) with AML (13 de novo, 10 transformed from MDS) have received oral AZA on 7-day QD (n=8), 14-day QD (n=4), 21-day QD (n=4), 14-day BID (n=4), or 21-day BID (n=3) treatment schedules. At baseline, 14 (61%) and 8 (35%) pts were red blood cell (RBC) or platelet transfusion dependent, respectively; 13 pts (57%) had prior AML treatment, primarily intensive chemotherapy. Eight pts had unfavorable and 12 pts had intermediate cytogenetics (data not available, n=3). At baseline, median (range) hematologic measures were WBC = 1.5 K/μL (0.4 − 21.2), ANC = 0.2 K/μL (0 − 3.5), platelets = 34.0 K/μL (6.0 − 102), and % BM blasts = 28.0% (2.0 − 92.0). Median duration of oral AZA (any regimen) was 4 cycles (range 1–14). Seven pts (30%) received ≥ 6 cycles of oral AZA and 16 pts discontinued before completing 6 cycles (Figure). PK results were consistent with recently published data (Garcia-Manero, JCO, 2011). Following a single 300 mg dose (n=8), AUC0-∞ = 230 ± 210 ng*hr/mL, Cmax = 150 ± 114 ng/mL, t1/2 = 0.54 ± 0.21 hr, and median Tmax = 0.8 hr. There was no accumulation following multiple doses. Compared with extrapolated cumulative exposure of SC AZA administered for 7 days per the approved dosing regimen, extrapolated cumulative exposures of oral AZA with extended dosing schedules ranged from 55% for 300 mg QD × 14 days to 104% for 200 mg BID × 21 days. Overall, hematologic improvement (HI) was achieved by 5 pts (22%) (Table). One pt receiving 7-day QD oral AZA achieved a CRi. Responses were seen in 3/13 pts with de novo AML and 3/10 with secondary AML (Figure), and in 2/13 pts with prior AML treatment and 4/10 pts without prior treatment. DNA methylation levels in whole blood were reduced after oral AZA in 4/7 tested pts. The most common AEs (any severity) were gastrointestinal. Most common grade 3–4 AEs were febrile neutropenia (35%), pneumonia and syncope (17% each), nausea (13%), and thrombocytopenia, diarrhea, fatigue, dehydration, headache and mental status changes (9% each). Two pts died due to causes related to AML, and 2 pts discontinued (treatment failure, withdrew consent), within the first 60 days on-study. Conclusions: Oral AZA treatment was well tolerated in this AML population of pts who were not candidates for other therapy. The oral formulation showed biological activity by reducing DNA methylation. Oral AZA also showed clinical activity in these AML pts, many of whom had complex cytogenetics and/or had failed prior therapy before study entry. Disclosures: Gore: Celgene Corporation: Consultancy, Equity Ownership, Research Funding. Off Label Use: Oral formulation for Azacitidine in AML patients. Cogle:Celgene Corporation: Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene Corporation: Employment, Equity Ownership. Shi:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Giordano:Celgene Corporation: Employment, Equity Ownership.

Abstract 1723 Background: Two multicenter studies (MDS-003/-004) found LEN leads to RBC transfusion independence (TI) in > 50% of pts with RBC transfusion dependent Low-/Int-1-risk MDS with del5q (List A et al. NEJM 2006;355: 1456–65; Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). RBC-TI ≥ 8 wks with LEN was associated with significantly reduced risk of AML progression and death (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). Alternative therapy is required for pts failing LEN therapy. Aims: To assess predictive factors of LEN response and long term outcomes (especially after primary or secondary LEN failure) of pts < 65 yrs included in MDS-003/-004; ie, those in whom intensive therapies including allogeneic stem cell transplantation (ASCT) may be considered. Methods: LEN was administered as follows (all 28-d cycles): 5 mg/d on d 1–28 and 10 mg/d on d 1–21 or 1–28. RBC-TI ≥ 26 wks and cytogenetic response (CyR; IWG 2000) are reported. Overall survival (OS) and AML progression were assessed using Kaplan-Meier method. Response rates and outcomes in pts < 65 yrs were retrospectively compared with pts ≥ 65 yrs. Primary failure was defined as lack of RBC-TI with LEN treatment and secondary failure as relapse after achievement of RBC-TI ≥ 26 wks. Cox proportional hazards models were used to evaluate the effect of potential risk factors (ie, age, sex, time since diagnosis, FAB classification, LEN dose, IPSS risk, WPSS risk, cytogenetics, bone marrow blast %, transfusion burden, no. of cytopenias, hemoglobin level, platelet and neutrophil counts, RBC-TI ≥ 26 wks [time-dependent variable] and CyR [categorical variable]) on OS and AML progression. Logistic model was used to evaluate the effect of potential risk factors on achievement of RBC-TI ≥ 26 wks. Results: The trials included 97 (33.9%) pts < 65 yrs. Of these, 73.2% were female; 20.6% were IPSS Low-, 52.6% Int-1-, and 4.1% Int-2-risk; 30.9% had del5q with ≥ 1 additional cytogenetic abnormality (8.2% had complex cytogenetics). At baseline (BL), median time since diagnosis was 2.4 yrs (range 0.2–20.7) and median RBC transfusion requirement was 6 units/8 wks (range 1–15). In pts ≥ 65 yrs (n = 189) most BL characteristics were similar except IPSS risk, which was lower (36.5% Low-, 37.0% Int-1-, 5.8% Int-2-risk; p =.012). RBC-TI ≥ 26 wks was achieved by 54 (55.7%) pts < 65 yrs (vs 49.7% pts ≥ 65 yrs; p =.563). The median duration of RBC-TI ≥ 26 wks in responders was not estimable in pts < 65 yrs or ≥ 65 yrs (log-rank p =.879). None of the potential risk factors assessed was a significant predictor of RBC-TI ≥ 26 wks in pts < 65 yrs, possibly due to small pt number. In pts < 65 yrs with available follow-up cytogenetics (n = 71), CyR was achieved by 32 (45.1%) pts (vs 64.5% pts ≥ 65 yrs; p =.014). At time of data cutoff, 51 (52.6%) pts < 65 yrs were alive (vs 36.0% pts ≥ 65 yrs; p =.008); 29 (29.9%) pts progressed to AML (vs 20.1% pts ≥ 65 yrs; p =.077). The 1-, 2-, and 3-yr AML-progression rates were 9.7%, 15.4%, and 24.0% in pts < 65 yrs; and 6.0%, 17.9%, and 22.3% in pts ≥ 65 yrs (log-rank p =.308). The 1-, 2-, and 3-yr OS rates were 91.7%, 78.1%, and 66.4% in pts < 65 yrs; and 83.1%, 65.2%, and 49.9% in pts ≥ 65 yrs (log-rank p Disclosures: Fenaux: Celgene Corporation: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Johnson & Johnson: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene Corporation: Employment. Shammo:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. del Cañizo:Celgene Corporation: Spanish advisory committee.

