A paradigm shift in the therapy of low blast count acute myeloid leukemia. Valeria Santini UF Ematologia, Università di Firenze
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1 A paradigm shift in the therapy of low blast count acute myeloid leukemia Valeria Santini UF Ematologia, Università di Firenze
2 Patients (%) AML is predominantly a disease of the elderly 40 69% of patients are 55 years old at diagnosis Median age at diagnosis = 66 years < Age at diagnosis (years) SEER Cancer Statistics, National Cancer Institute, USA Available at
3 5-year survival (%) AML in the elderly is associated with poor survival rates 5-year survival rates, % % 10 0 < Age at diagnosis (years) SEER Cancer Statistics, National Cancer Institute, USA Available at
4 Cumulative survival Intensive chemotherapy is associated with poor survival in patients with AML aged >60 years Patients with normal versus complex karyotype: CR: 70% vs 46% (p=0.02) Relapse after CR: 66% (OS 19mo) vs 92% (OS 11mo) OS: 18mo vs 4mo (p< ) Normal Abnormal non-complex Complex n=160 Median age 67 years Years Survival is particularly poor in patients with abnormal cytogenetic profiles Knipp S, et al. Cancer 2007;110:345 52
5 Factors that lead to poor survival in elderly patients with AML Comorbidities Different biological characteristics of the disease in the elderly associated myelodysplasia adverse cytogenetics expression of multidrug resistance phenotype Erba HP. Hematology Am Soc Hematol Educ Program 2007;420 8
6 Aberrant promoter methylation correlates with disease evolution (methylation array) 6 Jiang Y, et al. Blood 2009;113:
7 Multiple genes are hypermethylated in hematopoietic malignancies 7 (Claus, Lübbert, Oncogene 2003)
8 8 Blood 64: , 1984 No cytotoxicity differentiation
9 Hypomethylating Cytosine Analogues Cytosine 5-methylcytosine 5-azacytidine 5-aza-2 -deoxycytidine Azacitidine Decitabine Santini et al, Ann Int Med 2001
10 DNMT inhibitors induce DNA hypomethylation 10 A C G : : : T G C AZA D M T A z A C G : : : T G C DNMT mc : G DAC C : G G C DNMT : m G : C Azacitidine (AZA) is incorporated into RNA and then DNA Inactivates DNMT Leads to formation of newly synthesized DNA with unmethylated cytosine residues Results in hypomethylation and transcription of previously quiescent genes Silverman L. Oncologist 2001;6(S5):8 14 Permission from The Oncologist, AlphaMed Press
11 Hypomethylating agents are able to modify AML phenotype
12 MW(KDa) 120 AML proteome is modified by azacitidine treatment A125 A82 A69 A61 A83 A119 A184 A94 A123 A201 A184 A151 A191 A194 A204 A208 A306 A350 A406 A314 A299 A334 A362 A394 A274 A251 A330 A415 A355 A446 A AZA A541 A528 3 pi 11 Buchi et al, Leuk Res May;36(5):
13 UNKNOWN 31 ZNF268B gi Mass: Score: 42 Expect: 10 Queries matched: 17 0,4 HEAT SHOCK PROTEINS / CHAPERONS ID / Molecular Weight / MOWSE core/ Probability / Peptide Matching (numb.) CTRL/ AZA gi Mass: Score: 155 Expect: 4.7e-11 Queries 1 tumor rejection antigen (gp96) 1 matched: 36 1,16 Heat shock protein 90kDa alpha (cytosolic), class B 2 member 1 gi Mass: Score: 75 Expect: Queries matched: 16 0,91 gi Mass: Score: 186 Expect: 3.7e-14 Queries 3 Heat shock 70kDa protein 8 matched: 26 1,32 gi Mass: Score: 219 Expect: 1.9e-17 Queries 4 heat shock protein 60 [Homo sapiens matched: 30 1,00 gi Mass: Score: 153 Expect: 7.4e-11 Queries 5 Chaperonin containing TCP1, subunit 