Although rarely, switches between lymphoid and myeloid lineages may occur during treatment of acute leukemias (AL). Correct diagnosis relies upon confirmation by immunophenotyping of the lineage conversion and certification that the same cytogenetic/molecular alterations remain despite the phenotypic changes. From a total of 1,482 AL pediatric patients, we report nine cases of lineage conversion (0.6%), seven from lymphoid (four Pro-B, two Pre-B, one Common) to myelo-monocytic, and two from myeloid (bilineal, with myeloid predominance) to Pro-B. Eight patients were infants. Switches were suggested by morphology and confirmed with a median of 15 days (range: 8 days-6 months) from initiation of therapy. Of note, in five cases switches occurred before day 15. Stability of the clonal abnormalities was assessed by cytogenetic, RT-PCR/Ig-TCR rearrangement studies in all patients. Abnormalities in 11q23/MLL gene were detected in seven cases. Treatment schedules were ALL (two pts), Interfant-99 (five pts) and AML (two pts) protocols. Despite changing chemotherapy according to the new lineage, all patients died. Our findings support the association of lineage switches with MLL gene alterations and the involvement of a common lymphoid B-myeloid precursor. New therapies should be designed to address these rare cases. Possible mechanisms implicated are discussed. Am. J. Hematol. 87:890-897, 2012. V

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)–CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups.

Historically, t(1;19)(q23;p13.3) has been related to pre-B acute lymphoblastic leukemia (ALL) and associated with a poor prognosis. Current treatments have overcome this dismal outcome, but advantages in survival for the unbalanced group have been reported. We compared the outcome of balanced and unbalanced der(19)t(1;19) cases and also patients with t(1;19)/TCF3-PBX1 versus patients without this translocation, to assess its prognostic value. From January 1990 to December 2010, t(1;19)(q23;p13)/TCF3-PBX1 was detected in 48 cases. Patients were treated with Berlin-Frankfurt-Münster (BFM)-based protocols and classified into balanced (n = 17) and unbalanced (n = 23) groups. The probability of event-free survival (pEFS) (standard error) of patients with t(1;19)/TCF3-PBX1 was 85% (6%), for the unbalanced group 78% (10%), and 88% (8%) for the balanced. The pEFS of patients with t(1;19)/TCF3-PBX1 was significantly superior to that of patients without t(1;19)/TCF3-PBX1 (p-value <0.0001). Patients with t(1;19)/TCF3-PBX1 presented a good outcome with no differences between balanced and unbalanced subgroups. Thus, risk-adjustment therapy would not be necessary for cases with t(1;19)/TCF3-PBX1.

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MECP2 duplication syndrome (MDS) is an X‐linked neurodevelopmental disorder characterized by a severe to profound intellectual disability, early onset hypotonia and diverse psycho‐motor and behavioural features. To date, fewer than 200 cases have been published. We report the clinical and molecular characterization of a Spanish MDS cohort that included 19 boys and 2 girls. Clinical suspicions were confirmed by array comparative genomic hybridization and multiplex ligation‐dependent probe amplification (MLPA). Using, a custom in‐house MLPA assay, we performed a thorough study of the minimal duplicated region, from which we concluded a complete duplication of both MECP2 and IRAK1 was necessary for a correct MDS diagnosis, as patients with partial MECP2 duplications lacked some typical clinical traits present in other MDS patients. In addition, the duplication location may be related to phenotypic severity. This observation may provide a new approach for genotype‐phenotype correlations, and thus more personalized genetic counselling.