Abstract 603 Parenteral azacitidine (AZA) is approved for administration on days 1–7 of a 28-day treatment schedule. Based on the short plasma half-life of AZA, S-phase restricted incorporation into DNA, and rapid re-methylation of DNA, it is possible that chronic daily exposure could enhanced its clinical activity. An oral formulation would be convenient and allow evaluation of lower doses administered on extended schedules. The initial phase I study of oral AZA, administered daily on a 7-day schedule demonstrated that it was bioavailable, safe, and clinically active in patients with MDS and AML (Garcia-Manero G, et al. Blood 2009;114:A117). Here, we report the results of a multicenter phase I exploration of extended oral AZA schedules, including dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary response data. Patients aged ≥ 18 years with MDS, CMML or AML (not candidates for other therapies) were enrolled in the study. Inclusion criteria were a hemoglobin level of ≤ 9.0 g/dL, and/or platelet count of ≤ 50 × 109/L, and/or be RBC transfusion-dependent; prior azanucleoside therapy was not permitted. Patients received oral AZA daily (QD) or twice daily (BID) on 14- or 21-days schedules, with starting at a dose of 300 mg for QD dosing and 200 mg for BID dosing. Patients were enrolled into cohorts of 6 and evaluated for DLTs at the end of Cycle 1. Patients were monitored continuously for adverse events (AEs) and assessed for disease response at the end of every second cycle. During Cycle 1, on the first and last day of treatment, PK parameters were derived from AZA concentrations in the plasma after the first dose of the day. PD samples were collected during the first 2 cycles and DNA methylation changes were evaluated using a LINE-1 assay. To date, 25 patients (median age 68 years [range 44–87]; 14 male and 11 female) with MDS (n = 13), AML (n = 7 de novo and n = 3 transformed), and CMML (n = 2) have received oral AZA on extended treatment schedules. Two DLTs, grade 3 nausea and grade 3 vomiting, occurred in 1 of 6 DLT-evaluable patients treated at 14-days QD (n = 7). No DLTs were observed on the 21-day QD (n = 6) or 14-day BID (n = 6) schedules; safety evaluation for the 21-day BID schedule is ongoing (n = 6). The maximum tolerated dose has not been reached on these schedules; no patient has received > 300 mg per dose. Overall rates of all grades nausea, vomiting, diarrhea, constipation, and abdominal pain with the extended schedules were similar to those observed with the oral 7-day schedule. The rate of febrile neutropenia (all grades) was higher in the 21-day QD cohort. This was observed in 4 patients with baseline ANC < 500 and/or AML diagnosis. Most common grade 3/4 AEs in the QD schedules were febrile neutropenia (14-day, 1/7; 21-day, 4/6), anemia (14-day, 1/7; 21-day, 0/6), thrombocytopenia (14-day, 1/7; 21-day, 1/6), diarrhea (14-day, 0/7; 21-day, 1/6), nausea (14-day, 1/7; 21-day, 0/6), and vomiting (14-day, 1/7; 21-day, 0/6). Extended BID schedules are under evaluation. PK data have been generated for 19 of 25 patients. For the 300 mg 14-day QD, 300 mg 21-day QD, and 200 mg 14-day BID schedules, using mean AUC (first and last day) results, extrapolated cumulative exposures per cycle were ~28%, 42% and 26%, respectively, compared with historical exposure observed following subcutaneous administration. AZA exposure increased with increasing dose, but was not dose-proportional. Clinical responses were observed for MDS/CMML patients on both extended QD schedules, with assessment ongoing for BID schedules (Table). In summary, extended (14- and 21-day) dosing of oral AZA is generally well tolerated, with no AZA accumulation, and promising clinical responses were observed, including complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Table. Parameter, n (%) Oral AZA Treatment Schedule MDS/CMML Responders/Evaluable patients, (%) 14-day QD 21-day QD Overall response* (CR, mCR, any HI) 5/6 (83) 3/3 (100) CR 0/6 2/3 (67) mCR 0/6 3/3 (100) HI 5/6 (83) 3/3 (100) HI-erythroid 3/5 (60) 1/1 (100) HI-platelet† 2/5 (40) 3/3 (100) HI-neutrophil 0/1 0/1 Transfusion independence 3/4 (75) 1/2 (50) RBC 1/2 (50) 1/1 (100) Platelet 2/2 (100) 0/1 * International Working Group 2006 criteria, patients only counted once for overall response, but may be counted more than once in individual response categories. † Includes patients achieving partial (≥ 50%) or complete platelet transfusion independence. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Cogle:Celgene: Research Funding, Speakers Bureau. Ward:Celgene: Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment. Giordano:Celgene: Employment, Equity Ownership. Kantarjian:Celgene: Research Funding. Skikne:Celgene: Employment.

