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2000 96: 2405-2411

Acute megakaryocytic leukemia: the Eastern Cooperative Oncology

Group experience: Presented in part at the American Society of
Hematology meeting, New Orleans, LA, December 1999.
Martin S. Tallman, Donna Neuberg, John M. Bennett, Christopher J. Francois, Elisabeth Paietta,
Peter H. Wiernik, Gordon Dewald, Peter A. Cassileth, Martin M. Oken and Jacob M. Rowe

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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS

Acute megakaryocytic leukemia: the Eastern Cooperative

Oncology Group experience
Martin S. Tallman, Donna Neuberg, John M. Bennett, Christopher J. Francois, Elisabeth Paietta, Peter H. Wiernik, Gordon Dewald,
Peter A. Cassileth, Martin M. Oken, and Jacob M. Rowe

Acute megakaryocytic leukemia (AMegL)
is a rare subtype of acute myeloid leuke-
mia (AML) evolving from primitive
megakaryoblasts. Because of its rarity
and the lack of precise diagnostic criteria
in the past, few series of adults treated
with contemporary therapy have been
reported. Twenty among 1649 (1.2%) pa-
tients with newly diagnosed AML entered
on Eastern Cooperative Oncology Group
(ECOG) trials between 1984 and 1997
were found to have AMegL. The median
age was 42.5 years (range 18-70). Marrow
fibrosis, usually extensive, was present
in the bone marrow. Of the 8 patients who
had cytogenetic studies performed, ab-
normalities of chromosome 3 were the
most frequent. The most consistent immu-
nophenotypic finding was absence of my-
eloperoxidase in blast cells from 5 pa-
tients. In the most typical 3 cases, the
leukemic cells were positive for one to 2
platelet-specific antigens in addition to
lacking myeloperoxidase or an antigen
consistent with a lymphoid leukemia. My-
eloid antigens other than myeloperoxi-
dase and selected T-cell antigens (CD7
and/or CD2) were frequently expressed.
Induction therapy included an anthracy-
cline and cytarabine in all cases. Com-
plete remission (CR) was achieved in 10
of 20 patients (50%). Two patients remain
alive, one in CR at 160 months. Resistant
disease was the cause of induction failure in
all but 3 patients. The median CR duration
was 10.6 months (range 1-160 months).
The median survival for all patients was 10.4
months (range 1-160 months). Although
half of the patients achieved CR, the long-
term outcome is extremely poor, primarily
attributable to resistant disease. New thera-
peutic strategies are needed. (Blood. 2000;
96:2405-2411)
2000 by The American Society of Hematology

Introduction
Acute megakaryocytic leukemia (AMegL) is a rare subtype of
acute myeloid leukemia (AML) developing from primitive
megakaryoblasts, first described by Von Boros and colleagues in
1931.1 The disease can be identified by antibodies to glycoprotein
IIb/IIIa and is often associated with extensive myelofibrosis.2-9
Reports in the literature have been sporadic because of both the
rarity of the disease and the lack of well-established diagnostic
criteria. Precise diagnostic criteria were added to the French-
American-British (FAB) classification only relatively recently and
the disease is also referred to as FAB M7.10 Therefore, because
many cases were reported in older literature, patients previously
categorized as AMegL represent a heterogenous group.
Despite the paucity of reports, several unusual associations with
AMegL have been identified. First, AMegL has been linked to
primary mediastinal germ cell tumors.11-13 Second, children with
Down syndrome appear to have an increased incidence of AMegL
and such patients have a more favorable outcome than when
AMegL occurs without such an association in adults.14-19 Patients
also have been described with AMegL without Down syndrome,
but whose leukemic cells have abnormalities of chromosome 21,
the specific chromosome associated with Down syndrome.20,21
Third, extensive fibrosis is frequently, but not invariably, present.22-25
Although some patients achieve complete remission (CR),
few patients survive beyond 3 years.26-29 Clinical experience with
this rare leukemia remains limited. This analysis was designed
to determine the laboratory and clinical features, biologic character-
istics, and outcome of patients with AMegL treated with a
contemporary induction regimen that included an anthracycline
and cytarabine on Eastern Cooperative Oncology Group acute
leukemia protocols.
Materials and methods
Patients
The medical records of 20 patients with AMegL entered on 5 trials for
previously untreated AML conducted by the Eastern Cooperative Oncology
Group (ECOG) between 1983 and 1997 were retrospectively reviewed. The
total number of patients with AML included patients enrolled on a sixth
protocol E3993, a randomized trial of 3 anthracyclines in induction for
older adults, but there were no cases of AMegL identified on this trial. These
were the only 6 trials active during this period for patients whose conditions
were newly diagnosed. This recent 12-year period was selected because
patients were generally treated with anthracycline and cytarabine regimens
for induction.

