From bloodjournal.hematologylibrary.org by guest on March 6, 2014. For personal use only.

2006 107: 880-884

Prepublished online August 25, 2005;
doi:10.1182/blood-2005-06-2450

Adult acute megakaryocytic leukemia: an analysis of 37 patients treated

at M.D. Anderson Cancer Center
Yasuhiro Oki, Hagop M. Kantarjian, Xian Zhou, Jorge Cortes, Stefan Faderl, Srdan Verstovsek,
Susan O'Brien, Charles Koller, Miloslav Beran, B. Nebiyou Bekele, Sherry Pierce, Deborah Thomas,
Farhad Ravandi, William G. Wierda, Francis Giles, Alessandra Ferrajoli, Elias Jabbour, Michael J.
Keating, Carlos E. Bueso-Ramos, Elihu Estey and Guillermo Garcia-Manero

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CLINICAL TRIALS AND OBSERVATIONS

Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at

M.D. Anderson Cancer Center
Yasuhiro Oki, Hagop M. Kantarjian, Xian Zhou, Jorge Cortes, Stefan Faderl, Srdan Verstovsek, Susan OBrien, Charles Koller,
Miloslav Beran, B. Nebiyou Bekele, Sherry Pierce, Deborah Thomas, Farhad Ravandi, William G. Wierda, Francis Giles,
Alessandra Ferrajoli, Elias Jabbour, Michael J. Keating, Carlos E. Bueso-Ramos, Elihu Estey, and Guillermo Garcia-Manero

To characterize acute megakaryocytic leu-
kemia (FAB M7 AML), we identified 37
patients with M7 AML treated at M.D.
Anderson Cancer Center between 1987
and 2003 and compared them with 1800
patients with non-M7, non-M3 AML treated
during the same period. The median age
of the M7 AML group was 56 years (range,
21-78 years); 22 patients (59%) had an
antecedent hematologic disorder or my-
elodysplastic syndrome or both, and 7
patients (19%) had previously received
chemotherapy for other malignancies. Ex-
tensive bone marrow fibrosis was found
in 23 patients (62%). Poor cytogenetic
characteristics were observed in 49% of
patients with M7 AML versus 33% of oth-
ers (P < .001). Complete remission rates
were 43% with M7 AML and 57% with
non-M7 AML (P .089). Median overall
survival (OS) was 23 and 38 weeks, re-
spectively (P .006). Median disease-
free survivals were 23 versus 52 weeks,
respectively (P < .001). By multivariate
analysis, M7 AML was an independent
adverse prognostic factor for OS, inde-
pendent of other factors including cytoge-
netic abnormalities (hazard ratio 1.51,
P .049). These results confirm the poor
prognosis of M7 AML and indicate that
other biologic characteristics beyond cy-
togenetic abnormalities likely play a role
in this disease. (Blood. 2006;107:880-884)
2006 by The American Society of Hematology

