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Keywords:

  • 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).

Table 1. Baseline characteristics of patients grouped according to the MRC clinical risk score
ParameterMRC low risk n (%)MRC medium risk n (%)MRC high risk n (%)Total n (%)
  1. MRC, Medical Research Council; WCC, white cell count.

Sex
Female18 (69)78 (51)2 (7)98 (47)
Male8 (31)76 (49)25 (93)109 (53)
Age (years)
≤3013 (50)41 (27)054 (26)
31–509 (35)81 (53)7 (26)97 (47)
51–604 (15)32 (21)20 (74)56 (27)
Median31405641
WCC (x 109/l)
0–9·912 (46)72 (47)6 (22)90 (43)
10–49·910 (38)54 (35)8 (30)72 (35)
50–99·93 (12)18 (12)6 (22)27 (13)
100+1 (4)10 (6)7 (26)18 (9)
Median15124616
Cytogenetic risk
Favourable26 (100)15 (10)041 (20)
Intermediate0139 (90)24 (89)163 (79)
Adverse003 (11)3 (1)
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Figure 1. (A) Shorter overall survival (OS) for delayed (n = 9; * P = 0·0009) or no complete remission (CR, n = 56; ** P < 0·0001). (B) Frequency distribution of the MRC clinical risk scores (C) OS according to Medical Research Council (MRC) clinical scores divided into octiles (D) OS grouped into low, medium and high-risk MRC clinical score categories showing a difference between medium and high risk (*P < 0·0001) but not low and medium risk (P = 0·07). (E) Relapse-free survival (*P = 0·0049) and (F) OS (*P < 0·0001) of patients with intermediate-risk karyotype and “high” clinical risk is worse compared to intermediate risk karyotype alone.

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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.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. References
  5. Supporting Information

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.

Author contributions

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. References
  5. Supporting Information

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.

References

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. References
  5. Supporting Information
  • Bishop, J., Matthews, J., Young, G., Szer, J., Gillett, A., Joshua, D., Bradstock, K., Enno, A., Wolf, M. & Fox, R. (1996) A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood, 87, 1710.
  • Bradstock, K.F., Matthews, J.P., Lowenthal, R.M., Baxter, H., Catalano, J., Brighton, T., Gill, D., Eliadis, P., Joshua, D. & Cannell, P. (2005) A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood, 105, 481488.
  • Braess, J., Spiekermann, K., Staib, P., Grüneisen, A., Wörmann, B., Ludwig, W.-D., Serve, H., Reichle, A., Peceny, R., Oruzio, D., Schmid, C., Schiel, X., Hentrich, M., Sauerland, C., Unterhalt, M., Fiegl, M., Kern, W., Buske, C., Bohlander, S., Heinecke, A., Baurmann, H., Beelen, D.W., Berdel, W.E., Büchner, T. & Hiddemann, W. (2009) Dose-dense induction with sequential high-dose cytarabine and mitoxantone (S-HAM) and pegfilgrastim results in a high efficacy and a short duration of critical neutropenia in de novo acute myeloid leukemia: a pilot study of the AMLCG. Blood, 113, 39033910.
  • Burnett, A.K., Hills, R.K., Wheatley, K., Goldstone, A.H., Prentice, A.G. & Milligan, D. (2006) A sensitive risk score for directing treatment in younger patients with AML. Blood (ASH Annual Meeting Abstracts), 108, 18.
  • De Jonge, H.J.M., Valk, P.J.M., De Bont, E.S.J.M., Schuringa, J.J., Ossenkoppele, G., Vellenga, E. & Huls, G. (2011) Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD. Haematologica, 96, 13101317.
  • Grimwade, D., Walker, H., Oliver, F., Wheatley, K., Harrison, C., Harrison, G., Rees, J., Hann, I., Stevens, R. & Burnett, A. (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 Trial. Blood, 92, 2322.
  • How, J., Sykes, J., Gupta, V., Yee, K.W.L., Schimmer, A.D., Schuh, A.C., Minden, M.D., Kamel-Reid, S. & Brandwein, J.M. (2012) Influence of FLT3-internal tandem duplication allele burden and white blood cell count on the outcome in patients with intermediate-risk karyotype acute myeloid leukemia. Cancer, 118, 61106117.
  • Juliusson, G., Antunovic, P., Derolf, Å., Lehmann, S., Möllgård, L., Stockelberg, D., Tidefelt, U., Wahlin, A. & Höglund, M. (2009) Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood, 113, 41794187.
  • Pfirrmann, M., Ehninger, G., Thiede, C., Bornhäuser, M., Kramer, M., Röllig, C., Hasford, J. & Schaich, M. (2011) Prediction of post-remission survival in acute myeloid leukaemia: a post-hoc analysis of the AML96 trial. The Lancet Oncology, 13, 207214.
  • Ravandi, F., Cortes, J., Faderl, S., O'Brien, S., Garcia-Manero, G., Verstovsek, S., Santos, F.P.S., Shan, J., Brandt, M., de Lima, M., Pierce, S. & Kantarjian, H. (2010) Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy. Blood, 116, 58185823.

Supporting Information

  1. Top of page
  2. Acknowledgements
  3. Author contributions
  4. References
  5. Supporting Information
FilenameFormatSizeDescription
bjh12178-sup-0001-FigureS1.pdfapplication/PDF31KFigure 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.docWord document31KTable 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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