From the Northwestern University Medical School, Robert H. Lurie Cancer
Center, Chicago IL; Biostatistics, Dana-Farber Cancer Institute, Boston, MA;
University of Rochester Medical Center, Rochester, NY; Our Lady of Mercy
Medical Center, Bronx, NY; Cytogenetics Laboratory, Mayo Clinic, Rochester,
MN; University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL;
Virginia Piper Cancer Institute, Minneapolis, MN; Rambam Medical Center,
Technion Haifa, Israel; For The Eastern Cooperative Oncology Group,
Brookline, MA.
Submitted December 23, 1999; accepted June 8, 2000.
Orleans, LA, December 1999.
Reprints: Martin S. Tallman, Division of Hematology/Oncology, Department of
Medicine, Northwestern University Medical School, Robert H. Lurie Cancer
Center, 676 N St Clair St, #850, Chicago, IL 60611-2927; e-mail: m-tallman@
nwu.edu.
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.

Presented in part at the American Society of Hematology meeting, New 2000 by The American Society of Hematology

BLOOD, 1 OCTOBER 2000 VOLUME 96, NUMBER 7 2405

 From bloodjournal.hematologylibrary.org by guest on March 4, 2014. For personal use only.
2406 TALLMAN et al
Diagnosis of acute megakaryocytic leukemia (FAB M7)
The diagnosis of AMegL was established principally on morphologic
grounds at the individual institution, but subsequently centrally reviewed at
the time of study entry and again in preparation for this analysis by the same
single individual both times (J.M.B.).10,30 The bone marrow aspirate or
biopsy leukemic blast cell population must have represented 30% or more
of the myeloid marrow, excluding lymphocytes and plasma cells. The
majority of these cells were undifferentiated and therefore devoid of
myeloperoxidase by routine cytochemical methods. Some were easily
identified as early or dysplastic megakaryocytic precursors. Other cytochemi-
cal stains, including nonspecific esterases, periodic acid-Schiff, and acid
phosphatase reactions were not diagnostic. These were the prevailing
diagnostic criteria according to the FAB classification at the time these
ECOG studies were conducted. Confirmation of the cell of origin was
performed, whenever possible, to demonstrate either platelet peroxidase by
electron microscope, immunocytochemistry stain for factor VIII on the
bone marrow biopsy, or the presence of antibodies against glycoprotein
IIb/IIIa (CD41a) or glycoprotein IIIa (CD61). Myelofibrosis as demon-
strated with a reticulin stain was strongly positive in most cases. Bone
marrow reticulin was quantified, according to Bauermeister,31 as follows:
0: no reticulin fibers demonstrable; 1: occasional fine individual fibers and
foci of a fine fiber network; 2: fine fiber network throughout, no coarse
fibers; 3: diffuse fiber network with scattered thick coarse fibers; and 4:
diffuse coarse fiber network. Immunophenotyping was performed centrally
by multicolor flow cytometry in the ECOG Immunophenotyping Labora-
tory by a single individual (E.P.) as previously described for 7 of the
patients entered on the most recently trials.32 The immunophenotype results
from patients entered on to trials before the ECOG Immunophenotyping
Reference Laboratory was initiated were performed at the institution, but
centrally reviewed by the same individual (E.P.). Antibodies to platelet-
specific glycoproteins (GP) were used to characterize myeloperoxidase-
negative acute leukemia: CD41 (GPIIb/IIIa), CD36 (GPIIIb), as well as
antibody to blood group H antigen.33
Treatment
Patients with AMegL were identified from the ECOG database of patients
entered on the following 5 clinical trials for previously untreated AML. EST
3483 was a prospective randomized phase III trial of postremission therapy
in AML.34 Patients with previously untreated AML were given one to 2
courses of induction with daunorubicin 60 mg/m2 intravenously per day for
3 days, cytosine arabinoside 200 mg/m2 continuous intravenous (IV)
infusion for 5 days plus 6-thioguanine 100 mg/m2 orally every 12 hours for
5 days, and then randomized to either one course of intensive consolidation
therapy with high-dose cytosine arabinoside 3 gm/m2 IV every 12 hours
days 1 to 6, plus amsacrine 100 mg/m2 per day IV on days 7 to 9 or
maintenance therapy for 2 years with 6-thiogranine 40 mg/m2 twice daily
each week plus cytosine arabinoside 60 mg/m2 subcutaneously on day 5
each week or observation. Patients younger than 41 years with a histocom-
patible sibling were to undergo allogeneic transplantation. EST 1490 was a
randomized placebo-controlled phase III study of granulocyte-macrophage
colony-stimulating factor (GM-CSF) in adult patients (older than 55-70
years) with AML.35 Induction consisted of one to 2 courses of daunorubicin
