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F. Baron et al.
adverse-risk cytogenetics (NotAdvMK–, n=1,584), those without MK but with adverse-risk cytogenetics (AdvMK–, n=218) and those with a MK (MK+, n=188).
Achievement of complete response with or without blood count recovery
Patients with AdvMK– [odds ratio (OR)=1.80, 95% con- fidence interval (95% CI): 1.33-2.42] or MK+ (OR=3.09, 95% CI: 2.26-4.22) had a higher probability of not reach- ing a CR/CRi after induction compared to NotAdvMK– patients (Table 2). CR/CRi was achieved in 76%, 63% and 50% of NotAdvMK–, AdvMK– and MK+ patients, respec- tively. Comparing MK+ to MK– patients (NotAdvMK– or AdvMK–), the odds of not achieving a CR/CRi were almost three times higher (OR=2.85, 95% CI: 2.10-3.88) for MK+ patients. The probability of not achieving a CR/CRi was also significantly higher in MK+ than in AdvMK– patients (OR=1.72, 95% CI: 1.15-2.57).
In a multivariate logistic regression model including age, WHO Performance Status, and white blood cell count, AdvMK– (OR 1.91, 95% CI: 1.41-2.59) and MK+ (OR 3.34, 95% CI: 2.42-4.59) were associated with higher probabil- ities of not achieving a CR/CRi compared to NotAdvMK– (Table 2).
Overall survival
The 5-year OS rates were 39.1%, 24.1% and 7.2% in the NotAdvMK–, AdvMK– and MK+ patients, respectively (Figure 2A). The estimated hazard ratios comparing AdvMK– and MK+ patients to NotAdvMK– patients were 1.48 and 2.58, respectively (Table 3). Comparing MK+ to MK– (NotAdvMK– or AdvMK–) and AdvMK– patients, the estimates of the unadjusted hazard ratio were 2.44 (95% CI: 2.08-2.88) and 1.74 (95% CI: 1.41-2.15), respectively.
In a multivariate Cox model, in comparison to NotAdvMK– patients, those with AdvMK– (HR 1.51, 95% CI: 1.28-1.77) or MK+ (HR 2.71, 95% CI: 2.29-3.20) had a shorter OS (Table 3).
Overall survival from complete remission with or without hematologic recovery
The 5-year OS rates from CR/CRi were 48.5%, 35.5% and 11.4% in NotAdvMK–, AdvMK– and MK+ patients, respectively (Figure 2B). The estimated hazard ratios com- paring AdvMK– and MK+ patients to NotAdvMK– patients were 1.50 and 2.87, respectively (Table 4). Comparing MK+ to MK– (NotAdvMK– or AdvMK–) and AdvMK– patients, the estimates of the hazard ratio were 2.73 (95% CI: 2.17-3.45) and 1.91 (95% CI: 1.42-2.57), respectively.
In a multivariate Cox model, in comparison to NotAdvMK–, AdvMK– (HR 1.52, 95% CI: 1.23-1.88) and MK+ (HR 2.95, 95% CI: 2.32-3.74) were associated with shorter OS from CR/CRi (Table 4). In a sensitivity analy- sis, we modified the multivariate model by additionally stratifying it by donor availability. The results of this analysis were similar to those of the main analysis (HR=1.59, 95% CI: 1.28-1.98 for AdvMK– versus NotAdvMK– and HR=3.00, 95% CI: 2.35-3.82, for MK+ versus NotAdvMK–).
No impact of the type of anthracycline on outcomes in patients with a monosomal karyotype
Response data were available for 91 out of 93 MK+ patients from the AML-10 trial. CR/CRi was reached after induction by 18 out of 32 patients in the daunorubicin arm
(56%), 14 out of 28 patients (50%) in the mitoxantrone arm and 13 out of 31 (42%) patients in the idarubicin arm (P=0.54). The 5-year OS rates were 13.0% (95% CI: 4.1- 27.1%) in daunorubicin patients, 6.7% (95% CI: 1.2- 19.2%) in mitoxantrone patients, and 11.7% (95% CI: 3.1- 26.6%) in idarubicin patients (Figure 2C). The 5-year OS rates from CR/CRi were 17.6% (95% CI: 4.3-38.3%) in daunorubicin patients, 11.5% (95% CI: 0.9-37.5%) in idarubicin patients and 14.3% (95% CI: 2.3-36.6%) in mitoxantrone patients (logrank P=0.53).
No benefit of high-dose cytarabine in patients with monosomal karyotype
Response data after induction were available for 93 out of 95 MK+ and 978 out of 984 MK– patients from the AML- 12 trial. MK (present vs. absent) was of predictive impor- tance for the effect of high-dose cytarabine on the proba- bility of reaching CR/CRi after induction (interaction test P-value: 0.01). MK– patients randomized to the high-dose cytarabine arm were more likely to reach CR/CRi com-
Table 1. Patients’ characteristics. Study
N. of patients
MRC cytogenetic risk group, N. of patients (%)
Adverse Intermediate Missing
Trial AML-10
Daunorubicin, n. of patients (%) Idarubicin, n. of patients (%) Mitoxantrone, n. of patients (%)
AML-12
SDAC, n. of patients (%) HiDAC, n. of patients (%)
Male / Female, n.
Age (years), n. of patients (%) 15-25
26-45
46-60
WHO performance status, n. (%) 0
1
2-4 Missing
NotAdvMK-
1,584
0 1583 (100) 1
691 221 (32.0) 226 (32.7)
244 (35.3) 893 466 (52.2)
427 (47.8) 792 / 790
155 (10) 663 (42) 766 (48)
679 (43) 672 (42) 226 (14) 7 (0)
AdvMK-
218
218 (100)
0 9(95) 00
MK+
188
179 (5)
29 56 42
42 49
127 (22.8) (44.1) (33.1)
91 (46.2) (53.8)
93
32 (34.4) 31 (33.3) 30 (32.3) 95
47 (49.5) 48 (50.5)
107/111 109/79
WBC x109/L at diagnosis, n. of patients (%)
28 (13) 90 (41) 100 (46)
84 (39) 104 (48) 30 (14)
147 (67) 51 (23) 20 (9) 0 (0)
137
5 (54.7) 58 (42.3) 4 (2.9)
15 (8) 71 (38) 102 (54)
62 (33) 100 (53) 26 (14)
140 (75) 38 (20) 10 (5) 0 (0)
92
55 (59.8) 35 (38.0) 2 (2.2)
<25 25-99.9 ≥100 Missing
N. of patients with CR/CRi
afterinduction
Donor, n. among pts with CR/CRi (%) No
Yes
Missing
892 (56) 496 (31) 195 (12) 1 (0)
1194
710 (59.5) 412 (34.5) 72 (6.0)
NotAdvMK–: not adverse cytogenetic excluding a monosomal karyotype; AdvMK–: adverse cytogenetic excluding a monosomal karyotype; MK+: monosomal karyotype; SDAC, standard-dose cytarabine; HiDAC: high-dose cytarabine; WHO: World Health Organization; WBC: white blood cell count; CR: complete remission; CRi, complete remission with incomplete hematologic recovery.
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