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Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities amongst 5,876 younger adult patients treated in the UK Medical Research Council trials

David Grimwade, Robert K. Hills, Anthony V. Moorman, Helen Walker, Stephen Chatters, Anthony H. Goldstone, Keith Wheatley, Christine J. Harrison and Alan K. Burnett

Abstract

Diagnostic karyotype provides the framework for risk-stratification schemes in acute myeloid leukemia (AML); however, the prognostic significance of many rare recurring cytogenetic abnormalities remains uncertain. We studied outcome of 5,876 patients (16-59 years), classified into 54 cytogenetic subgroups, treated in the Medical Research Council trials. In multivariable analysis, t(15;17)(q22;q21), t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22) were the only abnormalities found to predict a relatively favorable prognosis (p<10-12). In patients with t(15;17) treated with extended ATRA and anthracycline-based chemotherapy, additional cytogenetic changes did not impact on prognosis. Similarly, additional abnormalities did not have a significant adverse effect in t(8;21) AML. Whereas in patients with inv(16), presence of additional changes, particularly +22, predicted a better outcome (p=0.004). In multivariable analyses, various abnormalities predicted a significantly poorer outcome, namely: abn(3q) [excluding t(3;5)(q25;q34)], inv(3)(q21q26)/t(3;3)(q21;q26), add(5q)/del(5q), -5, -7, add(7q)/del(7q), t(6;11)(q27;q23), t(10;11)(p11~13;q23), other t(11q23) [excluding t(9;11)(p21~22;q23) and t(11;19)(q23;p13)], t(9;22)(q34;q11), -17 and abn(17p). Patients lacking the aforementioned favorable or adverse aberrations, but with four or more unrelated abnormalities also exhibited a significantly poorer prognosis (designated "complex" karyotype group). These data allow more reliable prediction of outcome for patients with rarer abnormalities and may facilitate development of consensus in reporting of karyotypic information in clinical trials involving younger adults with AML. This study was registered at www.isrctn.org as ISRCTN55678797 and ISRCTN17161961.

  • Submitted November 24, 2009.
  • Accepted March 31, 2010.