60 mg/m2 for 3 days and cytosine arabinoside 100 mg/m2 daily for 7 days
by continuous IV infusion. If the day-10 bone marrow was hypoplastic,
patients were randomized to receive GM-CSF 250 g/m2 IV or placebo
until neutrophil recovery. Consolidation therapy consisted of cytosine
arabinoside 1.5 gm/m2 IV every 12 hours for 6 days. PC 486 was a phase II
pilot study of autologous bone marrow transplantation in patients with
AML in first CR using 4-hydroperoxy-cyclophosphamidetreated mar-
row.36,37 Induction consisted of daunorubicin 60 mg/m2 per day by IV push
for 3 days on days 1 to 3 and cytarabine 25 mg/m2 IV push, followed by
continuous plus thioguanine 100 mg/m2 every 12 hours orally on days 1 to
5. In EST 3489, remission was induced by idarubicin 12 mg/m2 IV for 3
days and cytosine arabinoside IV continuous infusion days 1 to 7.
Subsequently, patients with a suitably HLA-matched donor were assigned
to allogeneic transplantation and others were randomized to either autolo-
gous bone marrow transplantation or conventional consolidation chemo-
therapy.38 Postremission chemotherapy included high-dose cytosine arabi-
BLOOD, 1 OCTOBER 2000 VOLUME 96, NUMBER 7
noside 3 gm/m2 every 12 hours for 6 days and allogeneic bone marrow
transplantation. EST 4995 was a phase II study of an intensified induction
regimen, including daunorubicin 45 mg/m2 IV days 1 to 3, cytosine
arabinoside 100 mg/m2 per day IV days 1 to 7 and 3 days of high-dose
cytosine arabinoside 2 g/m2 IV days 8 to 10, followed by 2 cycles of
consolidation chemotherapy that includes high-dose cytosine arabinoside 3
gm/m2 IV every 12 hours days 1, 3, and 5, followed by either allogeneic or
autologous bone marrow or stem cell transplantation.39
Results
Clinical and laboratory characteristics at presentation
Twenty patients among 1649 (1.2%) patients entered on the 6
ECOG trials between 1984 and 1997 for previously untreated AML
had AMegL. Fourteen of the 20 patients (70%) were men and 6
(30%) were women (Table 1). The median age was 42.5 years with
a range of 18 to 70 years. The median white blood cell (WBC)
count was 2.0 109L (range 0.8-35.2), the median hemoglobin
was 8.8 g/dL (range 4-14), and the median platelet count was
65 109/L (range 12-1450). Three patients had a platelet count
greater than 1000 109/L. The median peripheral blast percentage
was 7.5% (range 0%-84%) and the median percentage of blasts in
the bone marrow was 59% (range 5%-99%). Marrow fibrosis was
present in the bone marrow core biopsy specimens from all 17
patients in whom it could be assessed. Fifteen patients (75%) had
extensive fibrosis (scattered or diffuse coarse fibers). Extramedul-
lary disease was present on clinical grounds at the time of diagnosis
in the spleen (one patient); and liver, spleen, and skin (one patient).
None of the patients had Down syndrome.
Cytogenetic studies
Eight of the 20 patients had cytogenetic studies carried out (Table
2). Karyotype analysis was normal in 2 cases. Abnormalities
involving chromosome 3 were the most frequent. Two patients had
a t(3;3) (q21;q26) translocation, one had a t(3;12)(q25;p11.2)
translocation, and one patient had an inv3(q21;q26) abnormality.
Twelve patients had no cytogenetic studies performed. Two other
cases had different chromosomally abnormal clones.
Central immunophenotyping
For patients entered on the early AML treatment study E3483,
central immunophenotyping was not yet performed in the ECOG.
Material for immunophenotyping was submitted to the ECOGs
reference laboratory for 9 of the more recent patients. Because of
marrow fibrosis, immunophenotyping studies were successful in
only 7 of these patients (patients 1, 4, 5, 6, 7, 8, ad 15) (Table 2).
The most consistent and significant finding with respect to diagno-
sis was the absence of myeloperoxidase in the blast cells from 5 of
the patients. HLA-DR and CD34 were commonly expressed. In the
immunophenotypically most typical cases of AMegL, patients 6, 7,
and 8, the leukemic cells were positive for one to 2 platelet-specific
antigens in addition to lacking myeloperoxidase or an antigen
profile consistent with a lymphoid leukemia. Myeloid antigens
other than myeloperoxidase and selected T-cell antigens (CD7
and/or CD2) were frequently expressed. B-cell antigens were not
detected. Blast cells from 2 patients expressed myeloperoxidase
(cases 4 and 15) as well as myelomonocytic antigens, but lacked
megakaryocytic markers.
Cytoimmunochemistry
All patients had a morphologic and/or histologic description
consistent with a diagnosis of AMegL. Platelet glycoprotein
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BLOOD, 1 OCTOBER 2000 VOLUME 96, NUMBER 7 ACUTE MEGAKARYOCYTIC LEUKEMIA 2407

