Prognostic Impact of MLL Rearrangements in AML

doi:10.1182/blood-2003-02-0434
Prepublished online June 12, 2003;
2003 102: 2395-2402
Torsten Haferlach
Claudia Schoch, Susanne Schnittger, Mirjam Klaus, Wolfgang Kern, Wolfgang Hiddemann and
cytogenetically analyzed AML cases
distribution, and prognostic impact in an unselected series of 1897
classification: incidence, partner chromosomes, FAB subtype, age
abnormalities as defined by the WHOMLLAML with 11q23/
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
AML with 11q23/MLL abnormalities as defined by the WHO classification:
incidence, partner chromosomes, FAB subtype, age distribution, and prognostic
impact in an unselected series of 1897 cytogenetically analyzedAML cases
Claudia Schoch, Susanne Schnittger, Mirjam Klaus, Wolfgang Kern, Wolfgang Hiddemann, and Torsten Haferlach
Acute myeloid leukemia (AML) cases with
11q23 abnormalities involving the MLL
gene comprise one category of recurring
genetic abnormalities in the WHO classifi-
cation. In an unselected series of 1897
AML cases, 54 patients with an 11q23/
MLL rearrangement were identified, result-
ing in an incidence of 2.8%. The incidence
of AML with MLL rearrangement was sig-
nificantly higher in therapy-related AML
(t-AML) than in de novo AML (9.4% vs
2.6%, P < .0001). The frequency of MLL
rearrangements was significantly higher
in patients younger than 60 years (5.3%
vs 0.8%, P < .0001). While the incidence
of MLL rearrangements in AML M4, M5a,
and M5b was 4.7%, 33.3%, and 15.9%,
respectively, it was found in only 0.9% of
all other French-American-British (FAB)
subtypes (P < .0001). Compared withAML
with intermediate karyotype, AML with
11q23/MLL rearrangement had a worse
outcome, which was rather comparable
with AML with unfavorable karyotype.
Compared with t-AML, the median overall
survival (OS) of de novo AML with MLL
rearrangement was significantly better
(2.5 vs 10 months, P ‫؍‬ .0143). No signifi-
cant differences in median OS were ob-
served between cases with t(9;11) com-
pared with all other MLL rearrangements
(10.0 vs 8.9 months, P ‫؍‬ .36). In conclu-
sion, the category AML with 11q23/MLL
abnormalities accounts for 2.8% of un-
selected AML, is closely associated with
monocytic differentiation, and has a dismal
prognosis. (Blood. 2003;102:2395-2402)
© 2003 by The American Society of Hematology
Introduction
Classification of acute myeloid leukemia (AML) has been based
on cytomorphology and cytochemistry since the introduction of
the French-American-British (FAB) classification in 1976.1 As
other techniques such as immunophenotyping as well as cytoge-
netics and moleculargenetics contributed to the definition of
AML subtypes, the FAB classification was updated accord-
ingly.2-5 In parallel, the MIC classification was published in
1986, which used morphology, immunophenotype, and cytoge-
netics to define subgroups in AML.6 This system already
proposed a category M5a/t(11q), although no detailed studies
are quoted to underline this decision. In 2001 the WHO
classification for tumors of hematopoietic and lymphoid tissues
was proposed.7 In an attempt to define biologic homogenous
entities that have clinical relevance, morphologic, immunophe-
notypic, genetic, and clinical features were incorporated into the
classification of AML.8 The WHO classification of AML
encompasses 4 major categories: (1) AML with recurring
genetic abnormalities, (2) AML with multilineage dysplasia,
(3) AML, therapy related, and (4) AML not otherwise catego-
rized. In the first category the following subcategories are
defined: (a) AML with t(8;21)(q22;q22); AML1/ETO, (b) AML
with abnormal bone marrow eosinophils inv(16)(p13q22) or
t(16;16)(p13;q22); CBFB/MYH11, (c) acute promyelocytic leu-
kemia (AML with t(15;17)(q22;q12); PML-RARA and variants),
and (d) AML with 11q23/MLL abnormalities. While a, b, and c
are homogenous entities on the cytogenetic as well as at the
molecular level and show close correlations with morphology,
AML with 11q23/MLL abnormalities is heterogeneous due to
the different partner chromosomes/partner genes. More than 50
partners of the MLL gene have been described and more than 30
partner genes have already been cloned and analyzed at the
molecular level.9,10 Therefore, it was the aim of this study to
characterize this subcategory of AML on the basis of a series of
1897 unselected and cytogenetically analyzed AML cases at
diagnosis with special emphasis on the overall incidence, the
different partner chromosomes, FAB subtype, age distribution,
and prognostic impact.
