Prognostic Significance and Risk Stratification in Acute Myeloid Leukaemia Patients in the Absence of Successful Cytogenetic Analysis

Cytogenetic analysis is a key tool in risk stratification of patients with acute myeloid leukaemia (AML).  Sometimes samples are not sent or metaphase analysis fails (~10% cases).  In these situations, a cytogenetic risk score cannot be assigned, preventing risk stratification.  It has been suggested that in the absence of cytogenetic data, both missing and failed, patients have a poor outcome (Mederios et al (Br. J. Haematol. 2014 164(2): 245-50); Lazarevic et al (Eur. J. Haematol. 2015 94(5): 419-23)).  In this study, we investigated the characteristics and prognostic significance of the provision of samples, and their successful analysis across the MRC UK series of AML trials (AML10 - AML16).

Data from 14265 non-APL patients recruited to successive UK AML trials (1988 - 2012) were analysed.  Patients were classified based on whether a sample was sent for cytogenetic analysis and the outcome of the analysis.  Rates of successful cytogenetic analysis were higher in patients treated on intensive chemotherapy protocols (intensive: 11104/13081 (85%); non-intensive 850/1184 (72%), p<.0001).  In intensively treated patients, there was a significant association between increasing age and missing or failed cytogenetic samples (p<.0001).  Stratification of intensively treated patients with successful cytogenetics, according to the criteria of Grimwade et al (Blood 2010 116(3):354-65), into favourable (18%), intermediate (62%) and adverse risk (19%) were analysed for outcomes and showed 10 year survival of 66%, 30% and 12%, respectively.  Survival at 10 years was 24% when no sample was sent compared to 32% when a sample failed cytogenetic analysis.  Survival for patients with failed cytogenetics was not significantly different from those with intermediate risk cytogenetics in either univariate analysis (p=0.10) or after adjustment for age, performance status, white cell count and secondary disease (p=0.06). Outcomes were significantly better than those for adverse risk patients (p<.0001 for both analyses). For those with no sample, survival was significantly worse than for the intermediate risk (p<.0001 in both analyses), although the effect size was not large (HR 1.18 in adjusted analyses), yet significantly better than adverse risk patients (p<.0001, HR 0.57).  While outcomes worsened with increasing age, a similar pattern was seen across all age groups (favourable/intermediate/adverse/no sample/failed: age<16 81%/57%/49%/63%/62%; age 16-59 67%/36%/13%/30%/41%; age 60+ 32%/12%/2%/8%/9%).

In the most recent trial, AML17 (2009-14) of younger patients, 97% had successful cytogenetic analysis, compared to 86% in AML10-15. Here too, there was no suggestion of poor outcomes for those patients with no cytogenetic result.  These results indicate that cytogenetic analysis is possible in the vast majority of younger patients, and suggest that absence of cytogenetic information is not in itself an adverse prognostic factor.  This poor prognosis identified in other studies may be due to selection bias in the decision to send samples.  The experience of AML17 demonstrates that, when cytogenetic analysis is required to guide treatment decisions, if results can be provided in real time, high levels of compliance can be achieved, not only in sending, but also in the quality of samples.