Acute megakaryoblastic leukemia

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					Acute megakaryoblastic leukemia
Author: Doctor Arnauld C. Verschuur1
Creation date: May 2004

Scientific Editor: Professor Gilles Vassal
 Department of Pediatric Oncology, Academic Medical Centre, University of Amsterdam, Emma
Childrens’ Hospital AMC, F8-243, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.

Disease name and synonyms
Differential diagnosis
Clinical presentation
Diagnostic methods
Management including treatment
Unresolved questions and conclusion

Acute myeloblastic leukemia (AML) is a group of malignant bone marrow neoplasms of myeloid
precursors of white blood cells. Acute megakaryoblastic leukemia (AML-M7) is a rare type of pediatric
AML. It represents approximately 1% of all leukemias during childhood and has an incidence of 0.5 per
million per year. In young children with Down syndrome, AML-M7 is the most common type of AML. The
symptoms may be non-specific: asthenia, pallor, fever, dizziness and respiratory symptoms. More specific
symptoms are bruises and/or (excessive) bleeding, coagulation disorders (DIC), neurological disorders
and gingival hyperplasia. Diagnostic methods include blood analysis, bone marrow aspirate for
cytochemical, immunological and cytogenetical analysis, and cerebrospinal fluid (CSF) investigations.
Treatment includes intensive multidrug chemotherapy and allogeneic bone marrow transplantation.
Nevertheless, outcome of AML remains poor with an overall survival of 35-60%. Patients with AML-M7
have a dismal prognosis, which is not the case for children with Down syndrome suffering from AML. New
therapeutics are required to increase the probability of cure in this serious disorder.

Acute non-lymphocytic leukemia (ANLL), Acute megakaryoblastic leukemia, AML-M7, Acute myeloblastic
leukemia (AML), Down syndrome

Disease name and synonyms                                         Definition
   • Acute megakaryoblastic leukemia                              AML-M7 is defined by more than 20% (WHO-
   • Acute megakaryocytic leukemia                                classification) or more than 30% (French-
   • Acute myeloblastic leukemia (AML) M7                         American-British (FAB) classification) of blasts of
       (FAB-classification)                                       megakaryocytic lineage in the bone marrow
   • Acute non-lymphocytic leukemia (ANLL)                        aspirate as determined by morphology and