Patients, materials, and methods
Patient material
Between January 1996 and August 2001, cytogenetics were successfully
performed in our laboratory on 1897 patients with newly diagnosed AML
who were the basis for this study without any further selection. This cohort
represents 98.2% of all AML cases sent to our laboratory for cytogenetic
analysis. Because no or only an insufficient number of metaphases was
obtained (Ͻ 15 metaphases if no clonal chromosomal abnormalities were
detected), 1.8% were scored not evaluable. Altogether 54 cases with an
11q23 abnormality involving the MLL gene were identified. In each case the
rearrangement of the MLL gene was proved either by reverse transcription–
polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridiza-
tion (FISH) with an MLL probe.
From the Laboratory for Leukemia Diagnostics, Department of Internal
Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University,
Munich, Germany.
Submitted February 10, 2003; accepted June 5, 2003. Prepublished online as
Blood First Edition Paper, June 12, 2003; DOI 10.1182/blood-2003-02-0434.
Reprints: Claudia Schoch, Laboratory for Leukemia Diagnostics, Department
of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-
University of Munich, Marchioninistr 15, 81377 Mu¨nchen, Germany; e-mail:
claudia.schoch@med3.med.uni-muenchen.de.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2003 by The American Society of Hematology
2395BLOOD, 1 OCTOBER 2003 ⅐ VOLUME 102, NUMBER 7

Treatment
Of 92 patients, 54 (58.7%) with t-AML and 1037 (95.1%) of 1091 cases
with de novo AML were treated within the German AML Cooperative
Group (AMLCG) trials of 1992 and 1999 or the AMLCG acute promyelo-
cytic leukemia trial, while the others were treated with comparable
therapies.11,12
In detail, patients within the AMLCG 1992 trial received the following
treatment. For remission induction, patients were treated according to the
double induction strategy. The first course consisted of thioguanine, AraC,
and daunorubicin TAD. The high-dose AraC and mitoxantrone (HAM)
course was scheduled to be started on day 21 unless patients had severe
life-threatening nonhematologic toxicity in case of which chemotherapy
was postponed until resolution of toxicity. The second course of the double
induction therapy was applied to patients older than 60 years only if they
had residual leukemic blasts of 5% or more in the bone marrow on day 16.
Consolidation therapy consisted of one course of TAD, which was applied 2
to 4 weeks after achievement of complete remission. Patients younger than
60 years with HLA-identical sibling donors subsequently underwent
allogeneic bone marrow or peripheral blood stem cell transplantation. All
other patients received further treatment according to the randomization
performed at study entry. Patients were randomized upfront to 3 years of
myelosuppressive maintenance therapy or to a second course of intensive
consolidation therapy following TAD consolidation. The second course of
consolidation therapy consisted of the sequential high-dose AraC and
mitoxantrone. The dose per application of high-dose AraC was 1 g/m2 in
patients younger than 60 years and 500 mg/m2 in older patients.
Patients treated within the AMLCG 1999 trial received the identical
treatment as described for the 1992 trial with regard to induction and
postremission therapy with the following exceptions: patients were random-
ized (1) to receive TAD/HAM or HAM/HAM as double induction therapy
and (2) to undergo autologous stem cell transplantation or 3 years of
maintenance after consolidation therapy (patients Ͻ 60 years only; all
patients Ն 60 years received maintenance treatment). In addition, patients
from 25 of the 52 participating study centers were randomized to receive or
not priming with granulocyte colony-stimulating factor (G-CSF) 2 days
before and during chemotherapy.
Cytomorphology
In 1293 of the 1897 patients, cytomorphologic analysis based on FAB
criteria was carried out in parallel in the same laboratory. In total, FAB
subtypes were available in 1490 cases.
Cytogenetics
Bone marrow or peripheral blood cells were cultured in RPMI 1640
medium supplemented with 20% fetal calf serum at 37°C for 24 and 48
hours. Unstimulated as well as cytokine-stimulated cultures as described
elsewhere were performed in parallel. Standard cytogenetic preparations
were made, a modified chromosome banding technique (GAG, Giemsa
bands by acetic saline Giemsa) was used, and 15 to 30 metaphases were
analyzed and classified according to the International System for Human
Cytogenetic Nomenclature.13,14 In 91.4% of cases with normal karyotype,
between 20 to 30 metaphases were analyzed, while in the other cases at least
15 metaphases were analyzed. Cases with fewer than 15 analyzable
metaphases and no clonal chromosomal aberrations were defined as failures.
FISH
FISH on interphase nuclei and/or metaphases was performed using
commercially available probes for flanking the breakpoints within the MLL
according to the protocol of the manufacturer (VYSIS, Downers Grove,
IL). In detail, the probe labeled in SpectrumGreen covers a 350-kb portion
centromeric of the MLL gene breakpoint cluster region and the Spectrum-
Orange-labeled probe a 190-kb portion largely telomeric of the breakpoint
cluster region. The signals were viewed with a Zeiss Axioskop (Zeiss, Jena,
Germany). For documentation the analyzing system ISIS (MetaSystems,
Altlussheim, Germany) was used. For each case 100 interphase nuclei
were evaluated.
