Acute myeloblastic leukemia with maturation by bcs24005


									Acute myeloblastic leukemia with maturation
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 myeloblastic leukemia with maturation (AML-M2) is one of the most
common type of pediatric AML. However, the condition is rare and represents approximately 5% of all
childhood leukemias and has an incidence of 1.6 - 2.2 per million per year. 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. A characteristic translocation
observed in AML-M2 is t(8;21). Treatment includes intensive multidrug chemotherapy and in selected
cases allogeneic bone marrow transplantation. Nevertheless, outcome of AML remains poor with an
overall survival of 35-60%. Children with AML-M2 carrying the t(8;21) translocation have a better
prognosis (69% survival). New therapeutics are required to increase the probability of cure in this serious

Acute non-lymphocytic leukemia (ANLL), Acute myeloblastic leukemia with maturation, AML-M2, AML,

Disease name and synonyms                                          Definition
   • Acute myeloblastic leukemia (AML) with                        AML-M2 is defined by more than 20% (WHO-
       maturation                                                  classification) or more than 30% (French-
   • AML-M2 (FAB-classification)                                   American-British     (FAB)-classification)   of
   • Acute        myeloid    leukemia     with                     myeloblasts in the bone marrow aspirate as
       t(8;21)(q22;q22),           (AML1/ETO)                      determined        by     morphology        and
       translocation (WHO classification)                          immunoflowcytometry. Maturation is defined as
   • Acute non-lymphocytic leukemia (ANLL)                         more than 10% of promyelocytes/ myelocytes in

Verschuur A. Acute myeloblastic leukemia with maturation. Orphanet Encyclopedia. May 2004.                                                                 1
the bone marrow aspirate. Monocytic cells                          purpura) may occur as well as enhanced
should comprise less than 20% of bone marrow                       bleeding (epistaxis, oral or gingival bleeding,
non-erythroid cells.                                               rectal blood loss, menorrhagia, cerebral
                                                                   hemorrhage). These bleeding disorders result
Differential diagnosis                                             from thrombocytopenia that may be associated
Other malignancies that should be differentiated                   to Disseminated Intravascular Coagulopathy
from AML are: acute lymphocytic leukemia (ALL)                     (DIC), which can lead to life-threatening
myelodysplastic syndrome (MDS), chronic                            situations. The complications due to bleeding
myeloid leukemia (CML) including juvenile                          contribute for 7-10% to the mortality that is
chronic myelomonocytic leukemia, bone marrow                       observed during the first days/weeks after
metastases of solid tumours such as                                diagnosis      (Creutzig,     1987).       However,
neuroblastoma, rhabdomyosarcoma and Ewing                          complications due to hemorrhage are more
sarcoma, bone marrow invasion by non-Hodgkin                       frequent in promyelocytic leukemia (AML-M3)
lymphoma (NHL).                                                    and monoblastic leukemia (AML-M5). Pallor may
Differential diagnosis also includes non-                          be predominant, and results from the decreased
malignant disorders such as transient leukemoid                    hemoglobin level. Pallor may be accompanied
reactions,      transient     myeloproliferative                   by dizziness, headache, tinnitus, collapses,
syndromes, juvenile chronic arthritis, infectious                  dyspnea and/or congestive heart failure. Gingival
mononucleosis, viral induced bone marrow                           hyperplasia may be present, but is not typical of
suppression, aplastic anemia, congenital or                        AML-M2.
acquired     neutropenia   and      autoimmune                     Dyspnea and/or hypoxia may also result from
cytopenia.                                                         leukostasis, which results in a decreased blood
                                                                   flow in some organs (lungs, CNS, liver, skin) due
Etiology                                                           to a dramatically increased White Blood Cell
Some congenital and acquired disorders may                         count (WBC) (> 100.000/ml) leading to
predispose to AML.                                                 hyperviscosity.
The congenital predisposing factors are:                           Neurological symptoms may occur: headache,
    • Down syndrome                                                nausea, vomiting, photophobia, cranial nerve
    • Twin with leukemia                                           palsies, papil edema and/or nuchal rigidity.
    • Fanconi’s anemia                                             These symptoms may result from leukostasis,
    • Bloom syndrome                                               but may also reveal meningeal invasion by
    • Ataxia teleangiectasia                                       myeloblasts or be the presenting symptoms of a
    • Neurofibromatosis type I                                     “chloroma”, which is a soft tissue mass
    • Li-Fraumeni syndrome                                         consisting of myeloblasts. These chloromas
    • Congenital      neutropenia     (Kostmann                    often have an orbital or periorbital localisation, or
        syndrome)                                                  may arise around the spinal cord, causing
    • Klinefelter’s syndrome                                       paraparesis or “cauda equina” syndrome. CNS
                                                                   leukemic infiltration occurs in 6-16% of AML
Acquired predisposing factors include:                             (Bisschop 2001, Abbott 2003) and is not specific
   • Prenatal       exposure      to     tobacco,                  of AML-M2.
       marijuana, alcohol                                          Renal insufficiency occurs seldomly. It is caused
   • Pesticides,       herbicides,     benzene,                    by hyperuricuria and/or hyperphosphaturia,
       petroleum                                                   leading to obstructing tubular deposits and
                                                                   oliguria/anuria. The etiology of these metabolic
   • Aplastic anemia
                                                                   disorders is called the “tumour lysis syndrome”,
   • Myelodysplastic syndrome
                                                                   where myeloblasts lyse spontaneously. This
   • Paroxysmal nocturnal hemoglobinuria
                                                                   situation is an emergency since life-threatening
   • Radiation                                                     hyperkalemia may be associated, requiring
   • Chemotherapy          (epipodophyllotoxins,                   hemodialysis or peritoneal dialysis.
       alkylating agents, anthracyclins)
                                                                   Diagnostic methods
Clinical presentation                                              Routine blood analysis shows in the majority of
Children with AML in general may present with a                    patients a normocytic, normochromic anemia,
broad variety of (atypical) symptoms, which may                    which may be as low as 3 gr/dl. Reticulocyte
range from minor symptoms to life-threatening                      count is low. Erythrocyte sedimentation rate
conditions. Most patients will present with fatigue                (ESR) is often increased. Thrombocyte count is
and/or asthenia, which is often accompanied by                     mostly decreased (<100.000/ml). WBC count
(persistent) fever. Severe infections may occur                    may be decreased, normal or (substantially)
due to the diminished neutrophil count and                         increased. WBC differential (the percentage of
function. Easy bruising (petechiae and/or                          each of the five types of white blood cells) may
                                                                   show myeloblasts that may contain Auer rods,