Introduction
Acute megakaryocytic leukemia was first described as a subtype of
acute myelogenous leukemia (AML) in 19311 and was incorporated into
the French-American-British (FAB) classification of AML as M7 in
1985.2 Bone marrow characteristics include proliferation of abnormal
megakaryoblasts identified by the presence of platelet-specific surface
glycoprotein and frequently extensive myelofibrosis.
M7 AML is a common form of childhood AML, occurring in
7% to 10% of cases3 and is associated with poor prognosis. Patients
with Down syndrome appear to have an increased incidence of M7
AML but have a more favorable prognosis compared to patients
without Down syndrome.3 In contrast, M7 AML is rare in adults,
occurring in about 1% of all AML cases.4,5 Because of its low
incidence, the reported clinical experience with this type of adult
leukemia is limited.
Herein, we summarize our experience with M7 AML at M.D.
Anderson Cancer Center (MDACC) between 1987 and 2003. The
purpose is to describe the clinical and biologic characteristics of patients
with M7 AML, to compare them to patients with other forms of AML,
and to assess the impact of this pathologic finding on prognosis.
Patients, materials, and methods
Study group
patients, according to the institutional guidelines and the Declaration
of Helsinki.
AML was diagnosed by the presence of at least 30% blasts in the bone
marrow.6 In patients with poor-quality marrow aspiration smears, the presence of
clusters of blasts in the marrow core biopsy or 5% or more circulating blasts were
used to support the diagnosis of AML. Diagnosis of M7 AML was established by
the FAB criteria2; blast cells needed to be identified as being of megakaryocyte
lineage by positive immunocytochemistry stain for platelet-specific antigens
including factor VIII, CD41, and CD61.
Laboratory data
Bone marrow cytogenetic characteristics were classified into 3 prognostic groups
(modified from previous reports7-9): poor (5, 7, 8, or 11q involvement);
favorable (t(8;21), inv(16), t(16,16)); and other (neither poor or favorable).
Treatment
Patients received several different induction regimens depending on time
period, age, performance status, and availability of clinical trials. Induction
regimens were categorized into 5 groups. Regimens containing cytarabine
(ara-C) and anthracyclines were group 1. Regimens containing ara-C and
fludarabine but not containing anthracyclines were group 2. Regimens
containing topotecan were group 3. Regimens containing ara-C and not
containing anthracyclines, fludarabine, or topotecan were group 4. Regi-
mens not containing ara-C were group 5.

Patients with newly diagnosed M7 AML at MDACC between 1987 and

Criteria for response and definition of disease-free survival
2003 were analyzed. Patients with newly diagnosed other AMLs, excluding
acute promyelocytic leukemia (APL), referred during the same period of Complete remission (CR) was defined by the presence of less than 5% blasts in
time were used as a control group. Informed consent was obtained from all the bone marrow, absence of extramedullary leukemia, and peripheral blood

From the Departments of Leukemia, Biostatistics and Applied Mathematics,
and Hematopathology, University of Texas M.D. Anderson Cancer Center,
Houston, TX.
Submitted June 21, 2005; accepted July 22, 2005. Prepublished online as
Blood First Edition Paper, August 25, 2005; DOI 10.1182/blood-2005-06-2450.
Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX
77030; e-mail: ggarciam@mdanderson.org.
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.

Reprints: Guillermo Garcia-Manero, Department of Leukemia, University of 2006 by The American Society of Hematology

880 BLOOD, 1 FEBRUARY 2006 VOLUME 107, NUMBER 3

 From bloodjournal.hematologylibrary.org by guest on March 6, 2014. For personal use only.

BLOOD, 1 FEBRUARY 2006 VOLUME 107, NUMBER 3 ADULT ACUTE MEGAKARYOCYTIC LEUKEMIA 881

Table 1. Patient characteristics

Characteristics M7 AML Non-M7 AML P

No. patients 37 1800

Female sex, no. (%) 15 (41) 776 (43) NS
Median age, y (range) 56 (21-78) 60 (15-89) NS
Performance status 3/4, no. (%) 3 (8) 210 (12) NS
AHD and/or MDS, no. (%) 22 (60) 701 (39) .012
Previous chemotherapy, no. (%) 6 (16) Data not available
Median platelet count, 109/L (range) 36 (5-2292) 49 (1-1505) NS
Median WBC count, 109/L (range) 3.6 (0.5-49.9) 11.1 (0.2-437) .001
Median Hgb level, g/dL (range) 7.7 (3.2-10.9) 8.1 (2.1-15) NS
Median PT, s (range) 12.7 (10.7-14.7) 12.5 (9.9-49.7) NS
Median PTT, s (range) 26.6 (22.4-294) 27.9 (11.8-277) NS
Median 2-M level, mg/dL (range) 2.65 (1.3-10.3) 2.8 (0.1-31.3) NS
Median total bilirubin level, mg/dL (range) 0.7 (0.1-3) 0.6 (0.1-9.2) NS
Median BM blast, % (range) 30 (0-80) 53 (0-98) .001
Median LDH level, IU/L (range) 891 (302-7101) 1073 (125-58 856) NS
Cytogenetics, no. (%)
Poor 18 (49) 592 (33) .045
Other 19 (51) 1060 (59)
Favorable 0 (0) 148 (8)
Extensive BM fibrosis*, no. (%) 23 (62) Data not available
Laminar flow room treatment, no. (%) 21 (57) 1021 (57) NS
CR, no. (%) 16 (43) 1030 (57) .089
Median OS, wk 23 38 .006
Median DFS, wk 23 52 .001