To determine the rate of false-positive interphases (cutoff level) 5 bone
marrow smears and 5 cytogenetic preparations obtained from healthy
donors or patients with non-Hodgkin lymphomas were analyzed. On each
slide, 500 interphase nuclei were scored. The cutoff level was determined as
mean plus 2 standard deviations (2.9%).
RT-PCR
Mononucleated bone marrow cells were obtained by Ficoll Hypaque
density gradient centrifugation. Total RNA was extracted from 107 cells
with RNeasy (Qiagen, Hilden, Germany) in cases diagnosed from 1997 to
2000. Since January 2001 in all cases mRNA was extracted with the
MagnaPureLC mRNA Kit I (Roche Diagnostics, Mannheim, Germany).
The cDNAsynthesis of 1 to 2 ␮g total RNAor mRNAfrom an equivalent of
107 cells was performed in a 50-␮L reaction using 300 U Superscript II
(GibcoBRL/Invitrogen, Karlsruhe, Germany) and random hexamer primers
(Pharmacia, Freiburg, Germany). MLL fusion transcripts were amplified as
described previously.15-18 For each sample an ABL-specific RT-PCR was
performed to control the integrity of DNA or RNA as described.19 Water
instead of cDNA was included as a blank sample in each experiment.
Amplification products were analyzed on 1.5% agarose gels stained with
ethidium bromide.
Strict precautions were taken to prevent contamination. Water instead of
cDNA was included as a blank sample in each experiment. Amplification
products were analyzed on 1.5% agarose gels stained with ethidium bromide.
Statistics
Overall survival (OS) was defined as time from start of therapy until death
and was calculated according to Kaplan-Meier,20 and the differences
between groups were analyzed using the log-rank statistics.21 Patients
undergoing bone marrow transplantations were not censored at bone
Figure 1. FAB subtype distribution in 54 AML with 11q23/MLL rearrangement:
43 de novo AML and 11 t-AML.
Table 1. FAB subtype distribution of AML with 11q23/MLL
rearrangement compared with the total AML cohort
Total cohort,
n (%)
MLL rearrangement,
n (%)
Total 1897 54
No data on FAB subtype 407 2
Data on FAB subtype 1490 (100) 52 (100)
M0 63 (4.2) 1 (1.9)
M1 221 (14.8) 4 (7.7)
M2 538 (36.1) 5 (9.6)
M3 75 (5.0) —
M3v 30 (2.0) —
M4 260 (17.4) 11 (21.2)
M4eo 85 (5.7) —
M5a 71 (4.8) 20 (38.5)
M5b 82 (5.5) 11 (21.2)
M6 53 (3.6) —
M7 12 (0.8) —
—indicates no care.
2396 SCHOCH et al BLOOD, 1 OCTOBER 2003 ⅐ VOLUME 102, NUMBER 7

marrow transplantation. Multivariate analysis was performed applying the
Cox model.All calculations were performed using SPSS 11.01 (Chicago, IL).
Results
Incidence of 11q23/MLL rearrangements in de novo AML versus
t-AML versus AML after an antecedent hematologic disorder
AML occurred de novo in 1632 patients (86%), after an antecedent
hematologic disorder in 148 (7.8%), and was therapy related in 117
cases (6.2%). In 54 AML cases an 11q23 rearrangement was
identified by chromosome banding analysis and an involvement of
the MLL gene was confirmed by FISH analysis and/or RT-PCR in
all cases. Therefore, the incidence was 54 (2.8%) of 1897. Of the
cases, 43 were de novo AML and 11 were t-AML. Preceding
tumors in patients with t-AML were Hodgkin disease (n ϭ 3),
breast cancer (n ϭ 2), testicular cancer (n ϭ 2), gastric cancer
(n ϭ 1), thymoma (n ϭ 1), neuroendrocrine tumor (n ϭ 1), and
non-Hodgkin lymphoma (n ϭ 1). The median latency period
between therapy for the primary tumor and diagnosis of t-AML was
24 months (range, 9-100 months). The incidence ofAML with MLL
rearrangement was significantly higher in t-AML than in de novo
AML (9.4% vs 2.6%; P Ͻ .0001). No case with 11q23/MLL
rearrangement occurred in AML after an antecedent
hematologic disorder.
Correlation with cytomorphology
FAB subtype distribution of cases with 11q23/MLL rearrangement
was M0: 1, M1: 4, M2: 4, M4: 11, M5a: 20, M5b: 11, no data: 2 and
did not differ between de novo AML and t-AML (Figure 1). In total
81% showed an involvement of the monocytic lineage. While the
incidence of MLL rearrangement in AML M4, M5a, and M5b was
4.7%, 33.3%, and 15.9%, respectively, it was found in only 0.9% of
all other FAB subtypes (P Ͻ .0001).
In Table 1 the FAB subtype distribution in the whole AML
cohort is compared with AML with an 11q23/MLL rearrangement.
