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Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom 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 on behalf of the National Cancer Research Institute Adult Leukaemia Working Group

Data supplements

Article Figures & Data

Figures

  • Figure 1

    Impact of cytogenetic entities recognized in 2008 WHO classification24 on survival. *Excluding patients with t(15;17), t(8;21), inv(16), t(9;11), t(6;9), inv(3)/t(3;3). **Excluding patients with any other abnormalities listed previously.

  • Figure 2

    Impact of karyotype complexity on survival in patients lacking cytogenetic abnormalities that confer relatively favorable or adverse prognoses in multivariable analysis.

  • Figure 3

    Outcome of patients according to original and refined MRC cytogenetic classification. The patients previously assigned to the “adverse-risk” group and reclassified as “intermediate-risk” all had t(3;5)(q21∼25;q31∼35).

Tables

  • Table 1

    Frequency and demographics of chromosomal abnormalities

    Chromosome involvedDescription of abnormalityPatients, no. (%)*Median age, y (range)PSecondary disease (% of those with abnormality)P
    Normal karyotype2432 (41)46 (16-59)135 (6)
    1Abnormality of 1p86 (2)43.5 (16-59).916 (19)< .001
    t(1;22)(p13;q13)1 (< 0.5)370
    Abnormality of 1q84 (1)48 (16-59).0912 (14).03
    3Monosomy 339 (1)51 (22-59).0029 (23).002
    Abnormality of 3q
    inv(3)(q21q26)/t(3;3)(q21;q26)69 (1)43 (18-59).711 (17).02
    t(3;5)(q21∼25;q31∼35)26 (< .5)30.5 (16-58).0053 (12).4
    Other abnormality of 3q108 (2)46.5 (18-59).0316 (15).008
    4Trisomy 470 (1)43 (18-59).75 (7)> .999
    5Abnormality of 5q
    Monosomy 5129 (2)51 (18-59)< .00124 (19)< .001
    del(5q)146 (2)51 (16-59)< .00128 (19)< .001
    add(5q)60 (1)45.5 (18-59).49 (15).04
    6Trisomy 665 (1)49 (16-59).0310 (15).03
    t(6;9)(p23;q34)42 (1)44 (19-59).52 (5).8
    Abnormality of 6q, not t(6;11)79 (1)44 (16-59).99 (11).19
    7Monosomy 7279 (5)47 (16-59)< .00154 (19)< .001
    Abnormality of 7q
    del(7q)145 (2)49 (16-59)< .00128 (19)< .001
    add(7q)68 (1)47 (16-59).029 (13).1
    Abnormality of 7p81 (1)42 (16-59).517 (21)< .001
    8Trisomy 8547 (10)44 (16-59).757 (10).008
    t(8;21)(q22;q22) and variants421 (7)40 (16-59)< .00113 (3)< .001
    Abnormality of 8p11∼1223 (< .5)32 (16-58).052 (9).7
    9Monosomy 925 (< .5)47 (17-57).43 (12).4
    t(9;22)(q34;q11) and variants47 (1)43 (22-58).71 (2).3
    Deletion of 9q, including add(9q)133 (2)45 (16-59).710 (8).9
    11Trisomy 1181 (1)51 (16-59)< .0017 (9).7
    All 11q23
    t(9;11)(p21∼22;q23)61 (1)38 (16-58)< .0016 (10).5
    t(10;11)(p11∼14;q13∼23)34 (1)33.5 (16-59)< .0010.18
    t(6;11)(q27;q23)24 (< .5)33 (17-57).0011 (4)> .999
    t(11;19)(q23;p13)30 (1)35.5 (16-57).014 (13).3
    Other 11q2362 (1)38.5 (17-59).0087 (11).2
    Abnormality of 11q (not 11q23)117 (2)43 (16-59).99 (8).9
    Abnormality of 11p13∼1537 (1)40 (16-57).147 (19).007
    12Abnormality of 12p
    Monosomy 1257 (1)52 (18-59)< .00111 (19).003
    Other abnormality of 12p1350 (1)46 (16-58).44 (8).8
    Other abnormality of 12p, not 12p1393 (2)45 (17-59).419 (20)< .001
    13Trisomy 1393 (2)50 (16-59)< .00112 (13).07
    Abnormality of 13q
    Monosomy 1373 (1)49 (16-59).0114 (19)< .001
    Deletion of 13q27 (< .5)42 (20-59).172 (7)> .999
    15t(15;17)(q22;q21) and variants788 (13)39 (16-59)< .00124 (3)< .001
    Abnormality of 15q, not t(15;17)40 (1)42.5 (19-58).43 (8)1.0
    16inv(16)(p13q22)/t(16;16)(p13;q22)284 (5)38 (16-59)< .00112 (4).04
    Abnormality of 16q, not inv(16)91 (2)43 (16-59).812 (13).04
    17Monosomy 17121 (2)51 (16-59)< .00115 (12).05
    Abnormality of 17p145 (2)46 (16-59).0320 (14).006
    18Monosomy 1897 (2)49 (18-59)< .00120 (21)< .001
    19Trisomy 1958 (1)41 (16-59).154 (7)> .999
    20Monosomy 2053 (1)49 (16-59).00410 (19).005
    Abnormality of 20q48 (1)49 (20-59).044 (8).8
    21Trisomy 21 (acquired)148 (3)46 (17-59).1321 (14).004
    Abnormality of 21q, not t(8;21)74 (1)49 (16-59).00415 (20)< .001
    22Trisomy 22113 (2)42 (18-59).910 (9).6
    XLoss of X109 (2)41 (16-59).169 (8).7
    YLoss of Y200 (3)42 (16-59).410 (5).2
    Other139 (2)46 (16-59).0514 (10).2
    Level of karyotype complexity
        1 abnormality1830 (31)42 (16-59)131 (7)
        2 abnormalities786 (13)40 (16-59)70 (9)
        3 abnormalities275 (5)41 (17-59)17 (6)
        4 abnormalities123 (2)42 (16-59)14 (11)
        5 or more abnormalities430 (7)49 (16-59)68 (16)
        P for trend.09< .001
    • Cases were categorized according to presence of the cytogenetic entities previously defined in a large cohort of pediatric AML patients treated in the MRC AML trials.21 According to this scheme, abnormal karyotypes with more than 1 abnormality were classified into several relevant groups. AML indicates acute myeloid leukemia; and MRC, Medical Research Council.