2 (beta) matched: 19 1,84 6 MTHSP75 gi Mass: Score: 117 Expect: 3e-07 Queries matched: 13 gi Mass: Score: 146 Expect: 3.7e-10 Queries 7 Chain F, Cypa Complexed With Hvgpia matched: 14 AZA 13 METABOLIC ENZYMES 8 enolase 1 variant gi Mass: Score: 61 Expect: 0.11 Queries matched: 21 1,31 9 prolyl 4-hydroxylase beta-subunit gi Mass: Score: 211 Expect: 1.2e-16 Queries matched: 31 1,38 gi Mass: Score: 86 Expect: Queries 10 glutathione S-transferase matched: 15 1,42 Procollagen-proline, 2-oxoglutarate 4-dioxygenase gi (proline 4-hydroxylase), beta polypeptide matched: 26 Mass: Score: 161 Expect: 1.2e-11 Queries CTRL gi Mass: Score: 115 Expect: 4.7e-07 Queries 12 inosine monophosphate dehydrogenase 2 matched: 23 1,52 gi Mass: Score: 91 Expect: Queries 13 Glyceraldehyde-3-phosphate dehydrogenase matched: 10 1,46 Chain D, Human B Lactate Dehydrogenase Complexed With Nad+ And 4- Hydroxy-1,2,5-Oxadiazole-3- Carboxylic Acid gi Mass: Score: 124 Expect: 5.9e-08 Queries matched: 15 0,04 14 Chain B, Triosephosphate Isomerase (Tim) (E.C ) 15 Complexed With 2-Phosphoglycolic Acid gi Mass: Score: 191 Expect: 1.2e-14 Queries matched: 17 1,15 16 proteasome (prosome, macropain) subunit, alpha type, 5 gi Mass: Score: 46 Expect: 3.5 Queries matched: 8 1,38 17 ER-60 protease CTRL gi Mass: Score: 83 Expect: Queries matched: 15 STRUCTURAL PROTEINS gi Mass: Score: 149 Expect: 1.9e-10 Queries 18 Alpha tubulin matched: 15 1,88 19 tubulin, beta polypeptide gi Mass: Score: 70 Expect: Queries matched: 19 1,64 gi Mass: Score: 142 Expect: 9.4e-10 Queries 20 ACTB protein matched: 17 0,76 21 VCP protein gi Mass: Score: 49 Expect: 2 Queries matched: 18 CTRL gi Mass: Score: 118 Expect: 2.4e-07 Queries 22 capping protein (actin filament) muscle Z-line, alpha 1 matched: 16 2,71 23 TPMsk3 gi Mass: Score: 74 Expect: Queries matched: 11 0,94 DNA BINDING /SIGNAL TRANSDUCTION 24 retinoblastoma binding protein 4 variant gi Mass: Score: 67 Expect: 0.03 Queries matched: 12 1,12 25 nucleophosmin gi Mass: Score: 76 Expect: Queries matched: 15 1,29 non-metastatic cells 1, protein (NM23A) expressed in 26 isoform a gi Mass: Score: 64 Expect: Queries matched: 14 2,75 27 Calreticulin gi Mass: Score: 46 Expect: 3.6 Queries matched: 8 0,65 gi Mass: Score: 154 Expect: 5.9e-11 Queries 28 Chain E, Human Pcna matched: 18 2,46 Chain B, Molecular Basis For The Recognition Of Phosphorylated And Phosphoacetylated Histone H3 By gi Mass: Score: 72 Expect: Queries matched: 8 1,56 30 calmodulin gi Mass: Score: 48 Expect: 2.4 Queries matched: 9 AZA
14 MW(KDa) Decitabine modifies proteome differently from azacitidine 120 DAC D155 D184 D137 D160 D320 D251 D307 D256 D283 D491 D347 D331 D345 D403 D402 D459 D424 D660 D363 D394 D388 D522 D531 D593 D565 D606 D D pi Buchi et al, Leuk Res May;36(5):
15 Hypomethylating agents are able to modify AML chromatin asset
16 Early (=day 5) in vivo DNA demethylation of multiple CpG islands in 8 AML patients following DAC treatment (unsorted peripheral blood blasts) 35 candidate genes 35 gene promoters 638 single CpGs Claus et al., Plass, Lübbert, Leuk. Res. 2013
17 Apoptotic cells (%) Viable cells (%) In vitro AZACITIDINE effect on AML cells AML1-ETO pos and neg ** ** ** ** Growth NT AZA 0.01μM AZA 0.1μM AZA 1μM AZA 10μM 0 AML1-ETO neg. AML1-ETO pos. ** =p<0.01 ** Enhanced sensitivity ** Apoptosis ** ** ** ** =p<0.01 Buchi et al, Epigenetics Dec 2;9(3).
