Role of Karyotype Assessment

Karyotype analysis should be considered a mandatory component of the workup for all patients with AML, since it provides important diagnostic and prognostic information. Approximately 60% of cases of AML are characterized by a clonal abnormality, and indeed, according to the new WHO classification, detection of t(15;17), t(8;21), inv(16)/t(16;16), and MLL gene rearrangement can form the basis of a diagnosis of AML in cases found to have less than 20% blasts in the bone marrow.15 Cytogenetic analysis is also of value in identifying patients who are candidates for molecularly targeted treatment approaches. In

Figure 30-2. Prognostic impact of diagnostic karyotype in children and younger adults entered into UK Medical Research Council AML10 trial. Patients with t(8;21), t(15;17), and inv(16) were found to have a superior overall survival and are assigned to the favorable risk group in the MRC classification system. Patients (lacking one of the above abnormalities) with complex karyotype (defined as five or more unrelated abnormalities) or presence of -5/del(5q), -7, or 3q abnormalities in the context of a noncomplex karyotype were found to have a very poor outcome and comprise the MRC adverse risk group. Patients with normal karyotype or other structural or numerical abnormalities (other intermediate) comprise the MRC standard risk group. (Figure prepared by Georgina Harrison, Clinical Trials Service Unit, Oxford, UK. Reprinted from Grimwade D. The clinical significance of cytogenetic abnormalities in acute myeloid leukaemia. Baillieres Best Pract Res Clin Haematol. 2001;14:497-529; copyright 2001, with permission from Elsevier.)

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particular, presence of the t(15;17), which generates the PML-RARA fusion in APL, predicts a favorable response to ATRA and arsenic trioxide, while detection of the rare, in AML,t(9;22)(q34;q11), which leads to the BCR-ABL fusion, identifies a group of patients with dismal prognosis when treated with conventional chemotherapy, who could potentially derive some benefit from imatinib.

Karyotype is the most important independent predictor of outcome identified to date for patients with AML. Analysis of large cohorts of patients receiving comparable treatment approaches has permitted the determination of the prognostic impact of the most common recurring cytogenetic abnormalities in AML (see Figure 30-2). Patients with t(15;17), t(8;21), and inv(16)/t(16;16), which lead to PML-RARA, AML1-ETO, and CBFB-MYH11 gene fusions, respectively, have a relatively favorable outcome; whereas monosomies of chromosome 5 or 7, del(5q), 3q abnormal ities, and t(9;22) are associated with an adverse prognosis. Consideration of the outcome of cases with more than one cytogenetic abnormality, in which the karyotype includes features that in their own right would confer favorable or adverse risk, respectively (see Figure 30-3), has led to the definition of hierarchical risk groups (see Table 30-6). The distribution of the cytogenetic risk groups varies substantially according to age. A greater proportion of younger patients have favorable risk abnormalities, while older patients are more likely to have AML with chromosome 5 and 7 abnormalities, often in the context of a complex karyotype, accounting for the expansion of the adverse risk group in the age group of individuals 55 years and older (see Figure 30-4). Cytogenetic classification of AML has proved to be of immense clinical value and is used to determine treatment approach in a number of clinical trials. It is now apparent that routine use of autologous or

Figure 30-3. Prognostic impact of additional cytogenetic abnormalities in children and younger adults entered into UK Medical Research Council AML10 and AML12 trials. Additional cytogenetic abnormalities from either intermediate or adverse risk categories did not confer a deleterious effect on outcome among patients with favorable kary-otypic features. In the remaining patients, presence of adverse karyotypic features was associated with a poorer prognosis in comparison to patients with intermediate risk abnormalities alone (provided that these did not number more than four unrelated abnormalities, i.e., a very complex karyotype, which is associated with a poor prognosis). Favorable, intermediate, and adverse risk groups are as defined in Table 30-6. (Figure prepared by Georgina Harrison, Clinical Trials Service Unit, Oxford, UK. Reprinted from Grimwade D. The clinical significance of cytogenetic abnormalities in acute myeloid leukaemia. Baillieres Best Pract Res Clin Haematol. 2001;14:514; copyright 2001, with permission from Elsevier.)

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Table 30-6. Definition of Risk Groups According to Diagnostic Karyotype, Based on the Classification System Adopted by the UK Medical Research Council Group

Cytogenetic Risk Group

Karyotype

Comments

inv(16)/t(16;16)

Whether alone or in conjunction with other abnormalities (including complex karyotype)

Other abnormalities (not classified as favorable or adverse)

Cases lacking favorable or adverse cytogenetic features

Adverse

abn(3q)

Complex (>5 unrelated abnormalities)

Whether alone or in conjunction with intermediate-risk or other adverse-risk abnormalities

allogeneic bone marrow transplantation (BMT) in first CR has little to offer those patients with favorable cytoge-netics, with any benefit in terms of reduced relapse risk being more than offset by treatment-related mortality and morbidity. Conversely, patients with adverse karyotypic features fare extremely poorly with conventional therapy and if no suitable allogeneic donor is available could be considered candidates for more experimental treatment approaches as part of first-line therapy.

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