    • * As percentage of cases with a successful cytogenetic result.

    • Other karyotypes, not classified into any listed group.

  • Table 2

    Impact of cytogenetic abnormalities compared with normal karyotype on disease outcome

    Chromosome involvedDescription of abnormalityCR*OSCIR
    Rate, %Unadjusted OR (99% CI), PAdjusted OR (99% CI), P10-y OS, %Unadjusted HR (99% CI), PAdjusted HR (99% CI), P§10-y CIRUnadjusted HR (99% CI), PAdjusted HR (99% CI), P§
    Normal karyotype903849
    1Abnormality of 1p684.13 (2.21-7.71), < .0015.51 (2.81-10.80), < .001202.58 (1.64-4.05), < .0012.20 (1.57-3.08), < .001581.64 (0.93-2.91), .031.62 (1.01-2.60), .008
    Abnormality of 1q635.19 (2.82-9.55), < .0015.78 (3.02-11.07), < .001212.26 (1.45-3.54), < .0011.88 (1.33-2.65), < .001551.26 (0.72-2.19), .31.30 (0.78-2.15), .19
    3Monosomy 34610.16 (4.36-23.65), < .00112.11 (5.02-29.19), < .001324.46 (10.01-59.76), < .0014.20 (2.68-6.58), < .0018275.92 (17.15-336.0), < .0015.17 (2.68-9.96), < .001
    Abnormality of 3q
    inv(3)(q21q26)/t(3;3)(q21;q26)3615.33 (7.86-29.88), < .00119.80 (9.79-40.07), < .001313.22 (7.14-24.48), < .0014.07 (2.89-5.72), < .0018914.41 (4.64-44.74), < .0014.04 (2.22-7.36), < .001
    t(3;5)(q21∼25;q31∼35)960.36 (0.03-5.06), .30.44 (0.03-6.51), .4341.38 (0.66-2.90), .31.41 (0.72-2.77), .18521.46 (0.61-3.50), .31.53 (0.72-3.25), .14
    Other abnormality of 3q596.08 (3.56-10.38), < .0016.98 (3.97-12.25), < .00111.35.20 (3.32-8.14), < .0012.77 (2.08-3.68), < .001715.21 (2.70-10.05), < .0012.71 (1.79-4.09), < .001
    4Trisomy 4871.31 (0.51-3.33), .51.55 (0.57-4.24), .3161.15 (0.74-1.80), .41.23 (0.80-1.88), .2541.09 (0.64-1.83), .71.13 (0.68-1.87), .5
    5Abnormality of 5q
    Monosomy 5576.56 (4.02-10.72), < .0017.58 (4.49-12.80), < .001020.31 (12.70-32.47), < .0014.33 (3.35-5.61), < .0017516.98 (8.42-34.23), < .0013.80 (2.59-5.57), < .001
    del(5q)586.22 (3.90-9.93), < .0017.28 (4.40-12.06), < .001125.14 (3.47-7.62), < .0012.90 (2.23-3.76), < .001643.02 (1.75-5.19), < .0012.19 (1.47-3.27), < .001
    add(5q)537.62 (3.83-15.17), < .00110.38 (4.96-21.72), < .0011010.49 (5.34-20.60), < .0013.58 (2.42-5.30), < .001646.05 (2.25-16.28), < .0012.84 (1.53-5.26), < .001
    6Trisomy 6782.44 (1.10-5.41), .0042.52 (1.11-5.73), .003212.34 (1.40-3.92), < .0011.88 (1.28-2.76), < .001622.12 (1.12-4.01), .0051.75 (1.08-2.85), .003
    t(6;9)(p23;q34)881.18 (0.34-4.06), .71.65 (0.47-5.82), .3271.47 (0.77-2.81), .141.55 (0.88-2.74), .04621.70 (0.76-3.79), .101.61 (0.82-3.16), .06
