General AML

The prognostic significance of monosomal karyotype in pediatric AML patients - a German study

In adult Acute Myeloid Leukemia (AML) patients, the presence of Monosomal Karyotype (MK) is associated with adverse prognosis. However, the prognostic significance of isolated or combined occurrence of MK with Complex Karyotype (CK), Hypodiploid Karyotype (HK), and trisomy 8 in pediatric AML patients is not very clear.

In an article published in Leukemia on 25th April 2017, Mareike Rasche from the University Hospital of Essen, Essen, Germany, and colleagues discussed results from their study, which evaluated the prognostic impact of defined chromosomal aberrations in pediatric AML patients treated in the AML-Berlin-Frankfurt-Münster (BFM) 04 study (a randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric AML [NCT00111345]).1,2

In total, 764 de novo AML pediatric patients (0–18 years) treated between March 2004–March 2012 according to the AML-BFM 04 study protocol were enrolled in this study. Cytogenetic data were available for 642 patients excluding patients with t(15;17)(PML-RARA fusion gene).

The key results of the study were:
  • 5-year Event Free Survival (EFS) was significantly lower in patients with MK+ (23±9% [n = 22]) compared to patients with HK+ (44±8% [n =37]) and CK+ (43±7% [n = 59]); P = 0.0003
  • 5-year Overall Survival (OS) was significantly lower in patients with MK+ (35±10%) compared to patients with HK+ (64±8%) and CK+ (58±7%); P < 0.0001
  • MK+ was an independent risk factor for EFS (HR = 2.44, P = 0.007) and non-response or relapse (HR = 2.56, P = 0.007)
  • 5-year EFS was poor in MK+ patients with monosomy 7 excluded (n = 18); 28±11%, P = 0.0081
  • 5-year EFS was worse in CK patients with MK+ (25±13%, P = 0.024) compared to patients without MK (47±8%, P = 0.46)
  • 5-year EFS was worse in HK patients with MK+ (10±10%, P < 0.0001) compared to patients without MK (57±10%, P = 0.50)
  • 5-year EFS was poor in HK+ patients with t(8,21) excluded (n = 16); 9±8%, P < 0.0001
  • 5-year EFS was poor in patients with isolated trisomy 8 (n = 16); 25±11%; P = 0.009

In summary, MK is a “strong and independent” prognostic factor for poor outcomes in pediatric AML patients. Additionally, HK without t(8,21) and trisomy 8 alone is associated with abysmal outcomes in pediatric AML patients.

The authors concluded by suggesting that their findings should be validated in an “independent patient cohort”, which could be important for risk stratification in pediatric AML patients.

Abstract

We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+), and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS; 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47; EFS 47±8%, P=0.46) than those with MK+ (n=12; EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16; EFS 25±11%; P=0.009). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.

References
  1. Rasche M. et al. Genotype-outcome correlations in pediatric AML: The impact of a monosomal karyotype in trial AML-BFM 2004. Leukemia. 2017 Apr 25. DOI: 10.1038/leu.2017.121. [Epub ahead of print].
  2. Creutzig U. et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood. 2013 Jul 4; 122(1): 37–43. DOI: 10.1182/blood-2013-02-484097. Epub 2013 May 23.