Table 1. Characteristics of patients with acute megakaryocytic leukemia

Age WBC Hb Plts Peripheral Marrow Marrow Cycles of
Patient ECOG study (y) Gender 109/L gm/dL 109/L blasts (%) blasts (%) fibrosis* induction

1 E3489 43 F 6.1 8.2 86 53 64 3 1

2 E3489 53 M 2.3 14.0 33 7 10 3 1
3 E3489 54 M 1.5 8.2 820 2 32 1 1
4 E3489 37 M 35.2 8.7 1016 3 74 3 1
5 E3489 26 F 15.6 8.2 33 79 31 4 1
6 E3489 42 F 0.9 8.6 1000 4 61 3 2
7 E4995 52 F 1.0 8.6 57 0 59 NA 1
8 E1490 65 M 2.4 11.9 161 38 90 1 1
9 E1490 70 M 1.1 8.0 23 20 50 NA 1
10 E3483 59 M 1.5 9.3 34 16 NA 2 1
11 E3483 42 M 11.7 9.5 40 63 NA 3 2
12 E3483 48 M 1.0 9.4 1450 0 5 3 1
13 E3483 61 M 3.4 9.1 23 12 NA 2 2
14 E3483 39 F 3.8 6.7 330 14 15 3 2
15 E3483 18 F 8.5 10.2 319 1 50 4 2
16 PC486 35 M 1.7 10.5 73 0 99 3 1
17 PC486 38 M 1.0 9.9 12 2 90 NA 2
18 E3483 36 M 33.0 8.9 145 84 95 3 2
19 E3483 56 M 1.0 4.0 28 2 30 3 1
20 PC486 35 M 0.8 7.9 49 8 80 3 2

ECOG Eastern Cooperative Oncology Group; WBC white blood cell.

* As described by Bauermeister et al.31

staining was positive in the institution or ECOG reference labora-
tory in patients 1, 3, 7, and 8 (Table 3). Factor VIII was positive in
patients 2, 4, 7, 8, 9, 11, and 20. Therefore, in 13 of the 20 cases,
either myeloperoxidase was negative and/or platelet glycoprotein
CD41 and/or factor VIII was positive. Although nonspecific, the
alpha naphthyl acetate stain was negative in 2 cases (patients 11
and 18) and positive in only one case (patient 3). Granulocytic
dysplasia was present in patients 3, 5, 6, 8, and 15. Erythroid
dysplasia was present in patient 12.
Outcome
Complete remission was achieved in 10 of the 20 patients (50%)
(Table 4). Ten patients (50%) had no response. One patient remains
alive and in remission at 160 months. Resistant disease was the
cause for induction failure in all but 3 patients who died of
respiratory failure, sepsis, and probable infection.
Remission duration
The median remission duration among patients achieving CR was
10.6 months with a range of 1 to 160 months (Figure 1).
Overall survival
The median overall survival for all patients was 10.4 months with a
range of 1 to 160 months (Figure 1). Six patients survived for
more than 1 year beyond study entry. Of these, 5 achieved CR. The