NS indicates not significant; Hgb, hemoglobin; PT, prothrombin time; PTT, activated partial thrombin time; B2-M, 2-microglobulin; BM, bone marrow.
*BM fibrosis is based on the criteria of Bauermeister.17

count recovery with a neutrophil count of at least 1 109/L and a platelet count
of at least 100 109/L.10,11 Treatment failure was defined by the absence of
documented CR, including induction death or refractory disease. Relapse was
defined by an excess of 10% leukemic blasts in a marrow aspirate unrelated to
recovery of normal hematopoiesis or the development of new extramedullary
leukemia. Disease-free survival (DFS) was calculated from the time of first
documented CR to relapse or death in CR.
Statistical methods
The Fisher exact tests and t tests were used for the descriptive statistical analysis on
categorical and continuous data, respectively.12 Survival curves were estimated
according to the Kaplan-Meier product-limit method.13 Univariate and multivariate
logistic regression models14 were used to evaluate the associations between
multiple characteristics and CR. Clinical and biologic characteristics were also
analyzed for their association with survival using Cox proportional hazards
models.15 Survival times between patients with different characteristics were
compared by the log-rank test.16 Characteristics with P values below 10 in the
univariate Cox proportional hazards model were included in the multivariate
model. In this model a backward elimination with a P cutoff of .05 was used. Any
variable previously deleted could re-enter the final model if it had a P value below
.05 when added to that model. All computations were carried out in SAS
(Cary, NC).
Results
Patient characteristics

Table 2. Summary of cytogenetic abnormalities in patients with M7 From January 1987 to November 2003, 1837 patients were
AML diagnosed with untreated AML (excluding M3) at MDACC. Of
Affected chromosome and abnormality No. (%) these, 37 patients (2%) were characterized as having M7 AML. The
Chromosome 3
Monosomy 3 3 (8)
Inv(3)(q21q26) 1 (3)
Inv(3)(q26q28) 1 (3)
t(3;21) 1 (3)
Chromosome 5
5q deletion or monosomy 5 14 (38)
Chromosome 7
Monosomy 7 15 (41)
Chromosome 8
Trisomy 8 2 (5)
Philadelphia
t(9;22) 3 (8)
Other 1 (3)
Normal diploid
Insufficient metaphases 8 (22)
Multiple (3)* 11 (30)
Figure 1. Overall survival of patients with M7 and non-M7 AML. The median
*Multiple cytogenetic abnormalities were all associated with one or more of the survival time for patients with M7 and non-M7 AML was 23 and 38 weeks,
poor cytogenetic abnormalities. respectively (P .006).
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882 OKI et al BLOOD, 1 FEBRUARY 2006 VOLUME 107, NUMBER 3

Detailed results of the cytogenetic findings in patients with M7

AML are summarized in Table 2. It should be noted that 18 patients
(49%) had one or more of poor cytogenetic abnormalities (5, 7,
8, or 11q involvement). Abnormalities in chromosome 3 were
also frequently observed (6 patients, 16%), often associated with
other poor cytogenetic abnormalities (4 patients, 11%). The
Philadelphia chromosome abnormality was detected in 3 patients
(8%) without prior history or clinical features of chronic myeloid
leukemia, such as splenomegaly, basophilia, or thrombocytosis.
Outcome