Age distribution
The median age of cases with 11q23/MLL rearrangements was 48.5
years (48 years in de novo AML, 53 years in t-AML; range, 14-74
years), while in the total cohort the median age was 57.9 years
(range, 14-84 years). Thus, the incidence of MLL rearrangements
was significantly higher in patients younger than 60 years (5.3% vs
Table 3. Distribution of partner chromosomes with respect to de novo AML versus t-AML, age groups and FAB subtype
9p22 10p12 6q27 19p13 17q21 17q25 1q21 15q15 22q12 12q24 14q32 2q37 10q22 Total
Total 19 8 5 5 4 3 2 2 2 1 1 1 1 54
de novo 14 7 5 2 4 3 2 2 1 1 — 1 1 43
t-AML 5 1 — 3 — — — — 1 — 1 — — 11
Age group
14 to 19 y 2 — 1 — — — — — — — — — — 3
20 to 29 y 1 — — — — — — — — — — — — 1
30 to 39 y 5 2 1 2 3 1 — 1 — — — 1 — 16
40 to 49 y 4 2 — 3 1 1 1 — — — — — — 12
50 to 59 y 5 3 2 — — 1 1 1 1 — — — 1 15
60 to 69 y 2 1 — — — — — — — 1 1 — — 5
70 y or older — — 1 — — — — — 1 — — — — 2
FAB subtype
M0 — 1 — — — — — — — — — — — 1
M1 1 — — 1 — 1 — 1 — — — — — 4
M2 — — — 1 — — 2 1 — — 1 — — 5
M4 3 — 2 1 1 1 — — 1 — — 1 1 11
M5a 9 7 1 1 1 — — — — 1 — — — 20
M5b 5 — 2 — 2 1 — — 1 — — — — 11
No data 1 — — 1 — — — — — — — — — 2
— indicates no care.
Table 4. Number of cases analyzed by RT-PCR to confirm
the partner gene
No. analyzed
by RT-PCR Partner gene
9p22 18/19 AF9: 18
10p12 8/8 AF10: 8
6q27 5/5 AF6: 5
19p13 5/5 ENL: 2, ELL: 1, other: 2
17q21 2/4 AF17: 1, other: 1
17q25 0/3 —
1q21 1/2 AF1q21: 1
15q15 0/2 —
22q12 0/1 —
12q24 0/1 —
14q32 0/1 —
2q37 0/1 —
10q22 0/1
—indicates no care.
Table 2. Age distribution of AML with 11q23/MLL rearrangement
compared with the total AML cohort
Age, y
MLL
rearrangement,
n (%)
Without MLL
rearrangement,
n (%)
Total cohort,
n (%)
14 to 19 3 (5.6) 28 (1.5) 31 (1.6)
20 to 29 1 (1.9) 107 (5.8) 108 (5.7)
30 to 39 16 (29.6) 152 (8.3) 168 (8.9)
40 to 49 12 (22.2) 232 (12.6) 244 (12.9)
50 to 59 15 (27.8) 325 (17.6) 340 (17.9)
60 to 69 5 (9.3) 575 (31.2) 580 (30.6)
70 to 79 2 (3.7) 379 (20.6) 381 (20.1)
80 or older 0 (0) 45 (2.4) 45 (2.4)
Total 54 (100) 1843 (100) 1897 (100)
11q23/MLL REARRANGEMENTS IN AML 2397BLOOD, 1 OCTOBER 2003 ⅐ VOLUME 102, NUMBER 7

0.8%, P Ͻ .0001). The age distribution inAMLwith MLL rearrange-
ment compared with the total cohort of AML is shown in Table 2.
Partner chromosomes
The partner chromosomes of the MLL gene in the 54 cases were
9p22 (n ϭ 19; 35.2%), 10p12 (n ϭ 8; 14.8%), 6q27 (n ϭ 5; 9.3%),
19p13 (n ϭ 5; 9.3%), 17q21 (n ϭ 4; 7.4%), 17q25 (n ϭ 3; 5.6%),
1q21 (n ϭ 2; 3.7%), 15q15 (n ϭ 2; 3.7%), 22q12 (n ϭ 2; 3.7%),
and 2q37, 10q22, 12q24, and 14q32 in one case each (1.9%). In
Table 3 the different partner chromosomes are shown for de novo
AML and t-AML as well as the distribution with respect to age and
FAB subtype. No specific association was observed between
partner chromosomes and de novo versus t-AML or age or FAB
subtype. Table 4 provides information on the respective fusion
genes as assessed by RT-PCR. FISH was carried out with whole
chromosome painting probes for chromosomes 11 and the respec-
tive partner chromosome in those cases without an amplifiable
fusion gene to prove the partner chromosome.
Additional chromosomal aberrations
In 22 cases additional chromosome abnormalities were observed.