Table 2. Karyotype, immunophenotype, and immunohistochemical stain for factor VIII and platelet antigen expression
of patients with acute megakaryocytic leukemia
Patient Karyotype Immunophenotype/Immunohistochemical stain

1 46,XX,t(3;3)(q21;q26) POX,HLADR,Ly ag,My ag,CD41,Hag

2 N/A N/A/FVIII
3 46,XY,inv(3)(q21;q26) NA/PH ag
4 46,XY,t(3;3)(q21;q26) POX,HLADR,CD34,CD2,CD7,My ag,Mono ag/FVIII
5 46,XX POX,HLADR,CD34,CD7,CD33,CD13,Plt ag
6 46,XX,7,mar[4]/47,XX,mar[2]/92,XXXX,7,7,marx2[3]/46,XX[11] POX,HLADR,CD34,Ly ag,My ag,CD41,H ag
7 N/A POX,HLADR,CD34,CD117,My ag,CD41,CD61,CD36/FVIII
8 46,XY,t(8;17)(p21;p13)[3]/46,XY[25] POX,HLA-DR,CD34,TdT,CD2,My ag,CD41/FVIII
9 N/A N/A/FVIII
10 N/A N/A
11 N/A N/A/FVIII
12 N/A N/A
13 N/A N/A
14 N/A N/A
15 46,XX POX,HLA-DR,My ag,Mono ag,Plt ag
16 N/A N/A
17 N/A N/A
18 N/A N/A
19 N/A N/A
20 46,XY,t(3;12)(q25;p11.2),13,mar[6] N/A/FVIII

POX myeloperoxidase by antibody staining; Ly ag all lymphoid antigens (T-antigens: intracytoplasmic CD3, CD2, CD7, surface CD3, CD4, CD8; B-antigens:
intracytoplasmic CD22, CD19, CD24, surface CD22, CD20); My ag all myeloid antigens (CD33, CD13, CD65s, CD15); Mono ag monocytic antigens (CD11b, CD14);
TdT terminal transferase; H ag blood group H antigen; Plt ag; all platelet-specific antigens; FVIII factor VIII antigen expression.
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2408 TALLMAN et al BLOOD, 1 OCTOBER 2000 VOLUME 96, NUMBER 7

Table 3. Summary of megakaryocytic lineage markers

Patient POX FVIII Platelet antigen

1 NA *
2 NA
3 NA *
4 NA
5 NA
6 NA
7
8 NA
9 NA NA
10 NA NA NA
11 NA NA
12 NA NA NA
13 NA NA NA Figure 1. Duration of response and overall survival for 20 patients with
14 NA NA NA previously untreated acute megakaryocytic leukemia.
15 NA
16 NA NA NA
17 NA NA NA have generally been confined to either sporadic small series,2-9
18 NA NA reports of one or 2 cases40-44 or descriptions of the clinical course in
19 NA NA infants and children.45-50 Many cases previously reported antedated
20 NA the establishment of precise diagnostic methods. In fact, this
POX myeloperoxidase by antibody staining; FVIII factor VIII anti-
subtype became part of the FAB classification only in 1985.10 Since
gen expression. then, immunophenotyping by flow cytometry has emerged as a
* Outside institution (), but ECOG Reference Laboratory (). useful method to improve the diagnostic sensitivity because cells
from patients with AMegL express the megakaryocyte platelet
sixth patient was treated on PC486, a transplant study and died 3.1 lineage-specific marker CD61.51-53 Historically, the lack of specific
years after study entry. One patient treated on E3483 remained criteria for the diagnosis has led to reports of patients who likely
alive 6.8 years after study entry, and updated survival information had AMegL, but whose disease was labeled acute myelofibrosis or
was last obtained in February 1992. Two patients remain alive, one myelosclerosis.54-60 Given the sophisticated methods now available
treated on E3483 remains alive in CR at 160 months and one to assist in the diagnosis and advances in therapeutic strategies for
treated recently on E4995, who received a peripheral blood stem patients with AML, data regarding the biologic characteristics,
cell transplant off study, has relapsed and survives 22 months after response to contemporary induction therapy and natural history of
study entry. AMegL in adults are needed.
This analysis of 20 patients with AMegL represents cases with
morphology confirmed at central review, and treated with anthracy-
Discussion cline plus cytarabine-based induction. We found that the incidence
of AMegL in adults was lower (1.2%) than often reported
Although the first description of AMegL appeared in the literature (3%-10%), although many earlier series include infants and
almost 70 years ago,1 reports of the natural history of the disease children.8,9,27,53 Ribeiro and colleagues27 identified 14 cases among