    Abnormality of 6q, not t(6;11)635.05 (2.70-9.44), < .0016.15 (3.16-11.96), < .001212.52 (1.58-4.02), < .0012.09 (1.47-2.96), < .001531.32 (0.73-2.38), .21.33 (0.78-2.26), .17
    7Monosomy 7586.37 (4.46-9.11), < .0017.63 (5.18-11.24), < .00185.57 (4.20-7.38), < .0013.03 (2.50-3.67), < .001704.38 (2.92-6.55), < .0012.60 (1.98-3.42), < .001
    Abnormality of 7q
    del(7q)772.64 (1.54-4.52), < .0012.76 (1.56-4.89), < .001261.66 (1.20-2.31), < .0011.51 (1.14-1.98), < .001571.32 (0.88-1.98), .081.26 (0.87-1.81), .11
    add(7q)684.17 (2.09-8.30), < .0015.08 (2.43-10.61), < .001302.25 (1.34-3.79), < .0011.97 (1.33-2.94), < .001330.96 (0.50-1.85), .91.01 (0.52-1.98), 1.0
    Abnormality of 7p654.69 (2.50-8.79), < .0016.06 (3.09-11.92), < .001222.18 (1.39-3.43), < .0011.97 (1.39-2.80), < .001611.30 (0.75-2.25), .21.31 (0.79-2.17), .17
    8Trisomy 8802.20 (1.58-3.07), < .0012.64 (1.85-3.77), < .001371.21 (1.01-1.44), .0061.32 (1.12-1.57), < .001460.99 (0.80-1.23), .91.08 (0.87-1.35), .3
    t(8;21)(q22;q22) and variants970.26 (0.12-0.56), < .0010.36 (0.16-0.81), < .00161.58 (0.49-0.70), < .0010.60 (0.47-0.75), < .001270.54 (0.44-0.67), < .0010.51 (0.39-0.68), < .001
    Abnormality of 8p11∼12910.83 (0.12-5.62), 0.81.32 (0.19-9.26), .7500.91 (0.43-1.92), .81.22 (0.56-2.68), .5491.08 (0.46-2.53), .81.31 (0.57-2.98), .4
    9Monosomy 9684.10 (1.34-12.53), .0015.01 (1.57-15.99), < .00184.04 (1.69-9.67), < .0012.55 (1.42-4.57), < .001633.00 (0.92-9.78), .032.13 (0.89-5.06), .02
    t(9;22)(q34;q11) and variants723.43 (1.45-8.12), < .0012.80 (1.08-7.27), .004142.83 (1.53-5.23), < .0011.91 (1.22-3.00), < .001653.95 (1.59-9.83), < .0012.32 (1.27-4.23), < .001
    Deletion of 9q, including add(9q)861.39 (0.71-2.73), .21.82 (0.90-3.68), .03470.80 (0.58-1.09), .050.83 (0.58-1.19), .19350.66 (0.46-0.94), .0010.60 (0.38-0.96), .005
    11Trisomy 11752.86 (1.44-5.67), < .0013.25 (1.57-6.71), < .001132.26 (1.44-3.55), < .0011.84 (1.30-2.61), < .001712.71 (1.52-4.84), < .0012.01 (1.31-3.08), < .001
    All 11q23
    t(9;11)(p21∼22;q23)841.71 (0.69-4.23), .132.13 (0.82-5.51), .03391.24 (0.75-2.04), .31.36 (0.86-2.17), .08441.00 (0.56-1.79), 1.01.04 (0.57-1.89), .9
    t(10;11)(p11∼14;q13∼23)851.50 (0.43-5.29), .42.58 (0.70-9.53), .05123.57 (1.71-7.45), < .0013.29 (1.99-5.45), < .001714.94 (1.95-12.55), < .0013.39 (1.87-6.15), < .001
    t(6;11)(q27;q23)960.40 (0.03-5.54), .40.63 (0.04-9.04), .692.80 (1.23-6.38), .0042.56 (1.42-4.61), < .001765.10 (1.79-14.52), < .0012.97 (1.53-5.74), < .001
