Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study

Abstract

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.

Figure 1

Survival curves of the 756 pediatric patients with 11q23/MLL-rearranged AML included in this study. The probability of overall survival (pOS) at 5 years from diagnosis was 56% ± 2% (312 events); the probability of event-free survival (pEFS) was 44% ± 2% (417 events); and the probability of cumulative incidence of relapse (pCIR) was 35% ± 2% (257 events).

Figure 2

Survival curves for patients with 11q23/MLL-rearranged pediatric AML grouped on the basis of different translocation partners. (A) Event-free survival curves. (B) Overall survival curves. Assignment to 11q23-rearranged subgroups was based on translocation partners, as identified after central review of karyotyping. Some patients were assigned to 11q23 subgroups based on RT-PCR results only. If an MLL rearrangement was determined by FISH and the translocation partner was unknown, the patient was included in the “11q23/MLL-other” group. At least 10 patients had to be included to create a subgroup; otherwise, the cases were allocated to the 11q23/MLL-other group. Patients with a t(1;11)(q21;q23) showed independent favorable outcome with overall survival at 5 years of 100% ± 0%, and an event-free survival of 92% ± 5%. Several rearrangements were identified as predictors of poor clinical outcome, including t(6;11)(q27;q23), t(10;11)(p11.2;q23), t(4;11)(q21;q23), and t(10;11)(p12;q23).