Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia.
OBJECTIVE
In acute myeloid leukemia (AML), studies based on whole-genome sequencing have shown genomic diversity within leukemic clones. The aim of this study was to address clonal heterogeneity in AML based on metaphase cytogenetics.


METHODS
This analysis included all patients enrolled onto two consecutive, prospective, randomized multicenter trials of the Study Alliance Leukemia. Patients were newly diagnosed with non-M3 AML and were fit for intensive chemotherapy.


RESULTS
Cytogenetic subclones were detected in 418 (15.8%) of 2,639 patients from the whole study population and in 418 (32.8%) of 1,274 patients with aberrant karyotypes. Among those, 252 karyotypes (60.3%) displayed a defined number of distinct subclones, and 166 (39.7%) were classified as composite karyotypes. Subclone formation was particularly frequent in the cytogenetically adverse group, with subclone formation in 69.0%, 67.1%, and 64.8% of patients with complex aberrant, monosomal, and abnl(17p) karyotypes (P < .001 each). Two-subclone patterns typically followed a mother-daughter evolution, whereas for ≥ three subclones, a branched pattern prevailed. In non-core binding factor AML, subclone formation was associated with inferior event-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariate analysis. Subgroup analysis showed that subclone formation adds prognostic information particularly in the cytogenetic adverse-risk group. Allogeneic stem-cell transplantation improved the prognosis of patients with subclone karyotypes as shown in landmark analyses.


CONCLUSIONS
Cytogenetic subclones are frequent in AML and permit tracing of clonal evolution and architecture. They bear prognostic significance with clonal heterogeneity as an independent adverse prognostic marker in cytogenetically adverse-risk AML.
Tilmann Bochtler, Christoph E. Heilig, Anna Jauch, Johannes W.G. Janssen, Anthony D. Ho, and Alwin Krämer, University of Heidelberg; Tilmann Bochtler, Christina Kunz, Axel Benner, and Alwin Krämer, German Cancer Research Center (DKFZ), Heidelberg; and Friedrich Stölzel, Brigitte Mohr, Michael Kramer, Martin Bornhäuser, Gerhard Ehninger, and Markus Schaich, University Hospital Carl Gustav Carus, Dresden, Germany.
Tilmann
T
Bochtler
Friedrich
F
Stölzel
Christoph E
CE
Heilig
Christina
C
Kunz
Brigitte
B
Mohr
Anna
A
Jauch
Johannes W G
JW
Janssen
Michael
M
Kramer
Axel
A
Benner
Martin
M
Bornhäuser
Anthony D
AD
Ho
Gerhard
G
Ehninger
Markus
M
Schaich
Alwin
A
Krämer
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002869:Chromosome Aberrations; D005260:Female; D006801:Humans; D007621:Karyotyping / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008677:Metaphase / Q000235:genetics*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D055815:Young Adult