Pediatric Acute Myeloid Leukemia with t(8;16)(p11;p13): A Distinct Clinical and Biological Entity. Results of a Collaborative Study by the International Berlin-Frankfurt-Münster AML Study Group.
Authors: Coenen Eva A , Zwaan C. Michel , Harrison Christine J , Haas Oskar A. , de Haas Valerie , Mihal V , De Moerloose Barbara , Jeison M , Rubnitz Jeffrey , Tomizawa Daisuke , Johnston Donna , Alonzo Todd A. , Hasle Henrik , Reinhardt Dirk , Auvrignon Anne , Dworzak Michael , Pession Andrea , van der Velden Vincent H.J. , Swansbury John , Wong Kit Fai , Terui Kiminori , Savasan Sureyya , Winstanley M , Vaitkeviciene G , Zimmermann Martin , Pieters Rob , van den Heuvel-Eibrink Marry M. 
Published: October 2019

Abstract
Abstract 2516

Introduction:
In pediatric acute myeloid leukemia (AML) cytogenetic abnormalities are important for prognosis and treatment stratification. Some recurring cytogenetic abnormalities occur so rarely that large collaborative studies are required to define their prognostic impact. t(8;16)(p11;p13) is an aberration reported in <1% of pediatric AML patients. Recently, Haferlach et al. (Leukemia, 2009) reported that t(8;16)(p11;p13) represents a distinct clinical and biological subgroup in adult AML, with dismal clinical outcome (median overall survival (OS) 4.7 months). In pediatric AML case reports are available, but studies of larger series are lacking.

Methods:
We collected data on patients with t(8;16)(p11;p13) (n=39) from 18 collaborative study groups belonging to the International Berlin-Frankfurt-Münster AML-Committee. Data collection included clinical characteristics, karyotype, morphology and immunophenotype, which were centrally reviewed by the co-authors. In addition, the literature was screened for reports on pediatric t(8;16)(p11;p13), which found an additional 23 cases.

Results:
A total of 62 pediatric AML patients with t(8;16)(p11;p13) were identified, diagnosed between 1978–2010, including 2 secondary AML cases. They had a median age of 1.2 years (range 0–17 years) and 56% of the patients were younger than 2 years old. Median white blood cell count was 21.3 × 109/l (n= 59, range 1.1–173 × 109/l). FAB type was M4 or M5 in 95% of the cases and immunophenotypes showed monocytic differentiation. Erythrophagocytosis (23/33, 70%), leukemia cutis (21/36, 58%) and disseminated intravascular coagulation (DIC, 15/38, 39%) occurred frequently. At initial diagnosis, 35/57 (61%) of the patients showed t(8;16)(p11;p13) as the sole aberration (5 incomplete karyotypes were excluded). In the remaining 22 patients, no recurrent additional cytogenetic aberrations were found. In patients diagnosed after January 1st1993, and treated with chemotherapy at initial diagnosis (n= 34), the CR rate was 85% (29/34), 5-year OS was 59% (±9%), event free survival (EFS) was 57% (±9%) and the cumulative incidence of relapse (CIR) was 28% (±8%). The median follow-up time of survivors was 4 years. Outcome was is comparable to a reference cohort of AML-BFM patients (n= 543) treated in the same era, with OS of 62% (±2%), EFS of 50% (±2%) and CIR of 42% (±2%). Most striking was that in 7 neonates (<1 month of age) diagnosed with AML and t(8;16)(p11;p13), spontaneous complete remission was achieved. Three of these infants survived without recurrence of disease (follow-up 0.9–4.0 years). For those who relapsed (0.7–4 years after initial diagnosis), chemotherapy treatment was successful in 2/4 patients.
Gene expression data, using the Affymetrix Human Genome U133 plus 2.0 array, were available from 297 pediatric AML samples, of which 8 were t(8;16)(p11;p13). The gene expression signature of t(8;16)(p11;p13) AML clustered close to but distinct from MLL-rearranged AML using unsupervised analysis. Highly expressed genes included HOXA11, HOXA10, RET, PERP and GGA2, indicating a pathway in common with MLL-rearranged AML with distinct features. PERP is a direct target gene of p53 and acts as an effector of apoptosis, GGA2 codes for a protein that regulates protein trafficking within the cell. PERP and GGA2 knockdown in high expressing cell lines did not result in significant changes in cell proliferation or apoptosis, thus their function in leukemic blasts remains unknown.
DNA methylation profiling was performed using Agilent 244K Human CpG Island arrays on 167 pediatric AML samples of which 12 had t(8;16)(p11;p13). Differential methylation of the TRIM59 promoter, an oncogene described in prostate cancer located on chromosome 3, was confirmed by pyrosequencing, with subsequent mRNA overexpression, validated by RT-qPCR.

Conclusion:
This study shows the distinct nature of t(8;16)(p11;p13) pediatric AML with remarkable clinical features such as high percentage of leukemia cutis and DIC. The 5-year OS of this pediatric cohort was intermediate (59%), and therefore different from the dismal prognosis reported in adult cases. In neonatal t(8;16)(p11;p13) AML, spontaneous remissions were reported. Profiling studies have shed light on potential oncogenic mechanisms involved in AML with t(8;16)(p11;p13), including HOX-gene upregulation similar to MLL-rearranged AML.

Disclosures:
No relevant conflicts of interest to declare.