Time from diagnosis to intensive chemotherapy initiation does not adversely impact the outcome of patients with acute myeloid leukemia by Sarah Bertoli, Emilie Bérard, Françoise Huguet, Anne Huynh, Suzanne Tavitian, François Vergez, Sophie Dobbelstein, Nicole Dastugue, Véronique Mansat-De Mas, Eric Delabesse, Eliane Duchayne, Cécile Demur, Audrey Sarry, Valérie Lauwers-Cances, Guy Laurent, Michel Attal, and Christian Récher Blood Volume 121(14):2618-2626 April 4, 2013 ©2013 by American Society of Hematology

Study profile. Study profile. Between 2000 and 2009, 599 patients with nonpromyelocytic AML were treated with intensive chemotherapy within a TDT inferior to 90 days. Modalities of consolidation treatment and response are detailed. AlloSCT, allogeneic stem cell transplantation; AutoSCT, autologous stem cell transplantation; HDAC, high-dose cytarabine. Sarah Bertoli et al. Blood 2013;121:2618-2626 ©2013 by American Society of Hematology

Estimated HR of death for each day delaying chemotherapy initiation. Estimated HR of death for each day delaying chemotherapy initiation. (A) RCS method shows the nonadjusted HR of death for each value of TDT compared with day 6. For example, the nonadjusted HR of death for a TDT of 1 day is equal to 1.38 (95% CI: 1.03-1.86) compared with day 6 according to the RCS method. The locations of the 4 knots used in the RCS method are 1, 5, 12, and 42 days (corresponding, respectively, to the 5th, 35th, 65th, and 95th percentile of the TDT).22 (B) RCS method shows the adjusted* estimated hazard ratio of death for each value of TDT compared with day 6. *Adjusted for age (HR = 1.36; 95% CI: 1.08-1.70; P = .008 for subjects >60 vs ≤60 years), ECOG performance status (HR = 1.46, 95% CI: 1.12-1.91, P = .006; HR = 1.76, 95% CI: 1.22-2.53, P = .002; and HR = 1.73, 95% CI: 0.97-3.07, P = .062, respectively, for ECOG 1, 2, and 3/4 vs 0), secondary AML (HR = 1.51; 95% CI: 1.18-1.93; P = .001 compared with de novo AML), WBC (HR = 1.59; 95% CI: 1.18-2.15; P = .002 for subjects >50 vs ≤50 G/L), ELN classification (HR = 2.29, 95% CI: 1.61-3.24, P < .001; HR = 2.79, 95% CI: 1.98-3.94, P < .001; and HR = 3.86, 95% CI: 2.69-5.55, P < .001, respectively, for intermediate I, intermediate II, and adverse vs favorable), and consolidation (HR = 0.47, 95% CI: 0.30-0.76, P = .002 and HR = 0.63, 95% CI: 0.45-0.88, P = .007, respectively, for autologous stem cell transplantation and allogeneic stem cell transplantation vs high-dose cytarabine only). Sarah Bertoli et al. Blood 2013;121:2618-2626 ©2013 by American Society of Hematology

Kaplan-Meier estimates of overall survival. Kaplan-Meier estimates of overall survival. Overall survival according to (A) time from diagnosis to treatment (with a cutoff of 5 days), (B) age, (C) ECOG performance status, (D) AML status (secondary vs de novo), (E) white blood cell count, and (F) ELN classification. Sarah Bertoli et al. Blood 2013;121:2618-2626 ©2013 by American Society of Hematology