More than 2 additional abnormalities were found in 8 cases (in 3
cases only gains of whole chromosomes, in 5 cases numeric and
structural abnormalities). Karyotypes of the 22 cases with abnor-
malities in addition to the translocation involving the MLL gene are
shown in Table 5. Recurring additional abnormalities were ϩ8
(n ϭ 10), ϩ6 (n ϭ 3), ϩ20 (n ϭ 3), Ϫ7 (n ϭ 3), and del(3)(q21)
(n ϭ 2). Showing additional chromosomal aberrations were 1 (9%)
of 11 t-AML and 21 (48.9%) of 43 de novo AML.
Clinical outcome
For 51 of 54 patients with MLL rearrangement and for 1132 of 1843
AML cases without an MLL rearrangement, clinical follow-up data
were available. Median follow-up time was 16 months (range, 1 to
75 months). Patients with clinical follow-up data were younger and
more frequently had favorable karyotype characteristics compared
with cases without available clinical follow-up data (Table 6).
There were 2 cases with t(9;11) and 5 patients with other
11q23/MLL rearrangements who underwent an allogeneic stem
cell/bone marrow transplantation (6 in first complete remission, 1
case with a t(1;11) in second complete remission).
AML without MLL rearrangement were grouped according to
karyotype into 4 categories: (1) AML with t(15;17), (2) AML with
t(8;21) or inv(16)/t(16;16), (3) AML with intermediate karyotype
Table 5. Additional chromosomal aberrations in 22 of 54 patients with MLL rearrangement
Patient
no.
Age,
y FAB Karyotype
1 14 ND 46,XX,t(9;11)(p22;q23) [1]/47,idem,ϩ8, [11]/46,XX [3]
2 31 M5a 47,XY,ϩ8,t(9;11)(p22;q23) [21]
3 56 M5b 46,XX,t(9;11)(p22;q23) [16]/47,idem,ϩ8 [3]/46,XX [1]
49 M5b 47,XY,ϩ8,t(9;11)(p22;q23) [18]/46,XY [2]
5 14 ND 59,XY,ϩY,ϩ1,ϩ3,ϩ6,ϩ7,ϩ8,t(9;11)(p22;q23),ϩ10,ϩ16,ϩ18,ϩ20,ϩ21,ϩmar [17]/46,XY [3]
6 57 M5a 46,XX,der(9)t(9;11)(p22;q23)t(9;11)(p22;p13),der(11)t(9;11)(p22;q23)t(9;11)(p22;p13) [20]
7* 57 M5a 49,XX,ϩ8,Ϫ9,t(9;11)(p22;q23),ϩder(9)t(9;11)(p22;q23),ϩ13,inv(17)(p13q24),der(17)inv(17)(p13q24)
del(17)(p12p13),ϩ20 [20]
8 42 M5a 45,XY,del(8)(p11),t(9;11)(p22;q23),dic(16;17)(p11;p13),der(19)t(8;19)(q11;p13),der(22)t(8;22)(q11;p10)
[20]
9 32 M5a 46,XX,del(1)(p32),der(1)t(1;15)(q21;q15),der(10)t(10;11)(p13;q23)t(1;11)(p32;q24),der(11)t(11;16)
(q11;p11)del(11)(p15),der(15)t(10;15)(p13;q15),der(16)t(11;16)(q11;p11)t(1;11)(q21;q23) [14]/46,XX [1]
10 46 M5a 46,XY,t(10;11)(p13;q23) [5]/47,idem,ϩder(1;13)(p11;p10)del(13)(q12) [20]
11 55 M5a 46,XY,der(10)t(10;11)(p11;q23),der(11)t(10;11)(p1?1;q11),der(11)t(10;11)(p11;q23)t(10;11)(p1?1;q11)
[4]/46,XY [3]
12 18 M5b 46,XY,t(6;11)(q27;q23) [2]/50,idem,ϩ4,ϩder(6)t(6;11)(q27;q23),ϩ8,ϩ19 [10]/46,XY [8]
13 49 M2 47,XX,ϩ8,t(11;19)(q23;p13) [12]/46,XX [8]
14 49 M5a 46,XX,t(11;19)(q23;p13.3),add(21)(q22) [25]
15 38 M4 46,XY,t(11;17)(q23;q21) [10]/47,idem,ϩ8 [8]/46,XY [2]
16 46 M5b 45,XY,Ϫ7,t(11;17)(q23;q21) [22]/46,XY [1]
17 63 M1 45,XY,Ϫ7,t(11;17)(q23;q25) [19]/46,XY [3]
18 50 M5b 47,XX,t(11;17)(q23;q25),ϩ20 [18]/51,idem,ϩ5,ϩ6,ϩ19,ϩ20,ϩ21 [4]/46,XX [3]
19 35 M1 48,XX,del(3)(q21),ϩ6,t(11;15)(q23;q15),ϩ21 [18]
20 54 M2 46,XX,del(3)(q21),t(11;15)(q23;q15) [14]/47,idem,ϩder(15)t(11;15)(q23;q15) [5]/46,XX [1]
21 74 M4 46,XX,t(11;22)(q23;q12) [11]/45,idem,Ϫ7[3]/47,idem,ϩ8 [2]/46,XX [4]
22 62 M5a 46,XX,t(1;10)(q44;p11.2),t(11;12)(q23;q24),der(12)t(12;15)(q22;q15),der(15)t(12;15)(q22;q15)t(11;12)
(q23;q24)
ND indicates no data.