18 Hypomethylating agents are able to modify AML histone code redistributing H3K27 3 Me and H4 acetylated
19 IL3 promoter AML1 TGTGGT (-192 bp) AML1 ETO TGTGGG (-105 bp) IL3 promoter start site of transcription U937 AML1/ETO negative U937 AML1/ETO positive μm ponasterone A 48 h IP-Ac H4 A B IP-H3K27me3 IP-H3K9me2 IP-H3K4me3 IP no Ab INPUT NT AZA 1 μm DAC NT AZA 0.1 μm 1 μm HL60 - AML1/ETO negative IP-Ac H4 DAC 0.1 μm C IP-H3K27me3 IP no Ab INPUT NT AZA DAC 1 μm 0.1 μm KASUMI - AML1/ETO positive IP-Ac H4 IP no Ab D INPUT NT AZA 1 μm DAC 0.1 μm Buchi et al, Epigenetics Dec 2;9(3).
20 THE CHALLENGE: In MDS: Beneficial effects of hypomethylating agents are noted generally after 2-4 cycles of therapy CR and PR are achieved in a non substantial number of cases Achievement of sole hematological improvement may assure prolonged survival References: JCO : 1987;Lancet Oncol :223; JCO :3842; Blood :52; Cancer :1794; JCO 2002; Cancer :3830; JCO :3322; Leukemia :1207)
21 THE DOGMA: In AML: EARLY MARROW RESPONSE IS ESSENTIAL FOR PROLONGED OS CR CORRELATES WITH OS
22 AZA in AML AML in the elderly carries a poor prognosis even when treated with intensive chemotherapy (IC) (median survival of 7 to12 months) and most elderly AML patients cannot receive IC due to their age and/or comorbidities 1/3 of pts in AZA-001 had WHO AML with 20-30% of marrow blasts
23 Preselection and Randomization 113 WHO/AML patients enrolled Investigator preselection 63 BSC 34 LDAC 16 IC Randomization 36 AZA 27 BSC 14 AZA 20 LDAC 5 AZA 11 IC
24 Overall Survival in AML /RAEB-T: AZA vs CCR Fenaux et al. JCO, 2010
25 OS in Patients AML/RAEB-T Unfit for IC Fenaux et al. JCO, 2010
26 OS According to Investigator Preselection AZA (n=36) BSC Only (n=27) Median OS (months) HR (95% CI) 0.48 ( ) P year OS rate (%) < Fenaux et al. JCO 2010
27 OS According to Investigator Preselection AZA (n=14) LDAC (n=20) Median OS (months) HR (95% CI) 0.37 ( ) P year OS rate (%) Fenaux et al. JCO, 2010
28 OS According to Investigator Preselection Median OS (months) AZA (n=5) Not yet reached IC* (n=11) 14.2 HR (95% CI) 0.97 ( ) P year OS rate (%) *IC = intensive chemotherapy Fenaux et al. JCO, 2010
29 % of pts with CR Marrow CR Rates in AML/RAEB-T pts p=0.80 (10/55) (9/58) (3/20) (6/11) (0/27) Fenaux et al. JCO, 2010 CCR Regimens
30 DAC vs treatment of choice (LD Ara-C, BSC) in AML pts > 65 yrs Kantarjian et al, J Clin Oncol 30: , 2012
31 DAC vs treatment of choice in elderly AML DAC CR rate 17.6% Kantarjian et al, J Clin Oncol 30: , 2012
32 Kantarjian et al, J Clin Oncol 30: , 2012
33 DAC in elderly AML pts with > 30% BM blasts 227 AML patients median age 72 yrs 40% with comorbidities 32% adverse cytogenetics DAC 135 mg/m2 total dose IV over 72 hours every 6 weeks CR + PR rate 26%, 95% CI (20%, 32%) OS median 5.5 mos; 28% at 1yr Lübbert et al, Haematologica 2012
34 Patients with multiple monosomies treated with DAC do not have worse outcome than those with single monosomy Lübbert et al, Haematologica 2012
35 AML patients with at least 3 onosomies treated with DAC have better outcome than those with 1 or 2 monosomies CR/PR rate (%) MK-1 25 MK-2 22 MK>3 63 Lübbert et al, Haematologica 2012
36 Austrian Azacitidine Registry: baseline characteristics of 155 WHO AML-patients Patient characteristics (n=155) Median age (range): 73 (33 91) WHO diagnosis t-aml: 10% BM blasts <30%: 37% 30%: 63% MRC cytogenetics good: 2% intermediate: 74% poor: 17% WBC count 10 x 10 9 /L: 79% >10 x 10 9 /L: 21% ECOG PS 0 1: 73% 2 4: 27% Comorbidities 0: 22% 1: 78% Prior Treatment none: 40% yes: 60% Azacitidine Primary Endpoints Response Secondary Safety Prognostic markers Regimen* Median dose Appl. route AZA d1 7: 57% (924mg) } AZA d5 2 2: 22% (900mg) s.c. 88% AZA d1 5: 16% (685mg) i.v. 9% AZA others: 5% (700mg) i.v. + s.c. 3% *16% of pt.s received AZA 100mg/d flat dosing in 1 st cycle 22% of all cycles were applied as AZA-flat dosage Concomitant trt.: ESA (3%), ICT (3%), G-CSF (21%) Pleyer L, et al. J Hematol Oncol 2013;6:32
