Acute Myeloid Leukemia With Adverse Cytogenetic Risk

Acute myeloid leukemia (AML) encompasses multiple disease entities that differ with regard to marrow morphology, cytochemistry, immunophenotype, pretreatment clinical characteristics, and treatment outcome. The last of these is heavily influenced by cytogenetic and molecular genetic findings at diagnosis.[1,2] In this issue of ONCOLOGY, Drs. Orozco and Appelbaum review major cytogenetic subsets of AML that are associated with an adverse prognosis; they focus on two, partially overlapping, categories-AML with complex karyotype and AML with monosomal karyotype.

The definition of complex karyotype has varied among studies analyzing the impact of cytogenetics on clinical outcome, with ≥ 3 and ≥ 5 unrelated chromosome abnormalities being the most common definitions.[3] Very recent studies have proposed more refined definitions, such as the one used in the revised Medical Research Council (MRC) classification,[4] in which a karyotype was designated complex if it comprised ≥ 4 unrelated abnormalities, but only in the absence of those specific abnormalities that on their own conferred a favorable prognosis [ie, t(15;17)(q22;q21), t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22)] or an adverse prognosis [ie, abn(3q), except for t(3;5)(q25;q34); inv(3)(q21q26)/t(3;3)(q21;q26); add(5q)/del(5q), –5; add(7q)/del(7q), –7; t(6;11)(q27;q23), t(10;11)(p11~13;q23), other t(11q23) with the exception of t(9;11)(p22;q23) and t(11;19)(q23;p13); t(9;22)(q34;q11); –17 and abn(17p)] in the MRC study.[4]

An alternative definition of complex karyotype was used by an international expert panel working on behalf of the European LeukemiaNet (ELN). The panel proposed a standardized system for reporting cytogenetic and selected molecular abnormalities in studies correlating genetic findings with treatment outcome in AML[5]; in this system, which is based on the 2008 revision of the World Health Organization (WHO) Classification of Myeloid Neoplasms and Acute Leukemia,[6] complex karyotype is defined as ≥ 3 abnormalities in the absence of the WHO-designated recurring translocations or inversions-namely, t(8;21), inv(16) or t(16;16), t(15;17), t(9;11), t(v;11)(v;q23), t(6;9)(p23;q34), and inv(3) or t(3;3). Because the aforementioned definitions of complex karyotype have been introduced recently, it is currently unknown whether one of them is superior to the other.

The ability to predict treatment outcome using the ELN reporting system, which in addition to cytogenetics employs molecular alterations recognized in the WHO classification (ie, NPM1, CEBPA,FLT3 mutations) to divide patients with cytogenetically normal AML into the ELN Genetic Groups, has been recently tested in two large cohorts of AML patients.[7-9] The ELN Adverse Group for the most part was comprised of patients with complex karyotypes with ≥ 3 abnormalities, which were detected in 65% of patients younger than 60 years and in 75% of patients aged 60 years or older;[8,9] the remaining Adverse Group patients harbored inv(3) or t(3;3), t(6;9), t(v;11)(v;q23), –5 or del(5q), –7, or abn(17p). Complete remission (CR) rates, disease-free survival (DFS), and overall survival (OS), in both younger and older ELN Adverse Group patients, were significantly worse than CR rates, DFS, and OS in patients classified in the ELN Favorable, Intermediate-I, and Intermediate-II Groups.[7-9] In our study,[9] the prognostic significance of the ELN classification was shown to be independent of other prognostic factors by multivariable analyses, thus supporting its use for risk-stratification in clinical trials.

Monosomal karyotype has been repeatedly shown to constitute a cytogenetic feature that is useful in identifying AML patients with very poor outcomes when treated with currently available therapy.[10-15] However, this patient subset is very heterogeneous cytogenetically, comprising both patients with a complex karyotype and patients with well-established disease entities, such as AML with inv(3) or t(3;3), t(6;9), or t(v;11)(v;q23).[10] Consequently, it is unlikely that there is one common molecular alteration underlying the development of the disease in all patients with monosomal karyotype that could potentially become a target for therapeutic intervention. Instead, it is likely that many separate molecular alterations will be found to characterize specific, cytogenetically defined components of the diverse group of patients classified as having a monosomal karyotype.