*t-AML; all other de novo AML.
Table 6. Median age and cytogenetics of patients with clinical follow-up data compared with cases without available clinical follow-up
Clinical
follow-up data n Age, y, median
Cytogenetics, n (%)
t(15;17) t(8;21), inv(16) Intermediate Unfavorable 11q23/MLL
Yes 1183 57.9 88 (7.4) 178 (15.0) 652 (55.2) 214 (18.1) 51 (4.3)
No 714 63.7 17 (2.4) 16 (2.2) 465 (65.1) 213 (29.8) 3 (0.4)
Total 1897 61.0 105 (5.5) 194 (10.2) 1117 (58.8) 427 (22.5) 54 (2.8)

(normal cytogenetics, other abnormalities than t(15;17), t(8;21),
inv(16)/t(16;16), or abnormalities defined as unfavorable), and
(4) AML with unfavorable karyotype (5qϪ/5, 7qϪ/Ϫ7, inv(3)/t(3;
3), 12pϪ, 17p abnormalities, and complex aberrant karyotypes [3
or more chromosomal aberrations]).
The median overall survival was 8.9 months in the group with
MLL rearrangement compared with 40.6 months in cases with
t(8;21) or inv(16)/t(16;16), 13.7 months in the intermediate group
and 5.7 months in the unfavorable group, respectively, the median
was not reached in AML with t(15;17) (P Ͻ .001, Figure 2). The
data for de novo AML only (n ϭ 1090) were as follows: median
overall survival not reached in cases with t(8;21) or inv(16)/t(16;
16), and in cases with t(15;17), 13.8 months in the intermediate
group, 5.7 months in the unfavorable group, and 10.0 months in the
group with11q23/MLL rearrangement (P Ͻ .001).
Univariate Cox regression analyses in the cohort of patients
with intermediate karyotypes or with 11q23/MLL rearrangements
using age, white blood cell count, 11q23/MLL rearrangements (vs
intermediate karyotype), and t-AML versus de novo AML as
covariates resulted in significant correlations of all tested parame-
ters with overall survival (Table 7). A multivariate analysis
confirmed the prognostic impact of all these parameters (Table 8).
In univariate Cox regression analyses of overall survival in the
cohort of patients with unfavorable karyotypes or with 11q23/MLL
rearrangements using age, white blood cell count, 11q23/MLL
rearrangements (vs unfavorable karyotype), and t-AML (vs de
novo AML) as covariates, only age and t-AML were significantly
correlated with overall survival (P Ͻ .001 and P ϭ .032). This was
confirmed in a multivariate analysis (P Ͻ .001 and P ϭ .031,
respectively).
Further evaluations were performed within the cohort of AML
with 11q23/MLL rearrangements. In univariate Cox regression
analysis for overall survival using age, white blood cell count,
t(9;11) (vs other 11q23/MLL rearrangements), additional abnormali-
ties (vs no additional abnormalities), and t-AML (vs de novo AML)
as covariates, only t-AML was significantly correlated with overall
survival (P ϭ .01). If only de novo AML cases were analyzed all
other parameters were also not significant. The median overall
survival of AML de novo with MLL rearrangement was 10 months
compared with 2.5 months in t-AML with MLL rearrangement
(P ϭ .0143, Figure 3). The median overall survival was 10.0
months in cases with t(9;11) compared with 8.9 months in AML
with other MLL rearrangements in the whole group (P ϭ .36,
Figure 4). Median age was 47 years (range, 18-67 years) in AML
with t(9;11) and 46 years (range, 18-65 years) in AML with other
MLL rearrangements. The median white blood cell count was
27 450/␮L (range, 250-220 000/␮L) in t(9;11) cases and 24 550/
␮L (range, 740-270 000/␮L) in cases with other MLL rearrange-
ments. In de novo AML the median overall survival was 10.6
versus 12.8 months (P ϭ .67). The median overall survival was
11.3 months in cases with MLL rearrangement as the sole
abnormality compared with 5.3 months in AML MLL rearrange-
ments and additional chromosomal aberrations (P ϭ .90, Figure 5).
Discussion
The MLL gene is fused to a large variety of more than 50 different
partner genes in acute myeloid leukemia.10 In childhood as well as
in adult leukemia t(9;11) is the most frequent translocation
involving the MLL gene and accounts for about one third of cases
with MLL rearrangement.22,23 In t-AML an even higher proportion
of 9p22 as translocation partner (48%) has been reported.24
Rearrangements involving AF10 on the short arm of chromosome
10 are observed in 15% to 20% in de novo AML with MLL
rearrangement but were reported only in 1% of t-AML in a large
series.24 All other partner genes are found with lower frequencies.