Table 4. Outcome of treatment of patients with acute megakaryocytic leukemia

Response to Remission duration Survival
Patient induction therapy (mo) (mo) Cause of induction failure Current status

1 CR 3 21 Deceased
2 NR 5 AMegL Deceased
3 CR 19 24 Deceased
4 CR 2 10 Deceased
5 NR 6 AMegL Deceased
6 NR 2 Sepsis Deceased
7 CR 15 22 Alive
8 CR 7 15 Deceased
9 CR 4 6 Deceased
10 CR 160 160 Alive
11 NR 3 AMegL Deceased
12 NR 1 Respiratory failure Deceased
13 NR 11 AMegL Deceased
14 NR 1 Probable infection Deceased
15 CR 12 30 Deceased
16 CR 1 4 Deceased
17 NR 37 AMegL Deceased
18 NR 10 AMegL Deceased
19 CR 9 10 Deceased
20 NR 10 AMegL Deceased

CR complete remission; NR no response or lack of complete remission; AMegL acute megakaryocytic leukemia.
 From bloodjournal.hematologylibrary.org by guest on March 4, 2014. For personal use only.
BLOOD, 1 OCTOBER 2000 VOLUME 96, NUMBER 7
150 consecutive patients (9.3%) seen at St. Jude Childrens
Research Hospital. The well-described, but unexplained associa-
tion of AMegL with Down syndrome may account for the apparent
higher incidence in the pediatric population. It is possible that the
true incidence of AMegL was underestimated in this patient
population, because strict FAB criteria were used requiring the
presence of at least 30% blasts.10 Under the revised World Health
Organization (WHO) criteria, the presence of 20% blasts would be
sufficient.61 In addition, inaspirable bone marrows have contributed
to the difficulty in establishing the diagnosis. Furthermore, patients
with particularly poor prognoses may not be entered on multiinsti-
tutional clinical trials. However, the precise incidence will require
further study because of the historical difficulty in establishing the
diagnosis. Clinically, AMegL and acute myelofibrosis are indistin-
guishable and careful examination of the morphology of marrow
blasts, together with immunoperoxidase staining or immunopheno-
typing for expression of factor VIII are often required. 62
Although a formal comparison of the distinctive clinical
features of only 20 cases of AMegL with other subtypes of AML is
difficult because of the small numbers of cases, several observa-
tions can be made. The median age of the patients reported here is
relatively young (42.5 years), compared with patients with other
subtypes of AML (63 years). However, all the protocols onto which
the patients reported here were entered, except one (E1490),
focused on relatively young patients for whom transplant was a
consideration. The median age of patients with other subtypes of
AML on these trials was 41 years. Therefore, no definitive
statement can be made about the median age of patients with AMegL
compared with that of patients with other subtypes of AML. Marrow
fibrosis is present in virtually all patients, in contrast to most other
patients with AML. Abnormalities of chromosome 3, particularly
3q abnormalities, are often present and may be associated with
preservation of the peripheral platelet count, as reported here.64
When the disease occurs in children, AMegL shows close
associations with either of 2 cytogenetic abnormalities, t(1;22)(p13;
q13) or numeric abnormalities of chromosome 21, especially
trisomy 21. However, cytogenetic changes in adults with this
disease are less clearly defined, but may involve rearrangements of
chromosome 3, especially at 3q21 and 3q26-27, monosomy 7,
monosomy or deletions of chromosome 5, and trisomy 8.65,66 In the
patients reported here, 20% showed a t(3;3) or inv3, which when
observed in other subtypes of AML are often associated with
thrombocytosis and other platelet abnormalities.67,68 Two other
patients demonstrated a monosomy 7 or deletion 5q.
Although morphologic and cytochemical criteria are used to
exclude other subtypes of AML, immunophenotyping is most
valuable to differentiate between a lymphoid and a megakaryocytic
nature of myeloperoxidase negative acute leukemia.33 An antigen
profile typical of AMegL was observed in 3 of our 7 patients in
whom immunophenotyping was successfully performed. The leuke-
mic blasts were negative by staining with antibody to myeloperox-
idase, lacked lymphoid antigens with the exception of selected
T-antigens (CD2 or CD7), and expressed platelet-specific antigens
on their surface (CD41, blood group H antigen, CD36). As
observed by others, CD41 was associated with CD34 expres-