37 Austrian Azacitidine Registry: Overall Survival and Response From initial diagnosis From AZA initiation Median OS (months) Response rates (% of pts) ORR (CR + mcr + PR + HI) ITT cohort N = 155 IWG-criteria (> 2 AZA cycles) N= CR mcr PR msd with HI HI only No response Patients received treatment until signs of overt disease progression Pleyer L, et al. J Hematol Oncol, 2013, 6:32
38 Patients (n) Cumulative patients (%) Austrian Azacitidine Registry: time to response Time to first response Time to best response % 23 77% % * Cycle % Cycle 5 The majority of AML patients responded during early cycles 1 st response was best response in 66% of pts Further deepening of response occurred in 34% of responders Median time form 1 st to best response: 3 months * Response assessed per IWG 2006 Criteria Patients received treatment until signs of overt disease progression Pleyer L, et al. J Hematol Oncol, 2013, 6:32
39 Austrian Azacitidine Registry: grade 3-4 AE NCI-Toxicity Criteria and CTCAE v.4 Grade 3-4 AE (n total events) N total events N pts., (%) Hematologic toxicity Thrombopenia Neutropenia Anemia (44.5) 38 (24.5) 49 (31.6) 33 (21.3) Infectious complications * (29.0) Febrile (18.1) neutropenia Non-hematologic toxicity Heart/blood pressure # (9.0) 1 1 (0.6) Thromboembolic 1 1 (0.6) Neurologic Fatigue limiting self care (10.3) Severe pain 3 3 (1.9) Novel solid tumor 3 3 (1.9) Emergency surgery 8 7 (4.5) Fall with fracture or hemorrhage (8.4) AZA was well tolerated in the majority of patients with AML * Dominated by pulmonary infections, sepsis and CMV-reactivations # Note: preexisting cardiac disease was documented in 77% of these pts. Pleyer L, et al. J Hematol Oncol 2013;6:32
40 Austrian Azacitidine Registry: safety NCI-Toxicity Criteria and CTCAEv.4 AE attributable to azacitidine (n=501) No Yes Unknown Grade 3 4 AEs (n=260) No Yes Unknown Consequence of AE (n=501) None Treatment Hospitalisation Life threatening/icu Death Consequence for azacitidine treatment (n=510)* None Dose reduction Treatment pause Termination of azacitidine treatment Prolongation of cycle >28 days Events, n total events (%) 317 (63.3) 158 (31.5) 26 (5.2) 183 (70.4) 51 (19.6) 26 (10.0) 176 (35.1) 177 (35.3) 112 (22.4) 6 (1.2) 30 (6.0) 353 (69.2) 30 (5.9) 72 (14.1) 48 (9.4) 7 (1.4) The number of AE declined continuously from 40% in cycle 1 to 20% as of cycle 10 * Amounts to >501 due to multiple choice nature of the answer Pleyer L, et al. J Hematol Oncol 2013;6:32
41 Austrian Azacitidine Registry: Baseline factors that did not affect survival in UVA Age Age WBC LDH <80 years 80 years <75 years 75 years 10 G/L >10 G/L 225 U/l >225U/l Patients, n Median OS, m P value Comorbidities <3 3 < HCT-CI Low risk Intermediate risk High risk MRC Good Intermediate Poor UVA: univariate analysis Pleyer L, et al. J Hematol Oncol 2013;6:32
42 Austrian Azacitidine Registry: Effect of age on OS Univariate analysis P = Age </>= 80 years did not significantly affect OS (P = 0.853) Pleyer L, et al. J Hematol Oncol, 2013, 6:32
43 Austrian Azacitidine Registry: Effect of BM-blast percentage on OS Univariate analysis P = BM-blast count did not significantly affect OS (P = 0.663) Some pts had < 20% BM blasts at the time of AZA initiation as they were refractory to prior conventional chemotherapy (n=50), or received AZA as maintenance after CTX (n=6) or as bridging to allo-sct (n=4) Pleyer L, et al. J Hematol Oncol, 2013, 6:32