Abstract 1755 Poster Board I-781 Background Karyotypic abnormalities are common in myelodysplastic syndromes (MDS), and specific chromosomal abnormalities are associated with poor prognosis. The phase III AZA-001 study (Lancet Oncol, 2009) showed azacitidine (AZA) prolonged overall survival (OS) regardless of IPSS cytogenetic risk category. This analysis assessed the effects of specific cytogenetic abnormalities on OS in patient (pt) subgroups treated with AZA or a conventional care regimen (CCR). Methods Pts with higher-risk MDS (FAB RAEB, RAEB-t, or CMML and IPSS Int-2 or High) were enrolled and randomized to receive AZA or CCR. CCR comprised 3 treatments: best supportive care only, low-dose ara-C, or induction chemotherapy. Erythropoietins were prohibited. OS was determined in subgroups of pts with del 5/5q-, del 7/7q-, or trisomy 8, each as part of a non-complex karyotype ( Results A total of 358 pts were enrolled (AZA 179, CCR 179). Of them, 153 had normal karyotypes (AZA 77, CCR 76). Median OS in pts with normal karyotypes was not reached at 21.1 months with AZA vs 17.2 months (95%CI: 15.2 – 24.1 months) with CCR; HR = 0.63 (95%CI: 0.39 – 1.03). Of remaining pts, 136 had del 5/5q-, del 7/7q-, and/or trisomy 8 as part of a non-complex or complex karyotype. AZA was associated with longer OS vs CCR in all subgroups of pts with non-complex cytogenetics, with HRs ranging from 0.20 (95%CI: 0.06 – 0.65) to 0.51 (95%CI: 0.05 – 4.74) (Table). In both the AZA and CCR treatment groups, pts in all subgroups with non-complex karyotypes had substantially longer OS than pts with complex karyotypes. Pts with complex karyotypes in some subgroups had longer OS with AZA vs CCR: median OS in pts with del 5/5q-, del 5/5q- WITHOUT del 7/7q-, or trisomy 8 as part of a complex karyotype treated with AZA survived 5.1, 8.0, and 12.4 months longer, respectively, than their counterparts who received CCR. HRs with AZA vs CCR in pts with complex cytogenetics ranged from 0.42 (95%CI: 0.10 – 1.69) to 0.55 (95%CI: 0.29 – 1.05). Conclusions These findings support earlier data showing effectiveness of AZA in higher-risk MDS pts with complex or non-complex karyotypes. Major gains in OS were obtained with AZA vs CCR (12-18 months longer OS with AZA) for the following categories: del 7/7q- (non-complex), del 7/7q- WITHOUT del 5/5q- (non-complex), and trisomy 8 (non-complex and complex). Pts with trisomy 8 treated with AZA experienced a 3-fold increase in median OS compared with similar pts who received CCR. Longer OS (AZA 15.3 vs CCR 7.3 months) was also obtained for pts with del5/5q- WITHOUT del7/7q- as part of a complex karyotype. The worse cytogenetic categories, del 7/7q- and del 5/5q- AND del 7/7q-, both with complex karyotype, were associated with the poorest OS regardless of treatment. Pt subgroups in this post hoc analysis were small and heterogeneous; confirmation of these findings in larger pt samples is warranted. Disclosures Mufti: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Santini:Celgene: Honoraria. Fenaux:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Epicept: Honoraria, Research Funding. Skikne:Celgene: Employment, Equity Ownership. Hellstrom-Lindberg:Celgene: Research Funding. Seymour:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Beach:Celgene: Employment, Equity Ownership. Backstrom:Celgene: Employment, Equity Ownership. Fernando:Celgene: Employment, Equity Ownership.