Figure 2. Disease-free survival of patients with M7 and non-M7 AML. The median
of disease-free survival for patients with M7 and non-M7 was 23 and 52 weeks,
respectively (P .001).
proportion of patients with M7 AML did not change significantly
over the time period: 3 (1.0%) of 313 during 1987-1990, 8 (2.3%)
of 352 during 1991-1994, 12 (2.8%) of 429 during 1995-1998, and
14 (1.9%) of 743 during 1999-2003. Patient characteristics are
summarized in Table 1. Several characteristics at presentation were
different between the 2 groups. M7 AML was associated more
frequently with antecedent hematologic disorder (AHD) or myelo-
dysplastic syndrome (MDS) (P .012), poor cytogenetics
(P .045), lower white blood cell (WBC) count (P .001), and a
lower percentage of bone marrow blasts (P .001). Assignment to
different treatment groups was not significantly different between
M7 and non-M7 groups.
In the M7 AML group, 10 patients (27%) had prior MDS, with
median duration of 4 months (range, 2-160 months) prior to the
diagnosis of M7 AML. Twelve (32%) other patients had various
AHDs (6 with myeloproliferative disorder, 2 with cytopenias, and 4
with other disorders). Two patients with myeloproliferative disor-
der had received chlorambucil. Four patients with MDS had
previously received chemotherapy for other malignancies (breast,
ovarian, nonsmall-cell lung cancer, and Waldenstrom macroglobu-
linemia). One patient without AHD/MDS had a previous history of
non-Hodgkin lymphoma. None of the patients with M7 AML had
Down syndrome or mediastinal germ cell tumor.18
The CR rate with M7 AML was 43% versus 57% with non-M7 AML
(P .089). Median OS times were 23 weeks and 38 weeks, respec-
tively (P .006; Figure 1). Among patients who achieved CR, the
median DFS durations were 23 weeks and 52 weeks, respectively
(P .001; Figure 2). Twenty-three (62%) patients with M7 AML had
refractory disease after first induction chemotherapy. None achieved CR
after salvage induction chemotherapy. All 3 patients with Philadelphia
chromosome-positive M7 AML achieved CR after induction therapy;
their survivals were 12, 56, and 92 weeks. Two patients with primary
refractory disease and 3 patients with relapsed disease underwent
allogeneic stem cell transplantation with active disease. Median survival
after stem cell transplantation in those 5 patients was 21 weeks (range,
8-72 weeks).
Prognostic factors for treatment response
The characteristics of patients with AML (including M7 AML)
with and without CR are shown in Table 3. By univariate analysis,
older age, poor performance status, induction therapy not in the
laminar flow room, AHD/MDS, lower hemoglobin level, higher
prothrombin time, higher 2-microglobulin concentration, higher
total bilirubin level, higher lactate dehydrogenase (LDH) level,
poor cytogenetics, and treatment group 4 (containing ara-C, not
containing anthracycline, fludarabine, topotecan) were associated
with treatment failure. M7 AML was marginally associated with
treatment failure by univariate analysis (P .093). By multivariate
analysis, older age, treatment outside the laminar flow room, poor
performance status, AHD/MDS, higher 2-microglobulin level,
higher prothrombin time, poor cytogenetics, and treatment group 4

Table 3. Characteristics of all AML patients with CR versus no CR

Characteristic CR No CR P

No. patients 1046 791

Female sex, no. (%) 468 (59) 323 (41) NS
Median age, y (range) 55 (15-89) 64 (16-89) .001
Performance status 3/4, no. (%) 63 (30) 150 (70) NS
AHD/MDS, no. (%) 317 (44) 406 (56) .012
Median platelet count, 109/L (range) 52 (1-1 355) 45 (3-2 292) .001
Median WBC count, 109/L (range) 10.2 (0.4-390) 11.7 (0.2-437) NS
Median Hgb level, g/dL (range) 8.2 (2.1-14.9) 7.9 (2.8-15) .003
Median PT, s (range) 12.3 (10.2-29.9) 12.8 (9.9-49.7) .001
Median PTT, s (range) 27.8 (14.6-277) 28 (11.8-294) .062
Median 2-M level, mg/dL (range) 2.6 (0.1-30.6) 3.3 (0.7-31.3) .001
Median total bilirubin level, mg/dL (range) 0.6 (0.1-7.4) 0.6 (0.1-9.2) .001
Median BM blast, % (range) 55 (0-98) 50.5 (0-98) .003
Median LDH level, IU/L (range) 1 030.5 (190-33 349) 1 177 (125-58 856) .003
Cytogenetics, no. (%)
Poor 250 (41) 360 (59) .001
Other 661 (61) 418 (39)
Favorable 135 (91) 13 (9)
M7 AML, no. (%) 16 (43) 21 (57) .089
Laminar flow room treatment, no. (%) 625 (60) 421 (540) NS
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BLOOD, 1 FEBRUARY 2006 VOLUME 107, NUMBER 3 ADULT ACUTE MEGAKARYOCYTIC LEUKEMIA 883