Verschuur A. Acute myeloblastic leukemia with maturation. Orphanet Encyclopedia. May 2004.                                                                       2
which are needle-shaped accumulations of                           Caucasians in the USA (Parkin, 1988). There is
myeloid granules. However, myeloblasts are not                     a peak incidence during infancy (Stiller 1995,
always observed in the differential, and only                      Kaatsch 1995), but AML may occur throughout
promyelocytes and/or myelocytes may be seen.                       childhood.
Neutrophil count is often decreased.                               As previously mentioned, the incidence is higher
A prolonged prothrombin time (PT) and or                           in some genetic congenital disorders. In Down
activated partial thromboplastin time (APTT) may                   syndrome, the relative risk of developing AML is
reveal DIC. Additional screening then may show                     20, and reaches 153 during the first four years of
decreased        fibrinogen      levels,  increased                life (Hasle, 2000). Children with Down syndrome
fibrinogen degradation products (FDP) or D-                        may develop all types of AML, although there is
dimers, and decreased anti thrombin III levels.                    a preponderance of megakaryocytic leukemia
Blood chemistry analysis should include plasma                     (AML-M7), which is very rare in the normal
electrolytes, uric acid, lactate dehydrogenase                     pediatric population.
(LDH), creatinin and Blood Urea Nitrogen (BUN).                    AML with maturation (FAB-M2) represents ±
A bone marrow aspirate is mandatory.                               30% of all pediatric cases of AML. However, the
Morphologic analysis after May-Grünwald-                           condition is rare and represents approximately
Giemsa staining generally shows a majority of                      5% of all childhood leukemias and has an
myeloblasts: 15-20 µm large cells, with a high                     incidence of 1.6 - 2.2 per million per year.
nuclear/cytoplasmic ratio. The nuclei generally
contain 1-3 nucleoli and fine chromatin. The                       Management including treatment
basophilic cytoplasm may contain granules                          AML remains a disease that is difficult to treat.
and/or      Auer       rods.     Special   stainings               Treatment consists of aggressive multidrugs
(myeloperoxidase, Sudan black B, chloroacetate                     chemotherapy regimens, which are associated
esterase) may help to make the distinction                         with non-negligible mortality and morbidity. The
between the various subtypes of AML and ALL.                       main drugs are cytarabine, anthracyclins
Immunophenotyping usually reveals positivity for                   (daunorubicin, idarubicin and mitoxantrone) and
MPO, CD13, CD15, CD33, CD34, CD65 and                              etoposide. These key-drugs are repeatedly
HLA-DR. CD117 may be co-expressed.                                 administered using various schemes of dosing
A specimen of the bone marrow aspirate is also                     and may be associated to drugs such as 6-
used for cytogenetic analysis in order to detect                   thioguanine, dexamethasone and amsacrin. In
any of the several chromosomal abnormalities                       most chemotherapy protocols, 4-6 courses of
observed in AML. The most widely observed                          multidrugs chemotherapy are administered with
abnormality in AML-M2 is the t(8;21) (q22;q22)                     an interval of 3-4 weeks. A high dose and time-
translocation, resulting in the AML1/ETO fusion                    intensity may positively influence the outcome of
product that functions as an active transcription                  the     treatment.      Chemotherapy      is   also
factor. Moreover, the detection of cytogenetic                     administered intrathecally in order to treat or
abnormalities may be of prognostic value, since                    prevent CNS-leukemia.
the t(8;21) translocation is associated with a                     Each course results temporarily in severe bone
good prognosis (Grimwade, 1988).                                   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 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.