    t(11;19)(q23;p13)970.30 (0.02-4.15), .20.45 (0.03-6.36), .4490.89 (0.46-1.71), .71.11 (0.55-2.22), .7441.03 (0.48-2.19), .91.21 (0.57-2.56), .5
    Other 11q23753.03 (1.41-6.53), < .0013.87 (1.70-8.82), < .001212.55 (1.52-4.27), < .0012.07 (1.41-3.04), < .001652.40 (1.26-4.59), .0021.84 (1.12-3.03), .001
    Abnormality of 11q (not 11q23)693.92 (2.27-6.76), < .0014.86 (2.72-8.68), < .001202.33 (1.59-3.42), < .0012.13 (1.59-2.86), < .001622.02 (1.23-3.32), < .0011.90 (1.28-2.82), < .001
    Abnormality of 11p13∼15733.23 (1.23-8.50), .0024.58 (1.66-12.64), < .001261.61 (0.86-3.01), .061.48 (0.87-2.52), .06531.08 (0.51-2.27), .81.02 (0.48-2.15), 1.0
    12Abnormality of 12p
    Monosomy 12596.07 (2.95-12.48), < .0016.54 (3.05-14.00), < .001611.79 (5.98-23.28), < .0013.67 (2.51-5.37), < .0018421.17 (7.65-58.60), < .0014.48 (2.65-7.58), < .001
    Other abnormality of 12p13635.06 (2.31-11.06), < .0016.00 (2.62-13.73), < .001144.18 (2.21-7.90), < .0012.58 (1.69-3.92), < .001481.44 (0.64-3.22), .31.31 (0.64-2.69), .3
    Other abnormality of 12p, not 12p13576.57 (3.73-11.58), < .0018.45 (4.57-15.62), < .001174.12 (2.56-6.65), < .0012.75 (1.98-3.82), < .001531.78 (0.94-3.37), .031.61 (0.93-2.80), .02
    13Trisomy 13703.75 (2.05-6.89), < .0013.62 (1.90-6.90), < .00192.54 (1.64-3.93), < .0011.86 (1.34-2.57), < .001721.82 (1.05-3.14), .0091.56 (1.00-2.42), .008
    Abnormality of 13q
    Monosomy 13605.87 (3.09-11.16), < .0017.07 (3.57-14.02), < .00189.02 (5.06-16.07), < .0013.48 (2.48-4.88), < .001675.88 (2.65-13.06), < .0012.90 (1.76-4.75), < .001
    Deletion of 13q851.51 (0.37-6.18), .42.10 (0.49-9.02), .18311.25 (0.64-2.46), .41.46 (0.78-2.75), .12611.45 (0.65-3.26), .21.61 (0.80-3.24), .07
    15t(15;17)(q22;q21) and variants930.67 (0.43-1.04), .021.11 (0.69-1.76), .6810.40 (0.34-0.47), < .0010.30 (0.23-0.39), < .001130.34 (0.29-0.41), < .0010.19 (0.13-0.27), < .001
    Abnormality of 15q, not t(15;17)782.53 (0.94-6.81), .023.36 (1.15-9.83), .002460.96 (0.53-1.72), .91.10 (0.60-2.03), .7450.91 (0.44-1.85), .81.07 (0.50-2.25), .8
    16inv(16)(p13q22)/t(16;16)(p13;q22)920.81 (0.46-1.44), .30.88 (0.48-1.62), .6550.66 (0.53-0.82), < .0010.64 (0.49-0.84), < .001460.86 (0.67-1.10), .100.85 (0.65-1.12), .12
    Abnormality of 16q, not inv(16)782.45 (1.25-4.82), < .0012.85 (1.41-5.79), < .001311.66 (1.10-2.51), .0031.60 (1.13-2.26), < .001581.44 (0.87-2.40), .071.36 (0.87-2.13), .08