Table 4. Multivariate analysis for CR Table 6. Summary of reports on adult M7 AML

Characteristic Odds ratio P MDACC ECOG5 GIMEMA4 GFHC19

Age 0.98 (0.97-0.99) .001 Time period 1987-2003 1984-1997 1982-1999 1988-2000
Performance status 3/4 0.52 (0.32-0.83) .007 No. of patients, M7
AHD/MDS 0.53 (0.40-0.70) .001 AML/all AML 37/1837 20/1649 24/3603 23/ND
2-M 0.90 (0.85-0.96) .001 Age, y (range) 54 (21-78) 42.5 (18-70) 51 (15-76) 58 (19-79)
PT 0.84 (0.77-0.92) .001 Male, % 58 70 58 57
Cytogenetics AHD/MDS, no. (%) 14 (37) ND ND 9 (39)
Poor vs favorable 0.10 (0.05-0.24) .001 Treatment related,
Others vs favorable 0.20 (0.09-0.46) .001 no. (%) 5 (13) ND 0 2 (9)
Treatment in laminar flow room 1.83 (1.35-2.50) .001 WBC count,
M7 AML 0.84 (0.36-1.96) .68 109/L (range) 3.5 (0.5-49.9) 2.0 (0.8-35.2) 7.1 (0.5-162) 4.6 (0.3-72.6)
Hgb level, g/dL 7.75 (3.2-
Each characteristic is associated with decrease (odds ratio 1) or increase
(range) 10.9) 8.8 (4-14) 8 (3.6-13) ND
(odds ratio 1) in the CR rate.
Platelet count,
109/L (range) 34.5 (5-2292) 65 (12-1450) 66 (20-572) 48 (4-490)
were independent predictive factors for treatment failure (Table 4). BM blast, %
(range) 30 (0-80) 59 (5-59) 74.5 (30-99) 53 (0-79)
M7 AML was not an independent predictive factor for treatment
CR rate, % 43 50 50 50
failure. Subset analysis of patients without the Philadelphia chromo-
DFS, mo (range) 6.5 (3-29) 10.6 (1-160) 8.2 (2.3-102.9) ND
some abnormality identified the same parameters to be associated OS, mo (range) 5.6 (0.5-37) 10.4 (1-160) 9.3 4.5 (0.07-53.5)
with treatment failure.
MDACC indicates M.D. Anderson Cancer Center; ECOG, Eastern Cooperative
Prognostic factors for OS Oncology Group; GIMEMA, Gruppo Italiano Malattie Ematologiche dell Adulto;
GFHC, Groupe Francais dHematologie Cellulaire; and ND, not described.
By univariate analysis, older age, treatment outside the laminar
flow room, poor performance status, AHD/MDS, higher WBC
count, lower hemoglobin concentration, higher prothrombin time, same time period. As in previous reports,4,5,19 we confirmed the
higher 2-microglobulin level, higher total bilirubin level, lower poor prognosis of patients with M7 AML. Although M7 AML was
bone marrow blast percentage, higher LDH concentration, poor not significantly associated with a lower CR rate compared with
cytogenetics, treatment group 4 (containing ara-C and not contain- other forms AML, OS and DFS were significantly worse in the M7
ing anthracycline, fludarabine, and topotecan), and M7 AML were AML group. By multivariate analysis, M7 AML was an indepen-
independent negative factors for OS. By multivariate analysis, dent adverse prognostic factor for OS along with other factors such
older age, treatment outside laminar flow room, poor performance as cytogenetic abnormalities and the presence of AHD/MDS.
status, AHD/MDS, higher WBC count, lower hemoglobin level, Previous reports of adult M7 AML are summarized in Table
higher 2-microglobulin concentration, higher total bilirubin level, 6.4,5,19 The characteristics of our patients were similar to those seen
lower bone marrow blast percentage, higher LDH level, poor in previous reports. Despite the fact that as many as 50% of patients
