Genotype-outcome correlations in pediatric AML: the impact of a monosomal karyotype in trial AML-BFM 2004

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=0.0091). 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.

Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO‐DBH‐AML study

“…Our study distinguishes MK as an independent predictor of inferior EFS but, in contrast to the findings by Rasche et al (), the high proportion of events did not translate into a poor OS. This discrepancy may be explained by the fact that the comparison group of the current study did not include patients with CBF abnormalities who, according to previous reports, fare exceedingly well after relapse (Kaspers et al , ; Karlsson et al , ).…”

“…Consistent with previous findings in adult AML populations (Grimwade et al, 1998;Slovak et al, 2000;Byrd et al, 2002;Haferlach et al, 2012), CK predicted an adverse prognosis in the present study and showed inferior EFS and OS compared to non-CK patients. The poor EFS associated with CK was mitigated by the omission of patients with MK and corresponds to the observations in the recent report from the AML-Berlin-Frankf€ urt-Muenster (BFM) 2004 trial (Rasche et al, 2017). Taken together, our data suggest that, in patients with multiple non-recurrent chromosomal abnormalities, the event of chromosome loss in particular heralds an increased risk of early events, such as primary refractoriness to chemotherapy.…”

“…Unlike previous studies (Breems et al , ; Rasche et al , ), we included marker and ring chromosomes as individual aberrations in both CK and MK, as it has been shown that extensive cytogenetic tests, such as spectral karyotyping, can identify marker chromosomes (Kerndrup & Kjeldsen, ). We only found marker chromosomes in 38 patients (5%), which indicates a high quality of the cytogenetic tests used.…”

“…The spectrum of genetic abnormalities in AML is highly age‐dependent (Creutzig et al , ) and the adverse prognosis of CK and MK evident in adults may not mirror paediatric AML populations. To our knowledge, a recent study by Rasche et al () is the only other study which has investigated CK and MK in a large cohort of paediatric AML (642 children with 22 cases of MK). They showed that MK was a strong and independent predictor of a dismal outcome.…”

Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy

“…Risk stratification in pediatric AML has previously been based on the presence of a handful of genetic features and responses to therapy. Those with favorable genetics include t(8;21), inv(16), NPM1 mutations, and CEBPA mutations, each of which carries EFS and OS rates of approximately 65–70% and 80%, respectively [ 1 , 4 , 11 ]. t(8;21) and inv(16), collectively termed core binding factor (CBF) AML, represent the most common cytogenetic subgroup in pediatric AML accounting for 20–25% of cases [ 1 , 10 ••, 11 ].…”