    17Monosomy 17566.76 (4.07-11.21), < .0018.20 (4.78-14.09), < .001315.22 (9.37-24.72), < .0013.96 (3.02-5.19), < .0018013.68 (6.68-28.01), < .0013.62 (2.43-5.41), < .001
    Abnormality of 17p684.08 (2.47-6.73), < .0014.91 (2.86-8.41), < .001252.50 (1.75-3.59), < .0012.11 (1.60-2.78), < .001561.84 (1.16-2.92), .0021.75 (1.20-2.56), < .001
    18Monosomy 18615.46 (3.10-9.63), < .0016.04 (3.29-11.06), < .001412.40 (7.28-21.11), < .0013.57 (2.64-4.84), < .0017815.76 (7.21-34.42), < .0013.61 (2.35-5.56), < .001
    19Trisomy 19812.04 (0.85-4.91), .042.28 (0.91-5.70), .02123.11 (1.81-5.34), < .0012.35 (1.61-3.42), < .001743.97 (2.00-7.86), < .0012.54 (1.62-3.99), < .001
    20Monosomy 20674.35 (1.99-9.54), < .0014.96 (2.19-11.21), < .00166.65 (3.43-12.89), < .0012.98 (1.99-4.45), < .001888.77 (3.68-20.89), < .0013.10 (1.88-5.14), < .001
    Abnormality of 20q664.49 (2.00-10.12), < .0014.93 (2.05-11.86), < .001163.59 (1.86-6.94), < .0012.59 (1.65-4.06), < .001713.81 (1.54-9.42), .0012.62 (1.44-4.77), < .001
    21Trisomy 21 (acquired)743.01 (1.79-5.07), < .0013.36 (1.92-5.88), < .001211.88 (1.35-2.62), < .0011.69 (1.28-2.21), < .001661.94 (1.28-2.96), < .0011.69 (1.20-2.37), < .001
    Abnormality of 21q, not t(8;21)713.59 (1.80-7.15), < .0014.10 (1.98-8.50), < .001172.37 (1.44-3.88), < .0011.93 (1.34-2.80), < .001611.89 (0.99-3.57), .021.66 (1.00-2.75), .009
    22Trisomy 22841.67 (0.84-3.31), .052.04 (1.00-4.14), .009470.85 (0.61-1.19), .20.90 (0.63-1.30), .5420.81 (0.55-1.20), .160.81 (0.52-1.26), .2
    XLoss of X871.28 (0.60-2.74), .41.89 (0.86-4.15), .03560.70 (0.51-0.97), .0030.75 (0.50-1.12), .06230.54 (0.37-0.78), < .0010.44 (0.24-0.79), < .001
    YLoss of Y891.08 (0.59-1.99), .71.47 (0.79-2.74), .11510.75 (0.58-0.96), .0020.79 (0.59-1.06), .04330.65 (0.48-0.86), < .0010.62 (0.42-0.90), < .001
    Level of karyotype complexity
        1 abnormality87per abnormality: OR 1.37 (1.30-1.46), < .001per abnormality: OR 1.42 (1.33-1.51), < .00147per abnormality HR 1.17 (1.13-1.20), < .001per abnormality: HR 1.19 (1.15-1.22), < .00142per abnormality: HR 1.09 (1.04-1.13), < .001per abnormality HR 1.11 (1.06-1.16), < .001
        2 abnormalities854540
        3 abnormalities834835
        4 abnormalities743051
        5 or more abnormalities621069
    • All odds ratios/hazard ratios are given compared with normal karyotype. CI indicates confidence interval; CIR, cumulative incidence of relapse; CR, complete remission; HR, hazard ratio; OR, odds ratio; and OS, overall survival.