Abstract 117 Background: Parenteral azacitidine significantly improves overall survival of subjects with higher-risk MDS and WHO AML (20–30% blasts) compared to conventional care (Fenaux, Lancet Oncol 2009; 10:223). An oral formulation would be a more convenient administration route for patients and allow the evaluation of extended low-dose regimens, which could in turn lead to better treatment efficacy and lower toxicity profiles. The aim of this phase 1 study is to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of increasing doses of orally-administered azacitidine in subjects with MDS or AML. Methods: Subjects aged ≥ 18 years with a diagnosis of MDS or AML (not candidates for other therapies) by WHO criteria were enrolled into this multicenter, Phase 1, dose escalation study. Prior treatment with azacitidine or other demethylating agent was permitted. To allow PD/PK analyses of oral vs. subcutaneous (SC) administration, azacitidine was administered SC (75 mg/m2/day x 7 days) in Cycle 1, then orally in Cycle 2 starting at a dose of 120 mg/day x 7 days of every 28-day cycle. A standard “3+3” dose escalation design was used and an expansion cohort at the MTD was planned. Subjects were evaluated for DLT during the first cycle of oral azacitidine therapy. Azacitidine levels in plasma and urine were measured. DNA methylation was assayed using Illumina's Infinium Human Methylation27 BeadArrays. Response was assessed according to International Working Group (IWG) criteria for MDS (2006) and AML (2003). Results: To date, 45 subjects have enrolled into the study. Forty subjects received both SC and oral azacitidine; 5 subjects received SC azacitidine only. Median age is 70 years (range 31–91). Thirty-four subjects had MDS, 9 AML, and 2 CMML. Median pretreatment WBC and platelet counts of MDS subjects were 2.5 × 109/L (range 0.8–39.4) and 55.0 × 109/L (range 4.0–234.0) respectively. For subjects with AML, the median pretreatment WBC and platelet counts were 1.8 × 109/L (range 0.5–3.4) and 42.8 × 109/L (range 10.0–82.0) respectively. Baseline cytogenetics for subjects with MDS were as follows: 12 complex karyotype; 10 diploid; 1 with −7; 1 with t(11q23) and 10 whose karyotype was unknown. Doses of oral azacitidine evaluated were 120, 180, 240, 300, 360, 480 and 600 mg. The MTD of oral azacitidine on a 7-day QD treatment schedule was 480 mg. The DLT was grade 3 or 4 diarrhea in 2 of 3 subjects enrolled in the 600 mg cohort. Other grade 3 or 4 AEs reported include febrile neutropenia (6 subjects), infection (6 subjects), nausea (2 subjects), vomiting (2 subjects), fatigue (2 subjects), and thrombocytopenia (2 subjects). The bioavailability of oral azacitidine ranged from 5% to 35%. The exposure (AUCinf) of oral azacitidine was highly variable compared to SC exposure, ranging from 15% to 74% (except for one subject whose PK exposure following oral therapy was 167% of his SC exposure). Median duration of oral azacitidine was 5+ cycles (range 1–19+) for subjects with MDS and 2.5+ cycles (range 1–6+) for subjects with AML. Responses were evaluated following 6 cycles of oral therapy. To date, 14 subjects have received ≥ 6 cycles of oral azacitidine: 4 (29%) had complete response (CR), 6 (43%) had stable disease (SD), 3 (21%) had disease progression, and 1 subject (7%) was not evaluated. Among subjects with CR or SD, hematologic improvement by disease-specific IWG criteria included erythroid response (n = 5), platelet response (n = 5) and neutrophil response (n = 3). Fourteen subjects are ongoing, but have not completed 6 cycles of oral therapy; 17 subjects discontinued prior to completing 6 cycles. Changes in DNA methylation were observed in the blood of MDS and AML subjects following SC and oral azacitidine treatment, and a set of CpG loci were identified for which these changes were associated with azacitidine AUCinf and/or Cmax.. In addition, approximately 260 hypomethylated loci were common to both SC and oral therapy. Conclusions: Results to date indicate that a 7-day dosing regimen of oral azacitidine is active and well tolerated, with a manageable side effect profile in subjects with MDS or AML. Oral azacitidine exposure was highly variable and lower than that of SC azacitidine. Changes in DNA methylation were observed in the blood of MDS and AML subjects following SC and oral therapy. Evaluation of prolonged and BID treatment schedules is planned. Disclosures: Garcia-Manero: Celgene: Research Funding. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Skikne:Celgene: Employment. Cogle:Celgene: Research Funding, Speakers Bureau; Eisai: Speakers Bureau. Ning:Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Ward:Celgene: Employment, Equity Ownership.

