Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23-or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/ MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (؎ 5%), with large differences across subgroups (11% ؎ 5% to 92% ؎ 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] ‫؍‬ 0.1, P ‫؍‬ .004); t(6; 11)(q27;q23) (HR ‫؍‬ 2.2, P < .001); t(10; 11)(p12;q23) (HR ‫؍‬ 1.5, P ‫؍‬ .005); and t(10;11)(p11.2;q23) (HR ‫؍‬ 2.5, P ‫؍‬ .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis. (Blood. 2009;114:2489-2496)

We present here a genome-wide map of abnormalities found in diagnostic samples from 45 adults and adolescents with acute lymphoblastic leukemia (ALL). A 500K SNP array analysis uncovered frequent genetic abnormalities, with cryptic deletions constituting half of the detected changes, implying that microdeletions are a characteristic feature of this malignancy. Importantly, the pattern of deletions resembled that recently reported in pediatric ALL, suggesting that adult, adolescent, and childhood cases may be more similar on the genetic level than previously thought. Thus, 70% of the cases displayed deletion of one or more of the CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. Furthermore, several genes not previously implicated in the pathogenesis of ALL were identified as possible recurrent targets of deletion. In total, the SNP array analysis identified 367 genetic abnormalities not corresponding to known copy number polymorphisms, with all but two cases (96%) displaying at least one cryptic change. The resolution level of this SNP array study is the highest used to date to investigate a malignant hematologic disorder. Our findings provide insights into the leukemogenic process and may be clinically important in adult and adolescent ALL. Most importantly, we report that microdeletions of key genes appear to be a common, characteristic feature of ALL that is shared among different clinical, morphological, and cytogenetic subgroups. A cute lymphoblastic leukemia (ALL) occurs at all ages but displays a bimodal distribution of incidence, with one peak in early childhood and a second in patients older than 50 years (1). For adult ALL, the yearly incidence is Ϸ2 per 100,000, with Ϸ75% of the cases being B lineage and the remainder of T cell origin (1, 2). The most prominent prognostic factors are age, white blood cell count (WCC), and different genetic abnormalities, with younger age and lower WCC being associated with an improved outcome (3, 4). Most adults, however, are considered to be high-risk, and the long-term disease-free survival rates are Ͻ40% (1, 3-5). This is in stark contrast to pediatric ALL, where refined treatment regimens have resulted in cure rates approaching 80% (6, 7). Treatment of adolescents (15-21 years old) on pediatric protocols has resulted in an increased overall survival but is still far from the outstanding results achieved in children (8). Hence, there is a need for novel prognostic markers in adult and adolescent ALL to allow a better risk stratification of these patients and to identify new treatment targets.Whereas genetic abnormalities in pediatric ALL are widely used in clinical practice for risk stratification purposes, most treatment protocols in adult ALL consider only the presence or absence of the Philadelphia chromosome, t(9;22)(q34;q11.2). The t(9;22), which results in the BCR/ABL1 fusion gene, is found in 20-30% of adult B cell precursor cases and is an adverse prognostic indicator (9-12). Other recurrent rearrangements include the t(4;11)(q21;q23) forming a MLL/AFF1 (prev...

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/MLLrearranged 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. (Blood. 2011;117(26):7102-7111)

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