    • * Remission rates include CR with incomplete count recovery (CRi).

    • Method of analysis was logistic regression.

    • Method of analysis was log-rank test except for complexity (Cox regression).

    • § Method of analysis was Cox regression.

  • Table 3

    Cytogenetic entities predicting significantly poorer overall survival in multivariable analysis

    FactorHR99% CIP to enter model
    Individual abnormalities
        Age, per year1.0181.013-1.023
        WBC, per unit increase1.0031.002-1.003
        Secondary disease1.541.31-1.82
        Performance status1.151.09-1.21
        −51.821.34-2.48< .001
        del(5q)/add(5q)1.731.37-2.19< .001
        inv(3)2.521.76-3.62< .001
        abn(3q)1.851.38-2.48< .001
        −71.511.22-1.88< .001
        t(10;11)2.621.59-4.29< .001
        +81.331.12-1.57< .001
        abn(17p)1.631.21-2.20< .001
        −171.581.15-2.17< .001
        t(6;11)2.251.26-4.03< .001
        add(7q)/del(7q)1.341.05-1.72.003
        t(11q23)*1.551.06-2.28.003
        t(9;22)1.641.04-2.56.004
    Additional effect of complexity in above model
        > 3 abnormalities1.581.29-1.93< .001
    • CI indicates confidence interval; HR, hazard ratio; and WBC, white blood cell.

    • * Excluding t(9;11)(p21∼22;q23) and t(11;19)(q23;p13).

  • Table 4

    Revised MRC prognostic classification based on multivariable analyses

    Cytogenetic abnormalityComments
    Favorable
        t(15;17)(q22;q21)
        t(8;21)(q22;q22)Irrespective of additional cytogenetic abnormalities*
        inv(16)(p13q22)/t(16;16)(p13;q22)
    Intermediate
        Entities not classified as favorable or adverse
    Adverse
        abn(3q) [excluding t(3;5)(q21∼25;q31∼35)],
        inv(3)(q21q26)/t(3;3)(q21;q26),
        add(5q), del(5q), −5,
        −7, add(7q)/del(7q),Excluding cases with favorable karyotype
        t(6;11)(q27;q23),
        t(10;11)(p11∼13;q23),
        t(11q23) [excluding t(9;11)(p21∼22;q23) and t(11;19)(q23;p13)]
        t(9;22)(q34;q11),
        −17/abn(17p),
        Complex (≥ 4 unrelated abnormalities)
    • * All favorable-risk abnormalities.

    • All adverse-risk abnormalities.