Distribution and Outcome According to Cytogenetics in 502 Paediatric AML Patients Treated in Study AML-BFM 98.
Authors: von Neuhoff Christine , Bradtke Jutta , Zimmermann Martin , Bourquin Jean-Pierre , Betts David , Stary Jan , Zemanova Zuzana , Dworzak Michael N , Reinhardt Dirk , Creutzig U. 
Published: October 2019

Cytogenetic analyses are essential for stratification and prognosis of childhood AML. We analysed the frequency of chromosomal aberrations and the outcome according to the cytogenetic findings in 457 patients with data (91%) out of the total group of 502 patients in study AML-BFM 98. The aim was to evaluate the prognostic impact of specific chromosomal aberrations in a large group of uniformly treated patients. The 502 patients <18 years were diagnosed between 1998 and 2003. According to the AML-BFM risk criteria, patients were assigned to a high risk (HR) and a standard risk (SR) group based on morphology, genetics and response on day 15 of therapy. Cytogenetic and FISH analyses - as well as RT-PCR if indicated - were performed according to standard protocols on bone marrow or peripheral blood prior to therapy. Initial characteristics of patients with or without cytogenetic data were essentially similar; only the percentage of patients with undifferentiated leukaemia was higher in patients without cytogenetic data (20% vs. 2.8%).

The number of patients in different karyotypic groups and their outcome are given in the table below:

Cytogenetic aberration Patients n (%) 5-year-EFS (SE) % p logrank* 5-year-OS (SE) % p logrank* *in comparison to the total group SE = standard error, OS = overall survival, EFS = event free survival Total patients with cytogenetic data 457 (100) 48 (2) 0.70 62 (2) 0.74 Normal karyotype 105 (23) 42 (5) 0.09 54 (5) 0.11 t(8;21) or AML1-ETO 57 (12) 84 (5) <0.0001 91 (4) <0.0001 t(15;17) or PML-RARα 27 (6) 73 (9) 0.03 92 (6) 0.015 Inversion 16, t(16;16) or CBFβ/MYH11 43 (9) 64 (8) 0.03 85 (6) 0.006 MLL-rearrangements 94 (21) 36 (5) 0.004 50 (5) 0.003 Deletion of 7q 13 (3) 46 (14) 0.84 62 (13) 0.68 Monosomy 7 10 (2) 10 (9) 0.0003 20 (13) 0.0002 Trisomy 8 38 (8) 46 (8) 0.87 64 (8) 0.65 Aberrations involving 12p 9 (2) 11 (10) 0.02 22 (14) <0.01 Aberrations of chromosome 5 12 (3) 67 (14) 0.19 64 (15) 0.58 3 or more chromosomal aberrations 33 (7) 33 (9) 0.06 48 (9) 0.20 Other cytogenetic aberrations 72 (16) 38 (6) 0.10 58 (6) 0.48 Patients without cytogenetic data 45 47(7) 0.70 60 (7) 0.74

Special results: Patients with t(8;21) had a low relapse rate (5-year cumulative incidence [CI] of relapse 17%, SE 6%) and a high overall survival (OS) rate (91%, SE 4%). It was noteworthy that all 15 children with t(8;21) and additional aberrations that were not either del(9q) or −X/−Y were surviving event free (EFS = 100%). We compared the outcome of patients having a translocation t(9;11) [n = 35], t(19;11) [n = 7] or t(10;11) [n = 12] with or without additional cytogenetic aberrations with the total group of patients with MLL-rearrangement: In patients with t(10;11), CI of relapse was 71%, (SE 16%) and significantly higher than in patients with other MLL-rearrangements (43%, SE 6%, pGray = 0.019).

Conclusion: Our results in cytogenetic findings confirm the favourable prognosis of the rearrangements t(8;21), t(15;17) and inv(16) and the unfavourable prognosis of complex karyotypes (3 or more chromosomal aberrations) and monosomy 7. It is remarkable that the EFS of patients with a MLL-rearrangement was worse than the average EFS of patients in the high-risk group (n = 317, EFS 39%, SE 3%). Poor outcome in paediatric patients with aberrations of 12p has been described in the context of t(7;12), but not as an independent prognostic factor. The favourable prognosis in patients with aberrations involving chromosome 5 was surprising and would warrant further investigations. Our results confirmed the high relevance of cytogenetics in childhood AML and emphasise that risk groups based on cytogenetic findings should be even more specific.