Verschuur A. Acute megakaryoblastic leukemia. Orphanet Encyclopedia. May 2004.                                                                    1
Differential diagnosis                                            (DIC), which can lead to life-threatening
Other malignancies that should be differentiated                  situations. The complications due to bleeding
from AML are: acute lymphocytic leukemia                          contribute for 7-10% to the mortality that is
(ALL), myelodysplastic syndrome (MDS), chronic                    observed during the first days/weeks after
myeloid leukemia (CML) including juvenile                         diagnosis      (Creutzig,     1987).       However,
chronic myelomonocytic leukemia, bone marrow                      complications due to hemorrhage are more
metastases of solid tumours such as                               frequent in promyelocytic leukemia (AML-M3)
neuroblastoma, rhabdomyosarcoma and Ewing                         and monoblastic leukemia (AML-M5). Pallor may
sarcoma, bone marrow invasion by non-Hodgkin                      be predominant, and results from the decreased
lymphoma (NHL). Differential diagnosis also                       hemoglobin level. Pallor may be accompanied
includes non-malignant disorders such as                          by dizziness, headache, tinnitus, collapses,
transient      leukemoid   reactions,     transient               dyspnea and/or congestive heart failure. Gingival
myeloproliferative syndromes, juvenile chronic                    hyperplasia may be present, but is not typical of
arthritis, infectious mononucleosis, viral induced                AML-M7.
bone marrow suppression, aplastic anemia,                         Dyspnea and/or hypoxia may also result from
congenital or acquired neutropenia and                            leukostasis, which results in a decreased blood
autoimmune cytopenia.                                             flow in some organs (lungs, CNS, liver, skin) due
                                                                  to a dramatically increased White Blood Cell
Etiology                                                          count (WBC) (>100.000/ml) leading to
Some congenital and acquired disorders may                        hyperviscosity.
predispose to AML.                                                Neurological symptoms may occur: headache,
The congenital predisposing factors are:                          nausea, vomiting, photophobia, cranial nerve
    • Down syndrome                                               palsies, papil edema and/or nuchal rigidity.
    • Twin with leukemia                                          These symptoms may result from leukostasis,
    • Fanconi’s anemia                                            but may also reveal meningeal invasion by
    • Bloom syndrome                                              myeloblasts or be the presenting symptoms of a
    • Ataxia teleangiectasia                                      “chloroma”, which is a soft tissue mass
    • Neurofibromatosis type I                                    consisting of myeloblasts. These chloromas
    • Li-Fraumeni syndrome                                        often have an orbital or periorbital localisation, or
    • Congenital      neutropenia     (Kostmann                   may arise around the spinal cord, causing
        syndrome)                                                 paraparesis or “cauda equina” syndrome. CNS
    • Klinefelter’s syndrome                                      leukemic infiltration occurs in 6-16% of AML
                                                                  (Bisschop 2001, Abbott 2003) and is not specific
Acquired predisposing factors include:                            of AML-M7.
                                                                  Renal insufficiency occurs seldomly. It is caused
   • Prenatal       exposure      to     tobacco,
                                                                  by hyperuricuria and/or hyperphosphaturia,
       marijuana, alcohol
                                                                  leading to obstructing tubular deposits and
   • Pesticides,       herbicides,     benzene,
                                                                  oliguria/anuria. The etiology of these metabolic
                                                                  disorders is called the “tumour lysis syndrome”,
   • Aplastic anemia                                              where myeloblasts lyse spontaneously. This
   • Myelodysplastic syndrome                                     situation is an emergency since life-threatening
   • Paroxysmal nocturnal hemoglobinuria                          hyperkalemia may be associated, requiring
   • Radiation                                                    hemodialysis or peritoneal dialysis.
   • Chemotherapy          (epipodophyllotoxins,
       alkylating agents, anthracyclins)                          Diagnostic methods
                                                                  Routine blood analysis shows in the majority of
Clinical presentation                                             patients a normocytic, normochromic anemia,
Children with AML in general may present with a                   which may be as low as 3 gr/dl. Reticulocyte
broad variety of (atypical) symptoms, which may                   count is low. Erythrocyte sedimentation rate
range from minor symptoms to life-threatening                     (ESR) is often increased. Thrombocyte count is
conditions. Most patients will present with fatigue               mostly decreased (<100.000/ml). WBC count
and/or asthenia, which is often accompanied by                    may be decreased, normal or (substantially)
(persistent) fever. Severe infections may occur                   increased. WBC differential (the percentage of
due to the diminished neutrophil count and                        each of the five types of white blood cells) may
function. Easy bruising (petechiae and/or                         show myeloblasts that may contain Auer rods,
purpura) may occur as well as enhanced                            which are needle-shaped accumulations of
bleeding (epistaxis, oral or gingival bleeding,                   myeloid granules. However, myeloblasts are not
rectal blood loss, menorrhagia, cerebral                          always observed in the WBC differential, and
hemorrhage). These bleeding disorders result                      only promyelocytes and/or myelocytes may be
from thrombocytopenia that may be associated                      seen. Neutrophil count is often decreased.
to Disseminated Intravascular Coagulopathy

