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

Abstract

Key Points• NUP98/KDM5A, CBFA2T3/ GLIS2, KMT2A-rearrangements, and monosomy 7 are associated with poor outcome; RBM15/ MKL1 and others fare better.• Screening for NUP98/ KDM5A, RBM15/MKL1, CBFA2T3/GLIS2, and KMT2A rearrangements combined with conventional karyotyping is advisable.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 5 61) showed a 4-year probability of overall survival of 35 6 6% vs 70 6 5% in the RBM15/MKL1-other groups (n 5 92, P < .0001) and 4-year probability of event-free survival of 33 6 6% vs 62 6 5% (P 5 .0013), the 4-year cumulative incidence of relapse being 42 6 7% and 19 6 4% (P 5 .003), respectively. We conclude that these genetic aberrations may be used for risk group stratification of pediatric AMKL and for treatment tailoring. (Blood. 2016;127(26):3424-3430)

Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene

“…Pediatric acute myeloid leukemia (AML) carrying CBFA2T3 - GLIS2 fusion gene deserves particular interest, being associated with a grim prognosis in all the reports published so far [1–3]. The incidence of this aberration is 17 and 8% in pediatric non-Down syndrome acute megakaryoblastic and in pediatric cytogenetically normal AML, respectively [1–3].…”

“…The incidence of this aberration is 17 and 8% in pediatric non-Down syndrome acute megakaryoblastic and in pediatric cytogenetically normal AML, respectively [1–3]. The expression profile of CBFA2T3 - GLIS2 is associated with upregulation of both Hedgehog (HH) and bone morphogenic protein (BMP) signaling [1, 4].…”

Mate pair sequencing improves detection of genomic abnormalities in acute myeloid leukemia

“…Sample number and type are listed on the X-axis, MPseq detected abnormality on the Y-axis and percent abnormal by FISH in the corresponding boxes.TA B L E 3 Additional information obtained from MPseq testing on nine samples that were not apparent through conventional karyotyping or FISH studies BM) in two pediatric patients with acute megakaryoblastic leukemia (AMKL) representing a rare subtype of AML [24][25][26]. Sample number and type are listed on the X-axis, MPseq detected abnormality on the Y-axis and percent abnormal by FISH in the corresponding boxes.TA B L E 3 Additional information obtained from MPseq testing on nine samples that were not apparent through conventional karyotyping or FISH studies BM) in two pediatric patients with acute megakaryoblastic leukemia (AMKL) representing a rare subtype of AML [24][25][26].…”

“…indicates detected by mate pair, but not by FISH. Since fusion of NUP98 with KDM5A is a recurrent rearrangement in pediatric non-Down syndrome AMKL,[24][25][26] the MPseq result would have provided a specific, molecularly defined diagnosis with risk group stratification.Importantly, a limitation of the MPseq assay is the inability to reliably detect clonal aberrations present at a very low level. Since fusion of NUP98 with KDM5A is a recurrent rearrangement in pediatric non-Down syndrome AMKL,[24][25][26] the MPseq result would have provided a specific, molecularly defined diagnosis with risk group stratification.Importantly, a limitation of the MPseq assay is the inability to reliably detect clonal aberrations present at a very low level.…”

One giant leap for pediatric AMKL

“…1 C hildren without trisomy 21/Down syndrome who develop AMKL represent a small subset of pediatric acute myeloid leukemia (AML). To date, the rarity of the disease and limitations of traditional karyotyping to identify potential drivers of megakaryocytic differentiation have precluded a reliable biologic approach to risk stratification.…”