The mechanisms of HSCM are not completely understood and involve the action of multiple cytokines and adhesion molecules. Historically, HSCM for AHSCT has been done using high dose chemotherapy, usually C, with growth factor (G-CSF or GM-CSF). However, the need for the chemotherapy in this instance has not been defined. We, retrospectively compared three HSCM approaches; C and GSCF, G-CSF and GM-CSF, and G-CSF alone in our institution from 2005–2007. Results: C (2.5gm/m2) with G-CSF (10mcg/kg) was used in 25 patients (pts) (n=18 multiple myeloma [MM], n=5 non-Hodgkin’s lymphoma [NHL], n=1 Hodgkin’s disease [HD] and n=1 systemic sclerosis). G-CSF 5mcg/kg with GM-CSF 5mcg/kg was used for HSCM in 10 pts (n=8 NHL and n=2 MM). G-CSF alone (10mcg/kg for at least 4 days) was used in 49 pts (n=28 MM, n=13 NHL, n=2 HD and n=6 other diagnosis). The age range was 35–72 in the C and G-CSF group, 30–69 in the G-CSF and GM-CSF, and 25–72 in the GCSF alone group. The median CD34+cells/kg collected was 6.4×106 (range 0.97–131), 12×106 (range 0.23–6.7), and 4.59×106 (range 0.66–7.38) in the C and GCSF, G-CSF and GM-CSF, and the G-CSF groups respectively. The collection sessions ranged from a median of 2.0 days (1 day in 44% pts, 2 days in 28%, 3 days in 16% and 4 days in 12% of pts) in the C and G-CSF group; to 2.5 days (1 day in 20% of pts, 2 days in 30%, 3 days in 30% and 4 days in 20% of pts) in the G-CSF and GM-CSF group; and 2 days (1 day in 22% of pts, 2 days in 37%, 3 days in 30% and 4 days in 10% of pts) in the G-CSF alone group. 3 pts (12%) failed HSCM with C plus GCSF, 1 subsequently collected with G-CSF alone. 5 pts (50%) failed HSCM with G-CSF +GMCSF, 2 of these had previously failed G-CSF alone, and 2 were re-mobilized with AMD 3100 protocol and 1 with C and GCSF. 6 pts (12%) failed HSCM with G-CSF alone, 3 subsequently underwent HSCM with higher dose of G-CSF and 2 were enrolled on AMD-3100 study. 2 pts (8%) with C and G-CSF HSCM developed neutropenic fever and needed hospitalization. All pts who had adequate HSCM (at least 2×10e6/kg) and subsequently underwent AHPCT had white blood and platelet engraftment. There was no difference in the day to engraftment based on the HSCM strategy. These data show that HSCM with G-CSF alone results in similar stem cell yield and stem cell collection sessions to C and G-CSF. Although the latter strategy achieved a higher median number of HSC (4.9 vs. 6.4 xe6/kg), this was not statistically significant (p= 0.08) in this group of pts. A higher percentage of pts achieved target stem cell collection in one day with C plus G-CSF (44%), than G-CSF alone (22%). On the other hand, the combination of C plus G-CSF carries risks related to high dose chemotherapy and necessitates hospitalization for its administration and management of neutropenic fever. The G-CSF+GM-CSF combination was the least effective in adequate HSCM. Analysis of DFS in the three mobilization strategies is pending.

Objectives and Methods: Thalidomide/dexamethasone is considered one of the current standard induction therapies for MM. We evaluated efficacy and toxicity of adding PLD to dexamethasone and low dose thalidomide. Stem cell harvest yield and QOL using FACT-G/Fact-Leu Tools were also assessed. Patients were treated with PLD (Doxil®) 40mg/m2 IV d1, thalidomide 100 mg PO Q HS, and dexamethasone 40 mg PO d1–4 and 15–18 Q 28 days for up to 4 cycles. Eligible patients subsequently underwent autologous stem cell harvest and transplant. Patients received prophylactic antimicrobials, erythropoietin injections and biphosphonate therapy. Results: Between 8/03 and 3/07, 25 patients were enrolled; 1 excluded for incorrect diagnosis. Median age 61 (49–79yrs); 17 males. Subclasses included IgGλ-9, IgGκ-7, non-secretory-3, IgAκ-2, IgAl-2 and κ light chain-1. At presentation, the patients had Drurie Salmon Stage IA-2, IB-1, IIA-5, IIIA-11, IIIB-5 (ISS stage 1–10, 2–8 and 3–6). Median B2M 3.5 (range: 1.1–41 mg/L). Eleven patients completed 4 cycles; one withdrew after cycle 1; 10 were taken off study (8 due to grade 3–4 toxicity: 5-infection, 1 acute renal failure, 1 dehydration and 1 arrhythmia; and 2 due to treatment delays more than 2 weeks secondary to infection). Median cycles received prior to being taken off study were 2. Two patients developed venous thrombotic events (VTE): one after cycle 1 while on low dose coumadin; another died of pulmonary embolism after cycle 1, while on aspirin, requiring amendment of protocol to therapeutic doses of coumadin. No further VTE were observed. There was another death due to pneumonia after cycle 2. Thirteen patients underwent stem cell harvest with cyclophosphamide and growth factor mobilization. The median harvest yield was 5.76 x106 CD34/kg (range: 3.87 – 31.94); median harvest days-3 (range: 1–7). Of the 20 patients who received at least one cycle and assessable for response, the ORR was 95% using SWOG/IBMTR criteria: PR-35%/75%; VGPR–40%/nCR-5%; CR-20%/15%; 1 had PD. The median serum M-protein response after cycle 1 (n=19): −53% (+17 to−86%), cycle 2 (n=18): −80.5% (−38% to −100%). One patient achieved CR after 2 cycles. Further responses after the 3rd and 4th cycles were minimal. The scores in most of the Fact-G/Fact-Leu subscales showed increasing trend corresponding to overall improvement in the patient’s QOL throughout the course of therapy as compared to baseline. The improvement was most noted in the emotional well-being subscale. Conclusions: DDt represents an active induction therapy for patients with MM. Major responses and treatment-related toxicity occur early in the course of therapy, arguing for early stem cell harvest and autologous transplant after two cycles of treatment. No adverse impact on stem cell harvest is associated with this therapy. Full dose anticoagulation to prevent VTE is essential when using this combination regimen. The overall QOL of patients improved while on treatment as compared to baseline.

