The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial

Abstract

Cytogenetics is considered one of the most valuable prognostic determinants in acute myeloid leukemia (AML). However, many studies on which this assertion is based were limited by relatively small sample sizes or varying treatment approach, leading to conflicting data regarding the prognostic implications of specific cytogenetic abnormalities. The Medical Research Council (MRC) AML 10 trial, which included children and adults up to 55 years of age, not only affords the opportunity to determine the independent prognostic significance of pretreatment cytogenetics in the context of large patient groups receiving comparable therapy, but also to address their impact on the outcome of subsequent transplantation procedures performed in first complete remission (CR). On the basis of response to induction treatment, relapse risk, and overall survival, three prognostic groups could be defined by cytogenetic abnormalities detected at presentation in comparison with the outcome of patients with normal karyotype. AML associated with t(8;21), t(15;17) or inv(16) predicted a relatively favorable outcome. Whereas in patients lacking these favorable changes, the presence of a complex karyotype, −5, del(5q), −7, or abnormalities of 3q defined a group with relatively poor prognosis. The remaining group of patients including those with 11q23 abnormalities, +8, +21, +22, del(9q), del(7q) or other miscellaneous structural or numerical defects not encompassed by the favorable or adverse risk groups were found to have an intermediate prognosis. The presence of additional cytogenetic abnormalities did not modify the outcome of patients with favorable cytogenetics. Subgroup analysis demonstrated that the three cytogenetically defined prognostic groups retained their predictive value in the context of secondary as well as de novo AML, within the pediatric age group and furthermore were found to be a key determinant of outcome from autologous or allogeneic bone marrow transplantation (BMT) in first CR. This study highlights the importance of diagnostic cytogenetics as an independent prognostic factor in AML, providing the framework for a stratified treatment approach of this disease, which has been adopted in the current MRC AML 12 trial.

Prognostic significance of quantitative analysis of WT1 gene transcripts by competitive reverse transcription polymerase chain reaction in acute leukaemia

“…AML 10/12 protocols included remission induction with daunorubicin, cytarabine and 6-thioguanine (DAT 3 + 10) followed by consolidation with DAT 3 + 8, amsacrine, cytarabine and etoposide (MACE), and mitoxantrone and cytarabine (MiDAC). Patients aged < 50 years either had an allogeneic stem cell transplant if they had a matched sibling donor or an autograft, except for patients with good risk cytogenetics (Grimwade et al, 1998).…”

“…Acute myeloid leukaemia. Patients were classified according to their karyotypic abnormalities (Grimwade et al, 1998).…”

Identification of acute myeloid leukemia patients with diminished expression of CD13 myeloid transcripts by competitive reverse transcription polymerase chain reaction (RT-PCR)

“…The division into CD13 low and CD13 high was made to enable a judgement of possible correlations between transcript levels and other parameters. The two groups were very similar regarding myeloid maturation of their cells as judged by immunophenotyping of CD14, HLA-DR and CD33, just as their chromosome abnormalities, a known very important prognostic factor [20], were comparable.…”

“…Ten microlitres of PCR product was loaded on an ethidiumbromide stained 2.5% agarose gel and electrophoretically separated before intensity of luminescence of target and HIS bands were measured by a chargedcoupled device (CCD) camera (BioRad, CA, USA). et al [20]. Patients with t(8;21), t (15;17), or inv (16) were classified as belonging to the favourable group.…”

“…At the time of diagnosis a chromosome study was carried out in 33/40 patients. The karyotypes were grouped into the three prognostic groups defined by Grimwade et al [20]. (See Section 2).…”