44 Austrian Azacitidine Registry: Effect of adverse events on OS - UVA Infectious complications None Grade 1-4 Febrile neutropenia No Yes Non-hematologic toxicity None Grade 1-2 Grade 3-4 GIT-toxicity None Grade 1-2 Grade 3-4 Injection site reaction None Erythema/soreness Pain/inflammation Unspecified pain None/mild Moderate/severe Patients, n Median OS, months P value n.a The occurrence of AE did not negatively impact OS UVA: univariate analysis Pleyer L, et al. J Hematol Oncol 2013;6:32
45 Austrian Azacitidine Registry: Effect of febrile neutropenia on OS Univariate analysis P = The occurrence of febrile neutropenia did not adversely affect OS (P = 0.364) Pleyer L, et al. J Hematol Oncol, 2013, 6:32
46 Austrian Azacitidine Registry: Effect of non-hematologic toxicity on OS Univariate analysis P = The occurrence of non-hematologic toxicity did not adversely affect OS (P = 0.549) Pleyer L, et al. J Hematol Oncol, 2013, 6:32
47 Austrian Azacitidine Registry: Effect of adverse events on OS UVA/MVA Fatigue None Relieved by rest Not relieved by rest Limiting self care Hematologic toxicity Yes Thrombocytopenia G3-4 Neutropenia G3-4 Anemia G3-4 No Dose reduction due to AE Yes No Univariate analyses Multivariate analyses n OS, m P value HR 95% CI P value HR 95% CI < (did not meet 0.25 criterium for model entry) Fatigue limiting self care may be a novel prognostic factor. Aplasia induction may be necessary prior to response. Dose reduction due to AE seems feasible and without negative effect on OS.. UVA: univariate analysis. MVA: multivariate analysis Pleyer L, et al. J Hematol Oncol 2013;6:32
48 Austrian Azacitidine Registry: Effect of hematologic toxicity on OS Multivariate analysis P = Hematologic toxicity did not adversely affect OS. In fact, a certain amount of aplasia induction may be necessary prior to response (P = ). Pleyer L, et al. J Hematol Oncol, 2013, 6:32
49 Austrian Azacitidine Registry: Effect of AZA dose and regimen on OS - UVA Patients, n Median OS, months P value Target dose <FDA target dose FDA target dose Predominant schedule (all pts.) d1-5 d1-7 or d Predominant schedule (responders) d1-5 d1-7 d5-2-2 others Predominant dose/cycle (responders) <600mg mg >800mg AZA dose or schedule did not negatively impact OS UVA: univariate analysis. Pleyer L, et al. J Hematol Oncol 2013;6:32
50 Austrian Azacitidine Registry: OS according to haematological improvement Multivariate analysis A significant survival benefit was seen in patients who achieved any kind of haematological improvement Pleyer L, et al. J Hematol Oncol, 2013, 6:32
51 Austrian Azacitidine Registry: Effect of response improvement on OS Univariate analysis Median time to first response: 4 months Median time from first response to best response: 2.8 months Improvement of response after initial response was associated with improved survival (24.7 vs 13.7 months) Pleyer L, et al. J Hematol Oncol, 2013, 6:32
52 Patients (%) French ATU programme: retrospective analysis of azacitidine as first-line therapy in AML Azacitidine demonstrates promising activity in patients with untreated AML Patient characteristics (n=137) Untreated patients with AML unsuitable for standard chemotherapy Age 65 years: 83% Cytogenetics adverse: 55% intermediate: 45% Type of AML post MDS: 36.5% therapy related: 27% de novo: 36.5% >30% blasts : 60% Azacitidine Dosing 75mg/m 2 /day x 7 days (64%) 75mg/m 2 /days x 5 days (17%) 100mg/day x 7days (17%) combined with valproic acid and/or ATRA: 31 patients (23%) Median cycles (range): 4 (1 24) Median follow-up: 5.6 months Survival Median OS: 9.4 months 1-year survival: 37% 23 CR/ CRi/ PR Response* OR = 43% HI SD without HI 20 PD Median duration response: 6.9 months Median cycles in responders: 9 (4 24) *Response evaluation by IWG criteria after 3 cycles Thépot S, et al. Oral presentation at ASH Abstract 843