cytogenetics, treatment group 4, and M7 AML were independent achieved CR, DFS of M7 AML was short, with a median duration
negative factors for OS (Table 5). Subset analysis of patients of 6 to 10 months. OS was also poor, with a median survival of only
without Philadelphia chromosome revealed the same results. 4 to 10 months.
Multiple chromosome aberrations have been identified in
patients with M7 AML (Table 2). Abnormalities of chromosome 3
Discussion have been typical in all series to date. Other common cytogenetic
findings include abnormalities of chromosome 5 or 7 or both,
In this report, we analyzed the clinical and laboratory characteris- which were most common in our study and that of the Groupe
tics of patients with M7 AML and compared them with those of a Francais dHematologie Cellulaire (GFHC).19 Although pediatric
large cohort of patients with other AMLs diagnosed during the M7 AML is often associated with t(1;22)(p13;q13) resulting in the
OTT-MAL fusion transcript, this abnormality has not been reported
in adults with M7 AML.
Table 5. Multivariate analysis for survival
A recent report from the European Group of Blood and Marrow
Characteristic Hazard ratio P
Transplantation (EBMT) described the characteristics and progno-
Age 1.03 (1.02-1.03) .001 sis of patients with M7 AML undergoing stem cell transplantation
Performance score 3/4 1.37 (1.08-1.74) .010 (37 autologous and 32 allogeneic) after first CR.20 Median times
WBC count 1.003 (1.00-1.004) .003
from diagnosis to autologous and allogeneic transplantation were
Hgb level 0.92 (0.89-0.96) .001
29 weeks (range, 15-114 weeks) and 20 weeks (range, 9-117),
2-M level 1.04 (1.02-1.06) .001
respectively. The 3-year OS rates were 30% and 43%, respectively.
Total bilirubin concentration 1.11 (0.97-1.28) .13
Bone marrow blast 0.997 (0.994-1.00) .034
The 3-year DFS rates were 27% and 46%, respectively. Given the
LDH level 1.0001 (1.00-1.0004) .001 dismal outcome of M7 AML even after achieving CR in our study
Cytogenetics and others, allogeneic transplantation during first CR appears to be
Poor vs favorable 4.10 (2.89-5.81) .001 beneficial in these patients.
Others vs favorable 2.38 (1.69-3.34) .001 The most important finding of our study is that a histopathologic
Treatment in laminar flow room 0.73 (0.63-0.85) .001 diagnosis of M7 AML was an independent adverse prognostic
M7 AML 1.66 (1.09-2.54) .019 factor for OS. Thus, the poor prognosis of M7 AML is not fully
Each characteristic is associated with longer (hazard ratio 1) or shorter (hazard dependent on cytogenetic abnormalities. It indicates that distinctive
ratio 1) OS time. biologic mechanisms play a role in M7 AML.
 From bloodjournal.hematologylibrary.org by guest on March 6, 2014. For personal use only.

884 OKI et al BLOOD, 1 FEBRUARY 2006 VOLUME 107, NUMBER 3

In conclusion, M7 AML is a rare form of adult AML, which is independent poor prognostic factor for OS. A better understanding
often observed in the setting of prior AHD/MDS or therapy-related of the pathophysiology of M7 AML and new therapeutic strategies
leukemia. Histopathologic evidence of M7 AML itself is an are needed for patients with M7 AML.

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