Researchers Analyze Karyotype Complexity and Prognosis in Acute Myeloid Leukemia

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Beyond diagnosis and classification, cytogenetic abnormalities also determine the therapeutic outcome for the patients, therefore having diagnostic, prognostic, and therapeutic importance.

AML risk stratification is based on the number of cytogenetic abnormalities observed in the patients. Currently, however, there is lack of universally adopted approach for adverse risk stratification. European Leukemia Net (ELN) classifies patients in adverse genetic risk category if they have karyotypes with three or more aberrations.²UK National Cancer Research Institute Adult Leukaemia Working Group (abbreviated as MRC for Medical Research Council), however requires four or more abnormalities to qualify as adverse prognosis.³

In addition to these differences on cutoff for adverse prognosis, several other inconsistencies preclude comparison of treatments and outcomes at different institutions.^4,5

Friedrich Stölzel, MD, Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany, et al, therefore, initiated a study to define the optimized cutoff of complexity in adult AML in the context of the number of unrelated aberrations (3 vs >4) as well as to define the impact of the pure hyperdiploid karyotype (HDK) within these groups. The study results were published recently inBlood Cancer Journal.⁶

Patients for the study were selected from the databases of three prospective, randomized trials of the Study Alliance Leukemia, which had enrolled a total of 3526 non-APL, intensively treated AML patients between February 1996 and November 2009. Patients with multiple cytogenetic aberrations (>3) as well as normal karyotype (NK as a control group) were identified for this study. Chromosomal analyses were performed on bone marrow and/or peripheral blood samples using standard techniques.⁷Karyotype description was performed in accordance with the International System for Human Cytogenetic Nomenclature criteria.⁸

Accordingly, the following cytogenetic nomenclature criteria were used:

• A balanced translocation was defined as a single abnormality, because the two breaks and fusions lead to one active chimeric fusion protein.
• A balanced translocation involving more than two chromosomes was also regarded as a single abnormality.
• Trisomies or monosomies were regarded as single abnormalities.
• Gain of two chromosomes, even if they were identical was regarded as two abnormalities.
• Unbalanced translocations leading to gain and loss of chromosomal material were counted as two abnormalities.
• The monosomal karyotype (MK) was defined by the presence of two or more distinct autosomal chromosome monosomies or a single autosomal chromosome monosomy in the presence of one or more structural chromosomal abnormalities.

The treatment regimen for the studies included double induction chemotherapy administration to patients aged ⩽60 years, including a risk-adapted consolidation strategy. This included HLA-compatible, related or unrelated allogeneic hematopoietic stem cell transplantation for intermediate-risk patients with a sibling donor and adverse-risk patients with a matched donor. In the AML2003 trial, patients were randomized up-front to undergo allogeneic hematopoietic stem cell transplantation early after induction chemotherapy-induced aplasia or during first remission in defined adverse-risk situations.

Collectively, the study showed that 84% of patients had >4 aberrations while only 16% had >3 aberrations. Patients with >4 aberrations fared worse than normal karyotype (NK) patients. This was true for the distinct groups CK4 (complex aberrant patients with four unrelated abnormalities), CK4+adv (complex aberrant patients with four unrelated abnormalities of which at least one aberration was at specific adverse risk), CK4-MK (patients with four or more unrelated aberrations without MK) and CK4+MK (patients with four or more unrelated aberrations with MK).

Unique adverse-risk aberrations were unfavorable for overall survival (OS). Patients with three unrelated aberrations had a worse outcome than NK patients although the effect was less impressive than in patients with >4 aberrations. Additionally, patients with a pure hyperdiploid karyotype (HDK) had an adverse risk irrespective of the number of chromosomal gains.

Based on their study, the team has recommended the following reclassification of cytogenetic risks:

Favorable risk:

• CBF-AML
• Intermediate risk:normal karyotype, t(9;11)

Adverse risk:

• three aberrations without specific adverse-risk abnormalities, without HDK
• Very adverse risk:>4 aberrations, HDK, specific adverse-risk abnormalities, as defined by the ELN and MRC

Current absence of a consistent definition for adverse-risk complex aberrant karyotype for AML makes this an important finding that may help to stratify patients to individual optimized treatment strategies and may therefore lead to improved individual survival prognostication.

References

1. Vardiman JW, Thiele J, Arber DA. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.Blood. 2009;114: 937-51
2. Dohner 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.Blood2010;115: 453-474.
3. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH 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: 354-365.
4. Chilton L, Hills RK, Harrison CJ, Burnett AK, Grimwade D, Moorman AV. Hyperdiploidy with 49-65 chromosomes represents a heterogeneous cytogenetic subgroup of acute myeloid leukemia with differential outcome.Leukemia. 2014; 28: 321-328.
5. Luquet I, Lai JL, Barin C, Baranger L, Bilhou-Nabera C, Lippert E et al. Hyperdiploid karyotypes in acute myeloid leukemia define a novel entity: a study of 38 patients from the Groupe Francophone de Cytogenetique Hematologique (GFCH).Leukemia. 2008; 22: 132-137.
6. Stölzel F, Mohr B, Kramer M et al. Karyotype complexity and prognosis in acute myeloid leukemia.Blood Cancer Journal. 2016; 6:e386.
7. Stölzel F, Pfirrmann M, Aulitzky WE, Kaufmann M, Bodenstein H, Bornhauser M, et al. Risk stratification using a new prognostic score for patients with secondary acute myeloid leukemia: results of the prospective AML96 trial.Leukemia. 2011; 25: 420-428.
8. Shaffer LG, McGowan-Jordan J, Schmid M. An international system for human cytogenetic nomenclature (ISCN) S. Karger: Basel, 2013.