Thrombocytopenia is a frequent complication in patients with hepatitis C. Possible mechanisms include hypersplenism, immune-mediated platelet destruction, and drug-induced impairment of platelet production. The immature platelet fraction (IPF), determined on an automated blood cell analyzer (Sysmex XE-2100), has been shown to be useful in differentiating consumptive and aplastic causes of thrombocytopenia. We studied 31 patients known to have hepatitis C, 21 with thrombocytopenia (platelet count 140,000/uL). None of the patients was taking interferon. Blood samples were drawn for CBC with platelet count, IPF (%), and thrombopoietin (TPO) assay (Quantikine TPO ELISA). The presence or absence of splenomegaly and liver function test results were noted. In the thrombocytopenic group IPF was elevated above the upper limit of the reference range (>7.1%) in 12/21 (57%) patients, suggestive of peripheral platelet consumption. TPO levels (known to correlate inversely with platelet/megakaryocyte mass) were within the normal range (

Oral mucositis (OM) is a commonly occurring side effect in patients (pts) undergoing AHSCT. Velafermin, recombinant human fibroblast growth factor-20, is under investigation for the prevention of severe OM. Previous studies demonstrated that velafermin at 30 mcg/kg was well tolerated and was effective in reducing the incidence of severe mucositis. The primary objective of this multicenter, randomized, double-blind, placebo controlled study was to confirm safety and efficacy of 30 mcg/kg velafermin for prevention of severe OM incidence (grade 3/4 OM based on the WHO grading system). The secondary objective was to evaluate safety and efficacy of 10 and 60 mcg/kg doses to better define the therapeutic range. Pts were randomized to receive placebo or velafermin at 30, 10 or 60 mcg/kg in a 3:3:1:1 ratio 24–36 hrs after stem cell infusion. Randomization was stratified by study center and OM risk factors identified from the previous placebo controlled study in a similar population including conditioning regimen and body mass index (BMI ≥30). Pts with multiple myeloma or lymphoma (≥18 y.o.) receiving ≥2X106 /kg CD34+ cells following chemotherapy with or without Total Body Irradiation (TBI) were eligible. OM status and safety data were collected for 30 days post treatment while mortality and disease progression were followed for 1 yr. An interim analysis by a data monitoring committee (DMC) was planned to assess safety and efficacy after 50% of pts completed the 30 day treatment period. A total of 390 pts who received melphalan (200 mg/m2) (n=239), BEAM (n=129), TBI (n=15), or other (n=7) were randomized and 384 pts were treated. The study drug was well tolerated in general and no pts discontinued study due to drug-related adverse events. There were 93 serious adverse events (SAEs) in 78 (20%) pts and no drug-related death was reported. Five infusion-related SAEs were reported including vasovagal episode (2), syncope (2), and anaphylactoid reaction (1). All 5 episodes occurred on the day of study drug infusion and resolved on the same day with no sequelae. Based on review of the results from the interim analysis, which included safety and efficacy data from 200 pts, the DMC recommended that the study continue to completion as planned. The last pt has completed the 30 day study period. The un-blinded results of the OM efficacy endpoints from velafermin treated groups or placebo as well as 30-day safety information from all pts will be reported.

Background:Occurrence of second hematological malignancies in patients with chronic lymphocytic leukemia (CLL) is well known but development of secondary solid tumors has not been well documented. Isolated case reports indicate, CLL patients may have a predisposition to develop solid tumors. There is not enough literature available to support this hypothesis. We here intend to study the incidence of secondary solid tumors in CLL patients with regard to their treatment and immunoglobulin levels. Methods: We reviewed the medical records of 323 CLL patients over the last 20 years at Veteran Affairs Medical Center, Kansas City. Broadly the patients were divided into two groups; the group who received chemotherapy for CLL(74/323) versus the group who did not receive treatment (249/323) and their median immunoglobulin levels were also documented. Patients who developed secondary hematological malignancies were excluded from this study. Results: The overall incidence of solid tumors was found to be 14.8% (48/323). In the chemotherapy treated CLL, the incidence of solid tumors was 18%(14/74) as compared to 13.6% (34/249) in the non-therapeutic group(P value 0.12). The most common malignancies noted were gastro-intestinal malignancies, genitor-urinary tumors and skin cancers including melanomas. Interestingly CLL patients who developed secondary solid tumors had a higher median IgG levels (1010 g/L) when compared to those who did not develop secondary tumors (738 g/L, P value Conclusion: Our study shows that there is a higher overall incidence of secondary solid tumors in patients with CLL when compared with incidence in the general population. There is no significant increase in the incidence of therapy related solid tumors in CLL patients. Upward drift in immunoglobulin levels should raise a suspicion for diagnosis of secondary solid tumors in patients with CLL. More studies are warranted to confirm this finding.

