Marker chromosomes can predict adverse prognosis in AML patients: A German study

Marker chromosomes are structurally abnormal chromosomes that are rearranged to a level that prevents its allocation to one of the known 23 chromosomes hence indicating gross structural chromosomal damage. The prognostic impact of marker chromosomes in Acute Myeloid Leukemia (AML) is unclear hence the rationale of this study.

Tilmann Bochtler from the German Cancer Research Center, University of Heidelberg, Germany, and colleagues recently published results from their study ahead of print in Blood on 24^th January 2017.

To assess the impact of marker chromosomes on the prognosis of AML patients and the mechanisms of marker chromosome formation, the authors retrospectively analyzed two prospective intensive chemotherapy trials, AML96 and AML2003 from the German Study Alliance Leukemia (SAL).

The key results are:

• In patients with aberrant Non-Core-Binding-Factor (CBF) karyotypes (n = 1,026), marker chromosomes were detected in 16.1% (165/1,026)
• Marker chromosomes were harbored in patients with adverse-risk cytogenetics (148/558)
• In the adverse-risk cytogenetic group, marker chromosomes were more frequent in patients with complex aberrant (40%), monosomal (50.2%), abnl(5q) (43.4%), abnl(7q) (32.9%), and abnl(17p) (41.2%) karyotypes; P < 0.001
• Complete Remission (CR) plus Complete Remission with Incomplete Recovery of Blood Counts (CRi) was significantly lower in marker chromosome-positive patients ≤60 years in both AML96 and AML2003 trials compared to marker chromosome-negative patients
• In the AML96 trial, median Event Free Survival (EFS) of patients ≤60 years with marker chromosome compared to patients with no marker chromosome; 2.24 vs 6.54 months, P < 0.001
• In the AML96 trial, median Overall Survival (OS) of patients ≤60 years with marker chromosome compared to patients with no marker chromosome; 5.72 vs 11.87months, P < 0.001
• In the AML2003 trial, median EFS of patients with  marker chromosome compared to patients with no marker chromosome; 3.45 vs 8.03 months, P = 0.01
• In the AML2003 trial, median OS of patients with marker chromosome compared to patients with no marker chromosome; 8.68 vs 20.78 months, P = 0.01
• In the AML96 trial, marker chromosome in patients ≤60 years significantly associated with poor OS (P = 0.01) and EFS (P = 0.008)
• Chromothripsis was detected in 36.7% (18/49) of marker chromosome-positive patients and in 2.9% marker chromosome-negative patients (1/34); P < 0.001

The presence of marker chromosomes suggest an activity of chromothripsis and can contribute to the poor prognosis in AML patients. Additionally, marker chromosomes do not reflect the poor prognosis of other adverse cytogenetic features, but can contribute to the poor prognostic impact by themselves in AML patients.

In summation, this is the first study to show that marker chromosomes can arise from chromothripsis, and it is frequently common in adverse-risk karyotypes and associated with a dismal prognosis in AML patients. 

Abstract

Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML are structurally highly abnormal marker chromosomes. In this study we have assessed frequency, cytogenetic characteristics, prognostic impact and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. In 2 large consecutive prospective, randomized, multicenter, intensive chemotherapy trials (AML96, AML2003) from the Study Alliance Leukemia (SAL) marker chromosomes were detectable in 165/1026 (16.1%) of aberrant non-core-binding-factor (CBF) karyotype patients. Adverse-risk karyotypes displayed a higher frequency of marker chromosomes (26.5% in adverse-risk, 40.3% in complex aberrant and 41.2% in abnormality (17p) karyotypes, p<.0001 each). Marker chromosomes were associated with a poorer prognosis compared to other non-CBF aberrant karyotypes and led to lower remission rates (CR+CRi), inferior event-free survival as well as overall survival in both trials. In multivariate analysis, marker chromosomes independently predicted poor prognosis in the AML96 trial ≤60 years. As detected by array-CGH, about one third of marker chromosomes (18/49) had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of marker chromosome-negative complex aberrant karyotypes (1/34). The chromothripsis-positive cases were characterized by a particularly high degree of karyotype complexity, TP53 mutations and dismal prognosis. In conclusion, marker chromosomes are indicative of chromothripsis and associated with poor prognosis per se and not merely by association with other adverse cytogenetic features.