MRC, Medical Research Council; WCC, white cell count.
Utility of a clinical risk score to identify high-risk patients with de novo acute myeloid leukaemia in first remission after high-dose cytarabine (HiDAC) based induction chemotherapy
Article first published online: 24 DEC 2012
© 2012 Blackwell Publishing Ltd
British Journal of Haematology
Volume 160, Issue 6, pages 861–863, March 2013
How to Cite
Ling, V., Burnett, A. K., Bradstock, K., Seymour, J. F., Hills, R. K. and Wei, A. (2013), Utility of a clinical risk score to identify high-risk patients with de novo acute myeloid leukaemia in first remission after high-dose cytarabine (HiDAC) based induction chemotherapy. British Journal of Haematology, 160: 861–863. doi: 10.1111/bjh.12178
- Issue published online: 4 MAR 2013
- Article first published online: 24 DEC 2012
- AML ;
- cytogenetics of leukaemia;
- prognostic factors
Induction chemotherapy combining anthracyclines and cytarabine has been the cornerstone of therapy for acute myeloid leukaemia (AML) for almost four decades. Several groups, including the Australasian Leukaemia and Lymphoma Group (ALLG), have incorporated high-dose cytarabine (HiDAC) into the initial induction regimen, resulting in very high rates (~80%) of first cycle complete remission (CR) and improved progression-free survival outcomes (Bishop et al, 1996; Bradstock et al, 2005; Braess et al, 2009; Ravandi et al, 2010).
Decisions regarding postremission strategies in adult AML rely heavily on cytogenetic and molecular risk factors. Recently, two posttreatment clinical risk scores have been proposed to stratify outcome in patients achieving CR after induction chemotherapy. The Study Alliance Leukaemia (SAL) score includes in its calculation the FLT3-internal tandem duplication (ITD) allelic ratio and the percentage of CD34 + blasts (Pfirrmann et al, 2011). The United Kingdom Medical Research Council (MRC) score is almost entirely clinically-based, and has been applied to adults under 60 years of age in CR after 1–2 cycles of standard-dose cytarabine (SDAC)-based induction chemotherapy: [0·01325*age (in years) + 0·16994*sex (1 = male, 0 = female) + 0·22131*diagnosis (1 = de novo, 2 = secondary) + 0·65082*cytogenetics (1 = favourable, 2 = intermediate, 3 = adverse) + 0·19529*status post cycle 1 (1 = complete remission, 2 = partial remission, 3 = no remission) + 0·00169* white cell count (WCC) at presentation (x 109/l)](Burnett et al, 2006).
We wished to validate the clinical utility of the MRC score using an independent AML cooperative group study cohort. In the ALLG AML M7 study, HiDAC-based induction chemotherapy was delivered as the initial treatment cycle to 292 patients with de novo AML aged 15–60 years (Bradstock et al, 2005). Details of the ALLG AML M7 study have been previously published (Bradstock et al, 2005). In brief, induction therapy was with “ICE”, comprising Idarubicin (9 mg/m2 on days 1, 2 and 3); high-dose Cytarabine (3 g/m2 12-hourly on days 1, 3, 5, and 7); and Etoposide (75 mg/m2 daily on days 1 to 7 inclusive). Cytogenetic stratification was based on the MRC method as previously described (Grimwade et al, 1998). Patients refractory to HiDAC induction (n = 56), or who only achieved CR after a second induction cycle (n = 9), had dismal survival outcomes (Fig. 1A), consistent with previously published reports (Ravandi et al, 2010). We therefore restricted our analysis to 207 patients in CR after one cycle of HiDAC-based induction chemotherapy and with evaluable cytogenetic data. Of the included patients, 41 patients (20%) had core-binding factor AML and 163 patients (79%) had intermediate-risk karyotype, whereas only 3 patients (1%) had an adverse-risk profile (Table 1). Overall survival (OS) was significantly different for each cytogenetic risk group; median OS was not reached, 5·7 years and 1·2 years for favourable, intermediate and adverse-risk groups, respectively (P = 0·0006) (data not shown).