The discovery that acquired TTP results from autoantibodies to ADAMTS-13, a von Willebrand factor-cleavage protein (vWF-CP), provided rationale for rituximab immunosuppression as an adjunct treatment. We previously reported our experience with 5 refractory TTP patients treated with rituximab (Ann Hematology 2005, 84:232). Rituximab was administered at 375 mg/m2 IV weekly for 4 weeks. Therapeutic plasma exchanges (TPE) were held at least 24 hours post rituximab. All patients attained durable remissions with a median response of 15 months (range: 10–21). Literature review revealed 11 other studies reporting longest response duration of 23 months. Since our initial report, we treated 5 additional patients with TTP: 1 refractory and 4 newly diagnosed. Of the previously reported 5 patients with refractory TTP, 3 were female and 2 were male patients with a median age of 37 years (27–70). All patients achieved complete responses (CR). The median duration of response has increased to 32 months with a follow up period of 25 to 51 months. The longest response has been sustained 44 months after the first dose of rituximab. One patient developed clinical relapse after 26 disease-free months. She achieved CR2 after another 4 doses of rituximab with continued response 12 months after re-treatment. Time to response was shorter with re-treatment, 4 weeks vs. 5 weeks at initial therapy. Our first male patient with refractory TTP who was treated in 4/02 remained in remission for 25 months until his death from unrelated causes. One additional male patient with refractory TTP was treated preemptively due to recurrent loss of vWF-CP activity after achieving initial response with TPE and steroids. Treatment resulted in reappearance of vWF-CP activity, with continued response 30 months from first dose of rituximab. Four newly diagnosed female patients were treated: 3 had idiopathic TTP, and 1 had associated SLE. Median age was 20 years (range: 16–30). The cohort had a median platelet count of 28×109/L (range: 11–56), median hemoglobin of 10g/dL (range: 6–12) and a median lactate dehydrogenase of 868 IU/L (range: 618–1737). The median TPE’s received prior to rituximab therapy was 6 (range: 4–9) and after initiation of rituximab was 17 (range: 12–19). All patients achieved CR with median time to response of 4.5 weeks (range: 3–8). Responses are maintained 13 to 27 months after initial rituximab dose. The patient with SLE attained a complete clinical response but developed persistently low platelets unrelated to her TTP. Among the 10 patients treated, decreased or absent vWF-CP activity with presence of inhibitor were noted in 6 patients, 3 had normal levels and 1 was not tested. Our experience suggests that rituximab is safe and effective in TTP patients with refractory and newly diagnosed disease. Time to response was similar among refractory and newly diagnosed patients. To our knowledge, 44 months is the longest remission duration reported in the literature among refractory TTP patients treated with rituximab. Extended follow up is necessary to determine durable remissions among patients with newly diagnosed disease.

Background: Thalidomide with dexamethasone is considered the current standard induction therapy for multiple myeloma. Previously, treatment consisted mainly of infusional vincristine, adrimaycin and dexamethasone (VAD). High dose thalidomide is associated with significant toxicity. We conducted a study to evaluate efficacy and toxicity of adding liposomal adriamycin (Doxil®) to dexamethasone and low dose thalidomide. Stem cell harvest yield was also assessed. Methods: Patients were treated with Doxil® 40mg/m2 IV d1, thalidomide 100 mg PO Q HS, and dexamethasone 40 mg PO d1–4 and 15–18 Q 28 days for 4 cycles. After 4 cycles, eligible patients underwent autologous stem cell transplant. Patients received prophylactic Amoxicillin 250 mg PO Q day and Acyclovir 200 mg PO BID. Erythropoietin and biphosphonates were administered. Aspirin was changed to full dose coumadin anticoagulation after one death from pulmonary embolism. Results: Between 3/03 and 5/05, 11 out of planned 25 patients were enrolled on the study; 1 patient excluded for wrong diagnosis. Median age 61.5 (51–81yrs); 7 males; 7 IgG, 2 IgA and 1λ-light chain subtypes; Stage IB-1, Stage IIA-4, Stage IIIA-5; median albumin 3.75 (range:1.6–5.1 g/dL), creatinine 0.95 (range: 0.7 – 2.7 mg/dL) and B2M 1.95 (range: 1.1–10.1 mg/L). Four patients completed 4 cycles; one is undergoing treatment; three patients taken off study-one after 2 cycles per patient’s request, one secondary to grade 4 toxicity after cycle 1, and another after greater than 3 weeks treatment delay after cycle 3 secondary to pneumonia. Three patients (30%) developed grade 3–4 toxicities- two due to pneumonia (after cycles 2 and 3, respectively); and one with dehydration and renal failure after cycle 1. There were 2 deaths-one secondary to pulmonary embolism after cycle 1; another due to myocardial infarction after cycle 2. Two patients developed VTE- one after cycle 1 while on low dose coumadin; another died of pulmonary embolism after cycle 1, while on aspirin, requiring amendment to full dose coumadin anticoagulation. No further thrombotic episodes were encountered. Five patients underwent stem cell harvest with cyclophosphamide mobilization. The median harvest yield was 9.76 x106 CD34/kg (range: 5.27 – 31.94) with a median of 1 day (range: 1–7) to achieve at least 5 x 106 CD34/kg. Of the ten patients who received at least one cycle and assessable for response, the ORR was 80% (near complete remission(nCR)-10%; PR-70%), 1 MR, 1 SD. The M-spike response after first cycle of therapy ranged from 8% to 71%, with six patients (60%) having greater than 50% reduction in M-protein level. One patient achieved nCR after 2 cycles. Responses after the 3rd and 4th cycles were minimal. Conclusions: Doxil®, dexamethasone and low dose thalidomide represents an active induction therapy for patients with untreated multiple myeloma. Major responses were achieved rapidly, arguing for early stem cell harvest and autologous transplant after two cycles of therapy. Treatment related complications occurred early in the course of treatment. Full dose anticoagulation to prevent deep venous thromboembolism is essential when using this combination regimen. No adverse impact on stem cell harvest is associated with this therapy.