Verschuur A. Acute megakaryoblastic leukemia. Orphanet Encyclopedia. May 2004.                                                                      2
A prolonged prothrombin time (PT) and/or                          (AML-M7), which is very rare in the normal
activated partial thromboplastin time (APTT) may                  pediatric population.
reveal DIC. Additional screening then may show                    The AML-M7 represents ± 5-10% of all pediatric
decreased        fibrinogen      levels,  increased               cases of AML and has an incidence of 0.5 per
fibrinogen degradation products (FDP) or D-                       million per year.
dimers, and decreased antithrombin III levels.
Blood chemistry analysis should include plasma                    Management including treatment
electrolytes, uric acid, lactate dehydrogenase                    AML remains a disease that is difficult to treat.
(LDH), creatinin and blood urea nitrogen (BUN).                   Treatment consists of aggressive multidrug
A bone marrow aspirate is mandatory.                              chemotherapy regimens, which are associated
Morphologic analysis after May-Grünwald-                          with non-negligible mortality and morbidity. The
Giemsa staining generally shows a majority of                     main drugs used for the treatment of AML are
blasts: 18-30 µm large cells, with a high                         cytarabine,        anthracyclins      (daunorubicin,
nuclear/cytoplasmic ratio but with more                           idarubicin and mitoxantrone) and etoposide.
cytoplasm than the other subtypes of AML. The                     These key-drugs are repeatedly administered
nuclei generally contain 1-3 nucleoli and fine                    using various schemes of dosing and may be
chromatin. Special stainings (myeloperoxidase,                    associated to drugs such as 6-thioguanine,
Sudan black B, chloroacetate esterase) may                        dexamethasone and amsacrin. In most
help to make the distinction between the various                  chemotherapy protocols, 4-6 courses of
subtypes of AML and ALL. Immunophenotyping                        multidrug chemotherapy are administered with
usually reveals positivity for CD33, CD13, CD41,                  an interval of 3-4 weeks. A high dose and time-
CD61 and factor VIII.                                             intensity may positively influence the outcome of
A specimen of the bone marrow aspirate is also                    the     treatment.      Chemotherapy       is   also
used for cytogenetic analysis in order to detect                  administered intrathecally in order to treat or
any of the several chromosomal abnormalities                      prevent CNS-leukemia.
observed in AML. The t(1;22) translocation is                     Each course results temporarily in severe bone
sometimes encountered in AML-M7.                                  marrow suppression, leading to prolonged
Cerebrospinal (CSF) analysis is also mandatory                    anemia, leukocytopenia, neutropenia and
in order to exclude CNS invasion, which is                        thrombocytopenia. This is often accompanied by
defined as > 5 cells/ml and by the presence of                    (opportunistic) bacterial or fungal infections,
myeloblasts.                                                      which may be life threatening. Moreover, the
Radiological investigations include chest X-ray,                  chemotherapy courses result in mucositis, which
abdominal ultrasound and in case of                               is due to a cytotoxic effect of the chemotherapy
neurological symptoms computed tomography                         on the epithelium of the intestinal tract, requiring
(CT) or magnetic resonance imaging (MRI) of                       various supportive care measures. The repeated
the     brain      using     appropriate    contrast.             administration of anthracyclins may cause a
Echocardiography should assess left ventricular                   decrease in cardiac contractility on the short
contractility prior to starting chemotherapy.                     (months) and long term (years).
                                                                  Supportive measures during and after treatment
Epidemiology                                                      comprise:
The incidence of pediatric AML is 4.8 – 6.6 per                       • Anti-emetic compounds (ondansetron,
million per year in children <15 years (Gurney,                             granisetron,                 domperidone,
1995). There is no male or female                                           dexamethasone,           metoclopramide,
preponderance. However, there is ethnic                                     alizapride, chlorpromazine)
variation in incidence, since there is a higher
                                                                      • Analgetics (paracetamol, tramadol,
incidence of pediatric AML in Asians and
Hispanics as compared to non-Hispanic
Caucasians in the USA (Gurney, 1995). Black                           • Prophylactic           and/or      therapeutic
children have a lower incidence of AML than                                 antibiotics and antifungal compounds.
Caucasians in the USA (Parkin, 1988). There is                        • Transfusions of leucocyte-depleted
a peak incidence during infancy (Stiller 1995,                              erythrocyte       concentrates      and/or
Kaatsch 1995), but AML may occur throughout                                 thrombocyte suspensions
childhood.                                                            • Enteral nutritional supplements or
As previously mentioned, the incidence is higher                            parenteral nutrition
in some genetic congenital disorders. In Down                         • Hematopoietic stem cell growth factors
syndrome, the relative risk of developing AML is                            (G-CSF)
20, and reaches 153 during the first four years of
life (Hasle, 2000). Children with Down syndrome                   Bone marrow transplantation
may develop all types of AML, although there is                   Some patients may benefit from allogeneic bone
a preponderance of megakaryocytic leukemia                        marrow transplantation (alloBMT). Whether a

Verschuur A. Acute megakaryoblastic leukemia. Orphanet Encyclopedia. May 2004.                                                                     3
patient with AML will be treated with alloBMT                     targeting CD33 and labelled with a radionuclide
depends on the type of AML, the associated                        or toxic compound. Moreover, “targeted
cytogenetic abnormality, the response to                          therapies” such as imatinib mesylate (Glivec ®),
chemotherapy and the availability of a donor.                     flt-3 inhibitors and farnesyl transferase inhibitors,
This treatment is applied when complete                           may act on tumour-specific cellular pathways,
remission is obtained after 2-4 courses of                        resulting possibly in less toxicity than the
induction and consolidation chemotherapy, and                     conventional chemotherapeutic compounds with
aims at removing the minimal residual disease.                    hopefully better anti-tumour effect.
The treatment consists of combining high-dose
chemotherapy with Total Body Irradiation (TBI),                   Unresolved questions and conclusion
which is followed by the reinfusion of HLA-                       The mechanisms underlying AML and the
identical hematopoietic stem cells of a sibling or                reasons for the difficulties of treating patients
a matched unrelated donor (MUD). The anti-                        with AML have only partly been unravelled. The
tumour effect is obtained by the cytotoxic effects                large difference in outcome between patients
of the chemotherapy and radiotherapy and by                       with/without Down syndrome suffering from
immunological effects (“Graft-versus-leukemia”                    AML-M7 remains to be understood. The various
effect) caused by minor immunological                             mechanisms of drug resistance certainly play a
disparities between donor and recipient.                          role in the moderate outcome of patients with
Although alloBMT has improved the outcome of                      AML after intensive chemotherapy. Novel
AML patients, it remains a highly specialized                     targeted therapies may hopefully improve
treatment with high treatment-related mortality                   treatment when combined with the conventional
(10-15%) and morbidity (Stevens, 1998).                           chemotherapeutic approaches.
AlloBMT is not indicated in patients with Down
syndrome and AML-M7, since they tend to have                      References
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Verschuur A. Acute megakaryoblastic leukemia. Orphanet Encyclopedia. May 2004.                                                                   5