sion.69,70 Interestingly, blast cells from patient 7 also stained for
CD36, which is generally considered a late differentiation marker
of CD34 negative megakaryocytic cells.33 Myeloid antigens such
as CD33 and CD13, as found in all 3 patients, are not uncommon in
this disease. Patient 1, while lacking megakaryocytic antigens, also
failed to express any of the other lineage-associated antigens tested.
In view of the t(3;3) found in this patients leukemic cells and
ACUTE MEGAKARYOCYTIC LEUKEMIA 2409
taking into consideration the morphologic picture, the overall
scheme suggests the diagnosis of AMegL. Blast cells from the
other myeloperoxidase negative, platelet glycoprotein negative
case, patient 5, expressed early myeloid antigens CD33 and CD13
but none of the later myeloid antigens, such as CD65s or CD15, or
monocytic antigens, CD11b and CD14. Given the myeloperoxidase
negativity and the AMegL morphology, the most likely immunodi-
agnosis in this case would also be AMegL. The 2 remaining
patients, however, present a diagnostic dilemma. Blast cells from
both patients 4 and 15 were positive for myeloperoxidase by
antibody staining as well as for all myeloid antigens tested, as well
as for the prototype monocytic antigen CD14. Without morpho-
logic information, this antigen profile is most consistent with acute
monocytic leukemia. Whenever tested, CD14 has been found to be
negative in other reports of AMegL immunophenotyping.65,66,69
Although in patient 4, the t(3;3) would support the AMegL
morphologic diagnosis, patient 15 demonstrated a normal karyo-
type, thereby adding to the diagnostic controversy. These immuno-
phenotypic findings in a small group of patients characterized as
AMegL by morphology further emphasize the importance of
sophisticated laboratory studies in the diagnosis of this rare,
clinically problematic group of patients.
All patients reported here were initially treated with cytarabine
and an anthracycline (daunorubicin or idarubicin) or a nonanthracy-
cline DNA intercalator (amsacrine or mitoxantrone). In contrast,
other reports have described the outcome with a variety of
treatment including low-dose cytarabine,8,9,27 etoposide,8 and bone
marrow transplantation.8,42,71 The CR rate achieved among patients
reported here was 50%, which is somewhat lower than that
generally achieved among patients with other morphologic sub-
types of AML but is higher than that generally reported in the
literature for adults with AMegL (25%-30%).3,8,59 It must be
emphasized that no definite statement can be made about the CR
rate with such relatively small numbers. The same applies to the
few other series that have been reported, each evaluating a small
number of cases treated in a heterogeneous way. Furthermore,
many reported patients have not received a conventional anthracy-
cline plus cytarabine combination for induction. In the series by
Ribeiro et al,27 the CR rate among 24 children and adolescents was
42% (ages 4 months to 21 years, median 23.5 months). The highest
CR rates have been reported by Ruiz-Arguelles and colleagues,26
who observed a CR rate of 73% for 26 patients treated with
aggressive chemotherapy and 84% for the 19 patients given
low-dose cytarabine, with median survivals of 10 and 4 months,
respectively.
The major cause of induction failure among patients reported
here was resistant disease. Furthermore, despite a CR rate of 50%,
the long-term outcome was extremely poor. Almost every patient
died of the disease with relatively short remission durations. Only
one patient remains alive and free of disease, a 59-year-old man
treated on E3483 who is well 12 years after the diagnosis. This
suggests that, although improvement in the CR rate is needed,
improved postremission therapy is mandatory. The results of
high-dose chemoradiotherapy and allogeneic stem cell transplanta-
tion have been reported only anecdotally.71 New therapeutic
strategies need to be pursued, including biologic agents such as
interferon72 and the apoptosis-inducing agent arsenic trioxide,
which has recently been shown to cause an inhibition of growth and
survival in megakaryocytic leukemia cell lines.73 The evaluation of
such novel treatments will require the collaboration of multiple
cooperative oncology groups.
 From bloodjournal.hematologylibrary.org by guest on March 4, 2014. For personal use only.
2410 TALLMAN et al
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