Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study

Abstract

We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.

Figure 1

Flow chart showing the presence and type of ACAs in 756 pediatric patients with 11q23/MLL-rearranged AML. Complete karyotypes were not available for 23 patients, and they were therefore excluded from analyses. The presence or absence of ACAs was determined for 733 patients for whom complete karyotypes were available. In the cohort having ACAs balanced karyotype was coded for 25 patients; the remaining had an unbalanced karyotype. The types of aberrations were coded as numerical, structural, or both, and the number of aberrations was also coded. Losses and gains are further coded in other figures.

Figure 2

Frequency (number of cases) of numerical and structural ACAs. (A) Numerical ACAs. Gains are shown on the positive y-axis, and losses are shown on the negative y-axis. Chromosomes are on the x-axis. (B) Structural ACAs The short arms (p) of the chromosomes are shown on the positive y-axis and the long arms (q) on the negative y-axis. Lightest shades are used for losses, medium-shaded colors are used for gains, and the darkest-shaded colors for breakpoints of balanced translocations. Chromosomes are on the x-axis. Balanced 11q23 translocations are not included in the figure.

Figure 3

Survival curves obtained from univariate analysis comparing patients with ACAs to patients without ACAs and comparing patients with complex karyotype with all patients with < 3 aberrations. (A-C) Patients with ACAs are compared to patients without ACAs. (D-F) Patients with complex karyotype are compared to patients with < 3 aberrations. EFS (A,D), OS (Survival; B,E), and CIR (C,F).

Figure 4

Comparison of survival curves obtained from univariate analysis for patients with trisomy 8, trisomy 19, and those with trisomy 21 and defined by strata of occurrence of trisomy 19 and trisomy 21. For curves A-I, patients with a specific trisomy are compared with patients with other ACAs. Patients with trisomy 8 are shown in parels A-C, patients with trisomy 19 in panels D-F, and patients with trisomy 21 in panels G-I. The strata of occurrence of trisomy 19 and trisomy 21 are shown in panels J-L. EFS (A,D,G,J), OS (Survival; B,E,H,K), and CIR (C,F,I,L).