Traditionally the iron status of a population is assessed by estimating the prevalence of iron deficiency anemia. This approach is inadequate in countries where the diet is heavily fortified with iron because it conveys no information about the iron-replete segment of the population. In the present study iron status of a US adult population was evaluated using data collected in the second National Health and Nutrition Examination Survey (NHANES II). Body iron was estimated in each of 2,829 individuals from measurements of hemoglobin concentration, serum ferritin, transferrin saturation, and erythrocyte protoporphyrin. When individuals between 18 and 64 years of age were divided on the basis of sex and menstrual status, body iron reserves were normally distributed and averaged 309 mg in women 18 to 44 years, 608 mg in women 45 to 64 years, and 776 mg in men 18 to 64 years. The dispersion of storage iron in these groups was similar, with standard deviations of 346, 372, and 313 mg, respectively. The prevalence of iron deficiency anemia was surprisingly low, ranging from only 0.2% in adult men to 2.6% and 1.9% in pre- and postmenopausal women, respectively. Epidemiologic methods that examine iron status in the entire population assume importance in light of evidence that in certain segments of the US population, iron deficiency anemia is now less common than the homozygous state for hereditary hemochromatosis.

Intervention strategies to combat iron deficiency anemia in developing countries may hasten the development of iron overload in patients with an inherited defect in hemoglobin synthesis. This risk could be diminished if there was a rapid and simple method available for detecting iron overload in population screening programs. We have developed such a method, which is in effect a semiquantitative ferritin measurement based on a modification of a two-site enzyme-linked immunoassay. The assay requires only 2 drops of whole blood and a total incubation time of 90 min. The procedure, which can readily distinguish iron deficiency from even a modest increase in storage iron, has a potentially wide application in settings where a prompt assessment of iron status is required.

The relationship between iron status and food iron absorption was evaluated in 75 normal volunteers, 15 patients with idiopathic hemochromatosis, and 22 heterozygotes by using double extrinsic radioiron tags to label independently the nonheme and heme iron components of a hamburger meal. In normal subjects, absorption from each of these pools was inversely correlated with storage iron, as measured by the serum ferritin concentration. In patients with hemochromatosis, absorption of both forms of iron was far greater than would be predicted from the relationship between absorption and serum ferritin observed in normal volunteers. Nevertheless, there was still a modest but statistically significant reduction in absorption of nonheme iron with increasing serum ferritin. This relationship could not be demonstrated in the case of heme iron absorption. In heterozygotes, nonheme iron absorption from a hamburger meal containing no supplementary iron did not differ significantly from that observed in normal volunteers. However, when this meal was both modified to promote bioavailability and supplemented with iron, absorption of nonheme iron was significantly elevated. These studies confirm the presence of excessive nonheme iron absorption even from unfortified meals in patients with idiopathic hemochromatosis and suggest in addition that they are particularly susceptible to iron loading from diets containing a high proportion of heme iron. Impaired regulation of nonheme iron absorption was also observed in heterozygous individuals, but a statistically significant abnormality was demonstrable only when the test meal contained a large highly bioavailable iron supplement.

The level of assimilation of dietary iron is believed to have an important influence on iron status. To examine the effect of enhancing the availability of dietary iron on iron balance, 17 adult volunteer subjects were given 2 g of ascorbic acid daily with meals for 16 weeks. Serum ferritin levels before and after the study averaged 46 and 43 micrograms/L, respectively, indicating a negligible effect on iron stores. When vitamin C supplementation was continued for an additional 20 months in five iron-replete and four iron-deficient subjects, serum ferritin determinations again failed to indicate any significant effect of the vitamin C on iron reserves. These findings were not explained by intestinal adaptation to the enhancing effect of the vitamin, because radioisotopic measurements of nonheme iron absorption showed no reduction in the enhancing effect of 1 g of ascorbic acid after four months of megadoses of vitamin C. It is concluded that altering the availability of nonheme dietary iron has little effect on iron status when the diet contains substantial amounts of meat.