Partner genes in 19p seem to be more frequently involved in
t-AML than in de novo AML.24 In our large series of 54 AML cases
with proven MLL rearrangement, 13 different partner genes
were observed.
Clonal chromosomal aberrations in addition to the 11q23
rearrangement were observed in 41% of our total cohort and in
48.8% of de novo AML. This frequency is comparable with data
reported in other adult and childhood series.22,23,25 The most
frequently reported additional aberration is trisomy 8.22,26
With regard to cytomorphology, our data confirm the correla-
tion of 11q23/MLL rearrangements with AML of the monocytic
lineage; however, also single cases with AML M0, M1, and M2
were detected. A correlation between the partner chromosomes and
FAB subtypes was not observed in our series.
Based on their recent evaluation on the prognostic impact of
cytogenetics, the Cancer and Leukemia Group B (CALGB)
assigned cases with t(9;11) to the intermediate group, while cases
with other balanced 11q23 abnormalities were grouped as unfavor-
able.27 Evaluation of 2 other large trials from the Medical Research
Figure 2. Overall survival of 1183 AML cases according to cytogenetics.
Table 7. Results of univariate Cox regression analyses in the cohort of patients with intermediate karyotypes
or patients with 11q23/MLL rearrangements
Age WBC MLL vs intermediate
t-AML vs
de novo AML
P Ͻ .001 .011 .006 .006
Hazard ratio 1.02 per year 1.02 per 10 000 WBC/␮L 1.65 1.84
95% CI 1.014-1.028 per year 1.004-1.03 per 10 000 WBC/␮L 1.16-2.35 1.19-2.84
WBC indicates white blood cell count.

Council in younger and in elderly patients revealed that patients
with 11q23 abnormalities showed an intermediate outcome with an
overall survival rate of 45% at 5 years (n ϭ 60; median age, 17
years) in the younger cohort and an overall survival rate of 0% at 5
years (n ϭ 11; median age, 64 years) in the cohort of elderly
cases.28,29 In contrast, in a combined analysis of Southwest
Oncology Group and Eastern Cooperative Oncology Group trials
including adult patients (age, 16-55 years) 11q abnormalities were
assigned to the unfavorable cytogenetic subgroup.30 Our data show
that de novoAML patients with 11q23/MLL rearrangements show a
worse outcome compared with the intermediate group. Their
prognosis is rather comparable with the unfavorable group.
We found that the median overall survival of patients with
t(9;11) was not signiﬁcantly different from patients with other MLL
rearrangements both in de novo and in t-AML. This is in contrast to
data from the CALGB indicating a median overall survival of 13.2
months in 23 cases of t(9;11) compared with 7.7 months in 24 cases
with other 11q23 rearrangements (P ϭ .009).25 In a recent update
of this series of AML from CALGB including 54 cases with
balanced 11q23 rearrangements, 27 cases with t(9;11) showed a
median overall survival of 13 months compared with 7.2 and 8.4
months for cases with other partner genes of 11q23. Based on these
differences, t(9;11) cases were assigned to the intermediate group
and the other 11q23 rearrangements to the unfavorable cytogenetic
group.27 In our cohort of de novo AML, 14 cases with t(9;11) had a
median overall survival of 10.0 months compared with 12.8
months of 26 patients with other MLL rearrangements. Thus, there
is no indication for a better outcome of AML with t(9;11) compared
with AML with other MLL rearrangements. Supporting the validity
of the present analyses with regard to prognostic impact of 11q23
abnormalities in all cases the MLL rearrangement was proved by
FISH or RT-PCR. This may be crucial, particularly in cases with
MLL-AF10 rearrangements, which often are complex on the
cytogenetic level and not distinguishable in certain cases from
CALM-AF10 rearrangements on the cytogenetic level.31,32 In
addition, the description of balanced translocations involving
11q23 but not the MLL gene33 and the reported differences in
clinical outcome between cases with MLL rearrangement and other
11q23 abnormalities34 further underline the need for molecular
analyses when evaluating the group of AML with 11q23/MLL
rearrangements.