Estimated probability of early death for each day delaying chemotherapy initiation. Estimated probability of early death for each day delaying chemotherapy initiation. The graph shows the estimated probability of early death for each value of TDT, adjusted* for the mean of all other variables of the model. The locations of the 3 knots used in the RCS method are 1, 8, and 32 days (corresponding, respectively, to the 10th, 50th, and 90th percentile of the TDT).22 *Adjusted for age (odds ratio [OR] = 2.41; 95% CI: 1.32-4.39; P = .004 for subjects >60 vs ≤60 years), ECOG performance status (OR = 1.87, 95% CI: 0.70-4.99, P = .213; OR = 3.23, 95% CI: 1.07-9.74, P = .037; and OR = 8.40, 95% CI: 2.20-32.0, P = .002, respectively, for ECOG 1, 2, and 3/4 vs 0), secondary AML (OR = 2.84; 95% CI: 1.48-5.46; P = .002 compared with de novo AML), WBC (OR = 4.48; 95% CI: 2.11-9.52; P < .001) for subjects >50 vs ≤50 G/L), and ELN classification (OR = 1.42, 95% CI: 0.56-3.62, P = .458; OR = 1.83, 95% CI: 0.71-4.71, P = .208; and OR = 0.78, 95% CI: 0.26-2.34, P = .659, respectively, for intermediate I, intermediate II, and adverse vs favorable). Sarah Bertoli et al. Blood 2013;121:2618-2626 ©2013 by American Society of Hematology

Estimated probability of induction failure for each day delaying chemotherapy initiation. Estimated probability of induction failure for each day delaying chemotherapy initiation. (A-D) Estimated adjusted probability of induction failure. Interaction between TDT and age and interaction between TDT and WBC were significant, and analyses were stratified by age (>60 vs ≤60 years) and WBC (>50 vs ≤50 G/L). (A-B) Estimated probability of induction failure in subjects with WBC ≤50 G/L for each value of TDT, adjusted** for the mean of all other variables of the model in (A) younger patients (≤60 years, n = 276) and (B) older patients (>60 years, n = 190). The locations of the 3 knots used in the RCS method are 3, 9, and 35 days (corresponding, respectively, to the 10th, 50th, and 90th percentile of the TDT).22 **Adjusted for ECOG performance status (OR = 1.75, 95% CI: 0.98-3.13, P = .058; OR = 2.81, 95% CI: 1.32-5.99, P = .007; and OR = 4.64, 95% CI: 1.17-18.39, P = .029, respectively, for ECOG 1, 2, and 3/4 vs 0), secondary AML (OR = 1.65; 95% CI: 0.99-2.74; P = .053 compared with de novo AML), ELN classification (OR = 2.06, 95% CI: 0.85-4.98, P = .107; OR = 3.83, 95% CI: 1.64-8.94, P = .002; and OR = 4.70, 95% CI: 2.00-11.04, P < .001, respectively, for intermediate I, intermediate II, and adverse vs favorable), and the interaction between TDT and age (>60 vs ≤60 years). (C-D) Estimated probability of induction failure in subjects with WBC >50 G/L for each value of TDT, adjusted*** for the mean of all other variables of the model in (C) younger patients (≤60 years, n = 82) and (D) older patients (>60 years, n = 51). The locations of the 3 knots used in the RCS method are 1, 2, and 10 days (corresponding, respectively, to the 10th, 50th, and 90th percentile of TDT).22 ***Adjusted for ECOG performance status (OR = 4.55, 95% CI: 0.56-36.7, P = .155; OR = 7.57, 95% CI: 0.76-74.9, P = .084; and OR = 4.75, 95% CI: 0.33-68.7, P = .253, respectively, for ECOG 1, 2, and 3/4 vs 0), secondary AML (OR = 20.57; 95% CI: 4.32-97.8; P < .001 compared with de novo AML), ELN classification (OR = 8.53, 95% CI: 2.17-33.5, P = .002; OR = 3.04, 95% CI: 0.66-14.0, P = .154; and OR = 4.94, 95% CI: 0.83-29.6, P = .080, respectively, for intermediate I, intermediate II, and adverse vs favorable), and the interaction between TDT and age (>60 vs ≤60 years). Sarah Bertoli et al. Blood 2013;121:2618-2626 ©2013 by American Society of Hematology