Verschuur A. Acute myeloblastic leukemia with maturation. Orphanet Encyclopedia. May 2004.                                                                      3
    •    Transfusions      of   leucocyte-depleted                 35-60% (Ravindranath, 1996; Perel, 2002).
         erythrocyte       concentrates     and/or                 Several prognostic factors have been identified:
         thrombocyte suspensions.                                  age, WBC count, response to induction therapy,
                                                                   FAB-type of AML, leukemic cytogenetic
    •    Enteral nutritional supplements or
                                                                   abnormalities, Down syndrome. The t(8;21)
         parenteral nutrition.
                                                                   translocation is associated with a better
    •    Hematopoietic stem cell growth factors                    prognosis as compared to the absence of
         (G-CSF).                                                  cytogenetic abnormalities: Three year overall
                                                                   survival of patients with a t(8;21) translocation is
Bone marrow transplantation                                        69% (Grimwade, 1998).
Some patients may benefit from allogeneic bone                     Novel therapies are emerging: new nucleoside
marrow transplantation (alloBMT). Whether a                        analogues (fludarabine, cladribine, cyclopentenyl
patient with AML will be treated with alloBMT                      cytosine, clofarabine), monoclonal antibodies
depends on the type of AML, the associated                         targeting CD33 and labelled with a radionuclide
cytogenetic abnormality, the response to                           or toxic compound. Moreover, “targeted
chemotherapy and the availability of a donor.                      therapies” such as imatinib mesylate (Glivec ®),
This treatment is applied when complete                            flt-3 inhibitors and farnesyl transferase inhibitors,
remission is obtained after 2-4 courses of                         may act on tumour-specific cellular pathways,
induction and consolidation chemotherapy, and                      resulting possibly in less toxicity than the
aims at removing the minimal residual disease.                     conventional chemotherapeutic compounds with
The treatment consists of combining high-dose                      hopefully better anti-tumour effect.
chemotherapy with Total Body Irradiation (TBI),
which is followed by the reinfusion of HLA-                        Unresolved questions and conclusion
identical hematopoietic stem cells of a sibling or                 The underlying mechanisms of AML and the
a matched unrelated donor (MUD). The anti-                         reasons for the difficulties of treating patients
tumour effect is obtained by the cytotoxic effects                 with AML have only partly been unravelled. The
of the chemotherapy and radiotherapy and by                        various mechanisms of drug resistance certainly
immunological effects (“Graft-versus-leukemia”                     play a role in the moderate outcome of AML
effect) caused by minor immunological                              patients after intensive chemotherapy. Novel
disparities between donor and recipient.                           targeted therapies may hopefully improve
Although alloBMT has improved the outcome of                       treatment when combined with the conventional
AML patients, it remains a highly specialized                      chemotherapeutic approaches.
treatment with high treatment-related mortality
(10-15%) and morbidity (Stevens, 1998).                            References
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Verschuur A. Acute myeloblastic leukemia with maturation. Orphanet Encyclopedia. May 2004.                                                                 5

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