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Blood. 2016 Jun 30;127(26):3424-30. doi: 10.1182/blood-2016-01-695551. Epub 2016 Apr 25.

Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study.

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Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands;
Pediatric Hematology/Oncology, University of Bologna, Bologna, Italy;
Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands;
Laboratory of Hematology, University Hospital Saint-Louis, Assistance Publique-Hôpitaux de Paris and EA3518, University Paris Diderot, Paris, France;
Pediatric Hematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic;
Acute Myeloid Leukemia-Berlin-Frankfurt-Munster Study Group, Pediatric Hematology/Oncology, University Hospital Essen, Essen, Germany;
Dutch Childhood Oncology Group, The Hague, The Netherlands;
Children's Oncology Group, Monrovia, CA;
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany;
Onco-Hematology, Dipartimento di Salute della Donna e del Bambino, University of Padova, Padova, Italy;
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands;
Fred Hutchinson Cancer Research Center, Seattle, WA;
Department of Pediatric Hematology/Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Pediatrico Bambino Gesù, Rome, Italy; and University of Pavia, Pavia, Italy.


Genetic abnormalities and early treatment response are the main prognostic factors in acute myeloid leukemia (AML). Acute megakaryoblastic leukemia (AMKL) is a rare subtype of AML. Deep sequencing has identified CBFA2T3/GLIS2 and NUP98/KDM5A as recurrent aberrations, occurring in similar frequencies as RBM15/MKL1 and KMT2A-rearrangements. We studied whether these cytogenetic aberrations can be used for risk group stratification. To assess frequencies and outcome parameters of recurrent cytogenetic aberrations in AMKL, samples and clinical data of patients treated by the Associazione Italiana Ematologia Oncologia Pediatrica, Berlin-Frankfurt-Munster Study Group, Children's Oncology Group, Dutch Childhood Oncology Group, and the Saint Louis Hôpital were collected, enabling us to screen 153 newly diagnosed pediatric AMKL cases for the aforementioned aberrations and to study their clinical characteristics and outcome. CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%; NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive. RBM15/MKL1-rearranged patients were significantly younger. No significant differences in sex and white blood cell count were found. NUP98/KDM5A, CBFA2T3/GLIS2, KMT2A-rearranged lesions and monosomy 7 (NCK-7) independently predicted a poor outcome, compared with RBM15/MKL1-rearranged patients and those with AMKL not carrying these molecular lesions. NCK-7-patients (n = 61) showed a 4-year probability of overall survival of 35 ± 6% vs 70 ± 5% in the RBM15/MKL1-other groups (n = 92, P < .0001) and 4-year probability of event-free survival of 33 ± 6% vs 62 ± 5% (P = .0013), the 4-year cumulative incidence of relapse being 42 ± 7% and 19 ± 4% (P = .003), respectively. We conclude that these genetic aberrations may be used for risk group stratification of pediatric AMKL and for treatment tailoring.

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