One such molecular abnormality, mutations in the TP53 gene, was identified recently in patients with complex monosomal karyotype. Rcker et al[16] analyzed the frequency of both TP53 mutations and TP53 losses (collectively referred to as TP53 alterations) among AML patients with a complex karyotype defined according to the ELN criteria.[5] Of these patients, 78% fulfilled criteria for having monosomal karyotype; 22% did not. Overall, 70% of all patients with a complex karyotype had TP53 alterations; they were found with even greater frequency-80%-in patients with a complex monosomal karyotype but were present in only 42% of patients with complex nonmonosomal karyotype.[16]

However, when Rcker et al[16] detected unbalanced chromosome abnormalities using array-based comparative genomic hybridization and single-nucleotide polymorphism (SNP) genomic profiling instead of standard G-banding analysis, the number of patients determined to have a complex monosomal karyotype diminished considerably, from 78% of all complex karyotype patients to 32%. This happened because of the previously described phenomenon [17,18] that a large proportion of chromosomes deemed lost in G-banded karyotypes were in fact not lost entirely (monosomy); rather, parts of these chromosomes were hidden in such structural abnormalities as marker chromosomes, ring chromosomes, unbalanced translocations, and/or unidentified material attached to a chromosome. In complex karyotype patients classified by array-based genomic profiling, TP53 alterations were still detected in 79% of those with monosomal karyotype, but they were now found in 66% of patients with nonmonosomal complex karyotype.[16] This example illustrates the fact that whether or not an individual patient is classified into the monosomal karyotype category depends on the genetic technique used, and that this descriptive category of AML will likely require re-evaluation in light of the growing significance of such emerging technologies as next-generation sequencing.[19]

Importantly, outcome analyses revealed that complex karyotype patients with TP53 alterations had significantly lower CR rates and worse relapse-free, overall, and event-free survival than those without TP53 alterations. In multivariable analysis for OS, TP53 alteration was the most important prognostic factor, followed by white blood cell count and age, whereas the monosomal karyotype category (defined using standard cytogenetic analysis) lost its prognostic impact.[16]

It is hoped that future studies will uncover other molecular alterations that will not only improve the prognostic stratification of patients with adverse cytogenetic-risk features but also become targets for novel therapeutic agents.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Acknowledgements: This work was supported in part by National Cancer Institute (Bethesda, MD) grants CA16058 and CA140158, and by the Coleman Leukemia Research Foundation.

References:

REFERENCES

1. Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004;18:115-36.

2. Smith ML, Hills RK, Grimwade D. Independent prognostic variables in acute myeloid leukaemia. Blood Rev. 2011;25:39-51.

3. Mrózek K. Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype. Semin Oncol. 2008;35:365-77.

4. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354-65.

5. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453-74.

6. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the WHO Classification of Myeloid Neoplasms and Acute Leukemia: rationale and important changes. Blood. 2009;114:937-51.

7. Röllig C, Bornhäuser M, Thiede C, et al. Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet Recommendations: evaluation of the proposed reporting system. J Clin Oncol. 2011;29:2758-65.

8. Mrózek K, Marcucci G, Maharry K, et al. Prognostic utility of the European LeukemiaNet (ELN) genetic-risk classification in adults with de novo acute myeloid leukemia (AML): a study of 1,550 patients (pts). Blood. 2011;118:190-1.

9. Mrózek K, Marcucci G, Nicolet D, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in acute myeloid leukemia: a study of 1,550 adults with primary disease. J Clin Oncol. 2012;

10. Breems DA, van Putten WLJ, De Greef GE, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26:4791-7.

11. Perrot A, Luquet I, Pigneux A, et al. Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities. Blood. 2011;118:679-85.

12. Oran B, Dolan M, Cao Q, et al. Monosomal karyotype provides better prognostic prediction after allogeneic stem cell transplantation in patients with acute myelogenous leukemia. Biol Blood Marrow Transplant. 2011;17:356-64.

13. Kayser S, Zucknick M, Döhner K, et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood. 2012;119:551-8.

14. Haferlach C, Alpermann T, Schnittger S, et al. Prognostic value of monosomal karyotype in comparison to complex aberrant karyotype in acute myeloid leukemia: a study on 824 cases with aberrant karyotype. Blood. 2012;119:2122-5.

15. Yanada M, Kurosawa S, Yamaguchi T, et al. Prognosis of acute myeloid leukemia harboring monosomal karyotype in patients treated with or without allogeneic hematopoietic cell transplantation after achieving complete remission. Haematologica. 2012;97:915-8.

16. Rücker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119:2114-21.

17. Mr ózek K, Heinonen K, Theil KS, Bloomfield CD. Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q. Genes Chromosomes Cancer. 2002;34:137-53.

18. Van Limbergen H, Poppe B, Michaux L, et al. Identification of cytogenetic subclasses and recurring chromosomal aberrations in AML and MDS with complex karyotypes using M-FISH. Genes Chromosomes Cancer. 2002;33:60-72.

19. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506-10.