|Parameter||MRC low risk n (%)||MRC medium risk n (%)||MRC high risk n (%)||Total n (%)|
|Female||18 (69)||78 (51)||2 (7)||98 (47)|
|Male||8 (31)||76 (49)||25 (93)||109 (53)|
|≤30||13 (50)||41 (27)||0||54 (26)|
|31–50||9 (35)||81 (53)||7 (26)||97 (47)|
|51–60||4 (15)||32 (21)||20 (74)||56 (27)|
|WCC (x 109/l)|
|0–9·9||12 (46)||72 (47)||6 (22)||90 (43)|
|10–49·9||10 (38)||54 (35)||8 (30)||72 (35)|
|50–99·9||3 (12)||18 (12)||6 (22)||27 (13)|
|100+||1 (4)||10 (6)||7 (26)||18 (9)|
|Favourable||26 (100)||15 (10)||0||41 (20)|
|Intermediate||0||139 (90)||24 (89)||163 (79)|
|Adverse||0||0||3 (11)||3 (1)|
The MRC risk score applied to our study subset resulted in scores ranging between 1·24 and 3·27 (Fig. 1B). MRC scores were ranked in ascending order and divided into octiles. From this, three risk groups emerged (Fig. 1C). Twenty-six patients (13%) with an MRC score ≤1·84 formed a “low-risk” group (5-year OS of 82%, median OS not reached). One hundred and fifty-four patients (74%) formed a “medium-risk” group (MRC score 1·85–2·62) with a 5-year OS of 60% and median survival approaching 5·7 years. The remaining 27 (13%) patients formed a “high-risk” group (MRC score ≥2·63) with a median OS of only 12 months (P < 0·0001) (Fig. 1D). The patient characteristics and relapse-free survival (RFS) of these three MRC risk groups are summarized in Table 1 and Supplementary Fig. 1. There were 24 patients with intermediate-risk karyotype re-classified as “high-risk” by the MRC clinical score (Supplementary Table I). These patients had RFS (Fig. 1E) and OS (Fig. 1F) outcomes similar to patients with adverse risk karyotype.
Patients with a high MRC risk score were older, presented with a higher baseline WCC and were more commonly male (Table 1). Increasing age (55 + years) is known to have a negative impact on OS, even when restricted to patients with a good performance score (Juliusson et al, 2009). Hyperleucocytosis is associated with poor OS, especially in patients with FLT3-ITD (De Jonge et al, 2011; How et al, 2012). Males with AML have OS rates consistently 6–8% lower than females across all age groups according to the Surveillance, Epidemiology and End Results 9 database for the period 1988–2008 (http://seer.cancer.gov/faststats/selections.php?series = age). The cause for poorer OS in males is not known and not solely related to the increased incidence of AML, especially among elderly men (Juliusson et al, 2009).
For adults with de novo AML receiving HiDAC-based induction, this study demonstrates the value of the MRC clinical score in identifying approximately 12% of patients with intermediate cytogenetic risk but a high clinical risk and poor outcome (Fig. 1E,F). The MRC clinical risk score originally applied to patients treated with SDAC-based induction also “moved” a similar proportion of patients from standard cytogenetic AML risk to the new “high-risk” clinical category (Burnett et al, 2006). The individual components of the score are readily determined by most treating units, making derivation of the MRC score simple and widely feasible. In conclusion, this study demonstrates the utility of the MRC clinical score as a useful postremission predictor of outcome after HiDAC-based induction therapy for patients with de-novo AML.
We acknowledge funding support from the Leukaemia Foundation of Australia, NHMRC and the Victorian Cancer Agency. We also acknowledge the Australasian Leukaemia and Lymphoma Group, trial investigators and data coordinators.
VL performed the research, analysed the data and wrote the paper, AKB and RKH provided essential tools for the study, KB analysed the data and wrote the paper, JFS analysed the data and wrote the paper and AW performed and designed the research, analysed the data and wrote the paper.
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|bjh12178-sup-0001-FigureS1.pdf||application/PDF||31K||Figure S1. Kaplan-Meier estimates of relapse free survival of patients grouped into low, medium and high-risk categories according to MRC scores.|
|bjh12178-sup-0002-TableS1.doc||Word document||31K||Table SI. Characteristics of patients shifting from favourable risk karyotype to medium risk by clinical score and intermediate risk karyotype to high risk based on the MRC risk score.|
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