In a collaborative analysis of 108 patients with AML and
t(9;11), prognosis was related to age with children 1 to 14 years old
showing a more favorable outcome than infants and adults 15 to 49
years of age; the poorest outcome was observed in patients 50 years
and older.22 With respect to age the CALGB cohort does not differ
from our cohort (median age in cases with t(9;11) 44 years and in
cases with other 11q23 translocations 39 years compared with 47
and 46 years, respectively). Rubnitz et al compared the outcome of
t(9;11)-positive cases versus other 11q23/MLL rearrangements in
childhood AML. They observed a more favorable outcome in cases
with t(9;11) than in patients with other 11q23/MLL rearrangements
(event-free survival at 5 years 65% [n ϭ 23] vs 24% [n ϭ 33]).23
But also in childhood AML results vary. In a large trial of the
Pediatric Oncology Group no differences in outcome were ob-
served between cases with t(9;11) and cases with other 11q23/MLL
rearrangement. Both groups showed a quite poor outcome.35 The
differences observed so far within the different published trials
with respect to the prognostic impact of t(9;11) versus other 11q23
translocations might be due to the still small number of patients or
the impact of different therapy protocols. The impact of allogeneic
bone marrow or stem cell transplantation on prognosis of cases
with 11q23/MLL rearrangement has to be further evaluated as it
has been reported that in younger patients those with an HLA-
identical donor had a better outcome compared with those without
a donor, especially in patients with unfavorable cytogenetics.36
Whether the reported differences in outcome between cases with
Figure 3. Overall survival of 40 de novo AML with 11q23/MLL rearrangement
compared with 11 t-AML with MLL rearrangement.
Figure 4. Overall survival of 19 AML with t(9;11) compared with 32 AML with
other 11q23/MLL rearrangements.
Table 8. Results of multivariate Cox regression analyses in the cohort of patients with intermediate karyotypes
or patients with 11q23/MLL rearrangements
Age WBC
MLL vs
intermediate
t-AML vs
de novo AML
P Ͻ .001 .001 Ͻ .001 .016
Hazard ratio 1.03 per year 1.02 per 10 000 WBC/␮L 2.12 1.73
95% CI 1.02-1.04 per year 1.008-1.03 per 10 000 WBC/␮L 1.45-3.08 1.11-2.69

t(9;11) versus other 11q23/MLL rearrangements reflect differences
in the frequency of allogeneic transplantation in the respective
trials remains unclear as the number of reported patients who
received an allograft is low in most series.
In our series a significant difference in outcome was demon-
strated in AML with 11q23/MLL rearrangement between de novo
and therapy-related cases. Karyotype abnormalities in addition to
the 11q23/MLL rearrangement had no influence on prognosis. This
confirms the data of Byrd et al who showed a comparable outcome
in cases with t(9;11) with and without additional aberrations.27 In
t-AML no differences in overall survival according to partner genes
were reported, but patients with additional karyotype abnormalities
showed a worse outcome.24
From a morphologic and a cytogenetic point of view, AML
cases with 11q23/MLL translocations are more heterogeneous than
AML with t(8;21), AML with t(15;17), and AML with inv(16)/t(16;
16). Furthermore, MLL rearrangements also occur in acute lympho-
blastic leukemia (ALL). Therefore, it can be speculated that they do
not comprise a biologic entity. However, it has been shown in AML
as well as inALL that cases with MLL rearrangements have specific
gene expression profiles that allow the distinction from other ALL
subtypes as well as from other AML subtypes.37,38 The ALL-MLL
group included cases with at least 5 different translocation partners,
while in the analysis of AML the 15 cases with 11q23/MLL
translocation included rearrangements with 7 different partner
genes.39,40 Therefore, it seems appropriate to regard AML with
11q23/MLL rearrangement as an entity as suggested by WHO as
long as no clear data are available that give evidence for major
differences in biology. This is in line with the distinct clinical
outcome that has been demonstrated in the present analysis.
In addition to rearrangements with a large variety of different
partner genes MLL rearrangements can be found within MLL as the
result from partial tandem duplication (MLL-PTD) usually span-
ning exons 3 through 9 or exons 3 through 11, which are also
mentioned in the WHO classification. Translocations of the MLL
gene and MLL-PTD seem to be mutually exclusive as they do not
occur together.41 In contrast to AML with translocations involving
MLL, AML cases with MLL-PTD usually are not associated with a
typical morphology.41-44 Clinical outcome in this AML subgroup is
also unfavorable.42,43,45 Similar to translocations of 11q23 involv-
ing the MLL gene, the MLL-PTD occurs significantly more
frequently in AML secondary to a previous cytotoxic therapy. In a
study analyzing AML with normal karyotype with MLL-PTD
(n ϭ 10) and AML with MLL translocations (n ϭ 15) using gene
expression analysis, differentially expressed genes were identified,
which allowed a clear distinction between both AML subtypes.46
Therefore, both groups have to be regarded as 2 different entities.
In conclusion, the present data suggest that AML with 11q23/
MLL rearrangement and different partner genes seem to comprise a
biologically and clinically homogeneous entity despite a large
variety of different partner genes of MLL. In the majority of cases
the monocytic lineage is involved. Overall survival is dismal and
comparable with AML with unfavorable karyotype. No influence
of the presence of t(9;11) or additional chromosomal abnormalities
on outcome were observed inAML with 11q23/MLL rearrangement.
Acknowledgments
We thank all participants of the AMLCG study group for sending
bone marrow and/or blood for cytogenetics and for clinical data,
especially Thomas Bu¨chner (coordinator of the trial) and Maria
Cristina Sauerland and Achim Heinecke (statisticians).
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