53 Probability of survival French ATU programme: retrospective analysis of azacitidine as first-line therapy in AML In AML patients treated with azacitidine, Marrow Blasts BM blast count at baseline does not appear to impact survival % 30% <30% >=30% 0.4 p= p= Time (months) Thépot S, et al. Oral presentation at ASH Abstract 843
54 AZA in patients with newly diagnosed or relapsed/refractory AML with >30% blasts Characteristic All patients (n=40) Newly diagnosed (n=20) Relapsed or refractory (n=20) Median age, years Male, n (%) 19 (48) 11 (55) 8 (40) Median bone marrow blasts, % Median WBC count 10 9 /L Cytogenetics, * n (%) Intermediate risk 28 (70) 15 (75) 13 (65) High risk 12 (30) 5 (25) 7 (35) AZA 75 mg/m 2 /day subcutaneously for 5 days every 4 weeks Primary endpoint: safety Secondary endpoints: OS and response *High-risk defined as 5/5q, 7/7q, abn(11q23), or complex karyotype with 3 cytogenetic abnormalities. Normal and all other karyotypes were defined as intermediate-risk Al-Ali HK, et al. Leuk Lymph 2012;53:110 7
55 Patients (%) Patients (%) AZA in patients with newly diagnosed or relapsed/ refractory AML with >30% blasts safety and response Median cycles: 3 Median follow-up: 13 months (range 9 16) CR+PR+HI Grade 3/4 haematological AEs Total (n=40) Newly diagnosed (n=20) Relapsed or refractory (n=20) 0 Thrombocytopenia Neutropenia Al-Ali HK, et al. Leuk Lymph 2012;53:110 7
56 Patients surviving (%) Patients surviving (%) AZA in patients with newly diagnosed or relapsed/ refractory AML with >30% blasts survival OS in patients with newly diagnosed or relapsed/refractory AML OS according to haematological response Newly diagnosed (n=20) Relapsed or refractory (n=20) 7.7 months NE (n=11) CR, PR, or HI (n=12) PD or NR (n=2) SD (n=15) CR/PR/HI censored SD censored months months p= Duration (months) p=0.045* Duration (months) AZA improves survival in AML patients (>30% blasts) with HI or better; newly diagnosed patients have longer OS compared with relapsed/refractory patients *versus CR+PR+HI Al-Ali HK, et al. Leuk Lymph 2012;53:110 7
57 Real-World Outcomes among AML Patients Treated with DAC or AZA Patients 18 years of age or older initiating treatment with AZA or DEC during 1 January 2006 to 30 April 2012 (N=1922) Patients with enrollment (with medical and pharmacy Benefit) at least 6 months prior to initiating treatment (N=1409) Patients with AML (N=487) AZA (N=288) DEC (N=199) Smith et al, poster EHA 2013
58 Real-World Outcomes among AML Patients Treated with DAC or AZA 485 pts Median OS (AZA 10.1 vs. DAC 6.9 mos.; p=0.007) Smith et al, poster EHA 2013
59 Investigator Selection IC, LDAC, or BSC AZA-AML-001 Study Design Randomized, open-label, multi-center, controlled, Phase III study Newly Diagnosed AML* N = 480 R A Vidaza 75 mg/m 2 SC x 7 days, repeat q28 days N = 240 Investigator s selection IC (7 +3), LDAC, or BSC B N = 240 *Patients with newly diagnosed de novo AML or AML secondary to prior MDS
60 LESSON LEARNED FROM AZACITIDINE TREATMENT OF HIGH RISK MDS
61 Proportion Surviving Fenaux et al. Lancet Oncol, 2009 Overall Survival: Azacitidine vs CCR ITT Population months Log-Rank p= HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = % Time (months) from Randomization Difference: 9.4 months Median AZA cycles: 9 (1-39) 50.8% 24.4 months CCR AZA
62 Proportion Surviving AZA vs CCR: OS in Pts with Best Response of CR 21.9 months 78.4% 43.7% Log rank p = HR=0.39 [95% CI: ] Death: AZA = 7, CCR = 9 Difference: 4.4 months 26.3 months CCR-CR AZA-CR Time (months) from Randomization 24
63 Proportion Surviving AZA vs CCR: OS in Pts with Best Response of HI 16.6 months 71.7% Log rank p = < HR=0.23 [95% CI: ] Death: AZA = 8, CCR = 27 AZA - HI CCR - HI # at risk Time (months) from Randomization AZA CCR % Median not reached
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