Acute myelomonocytic leukemia
Author: Doctor Arnauld C. Verschuur1
Creation date: May 2004
Scientific Editor: Professor Gilles Vassal
1
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.
mailto:a.c.verschuur@amc.uva.nl
Abstract
Keywords
Disease name and synonyms
Definition
Differential diagnosis
Etiology
Clinical presentation
Diagnostic methods
Epidemiology
Management including treatment
Outcome
Unresolved questions and conclusion
References
Abstract
Acute myeloblastic leukemia (AML) is a group of malignant bone marrow neoplasms of myeloid
precursors of white blood cells. Acute myelomonocytic leukemia (AML-M4) is a common type of pediatric
AML. However, the condition is rare and represents approximately 3 % of all leukemias during childhood
and has an incidence of 1.1 – 1.7 per million per year. The symptoms may be aspecific: 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 chromosomal abnormality
observed in AML-M4 is inv(16). 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-M4 carrying the inv(16) abnormality have a better prognosis
(61% 5-year overall survival). New therapeutics are required to increase the probability of cure in this
serious disorder.
Keywords
Acute non-lymphocytic leukemia (ANLL), Acute myeloblastic leukemia (AML), Acute myelomonocytic
leukemia, AML-M4, AML-M4eo
Disease name and synonyms Definition
• Acute myelomonocytic leukemia AML-M4 is defined by more than 20% (WHO-
• Acute myeloblastic leukemia (AML) M4 classification) or more than 30% (French-
(FAB-classification) American-British (FAB) classification) of
• Acute myeloid leukemia with myeloblasts in the bone marrow aspirate.
inv(16)(p13;q22) or t(16;16)(p13;q22) Moreover, 20% of non-erythroid cells are of
(WHO classification) monocytic origin.
• Acute non-lymphocytic leukemia (ANLL)
Verschuur A. Acute myelomonocytic leukemia. Orphanet Encyclopedia. May 2004.
http://www.orpha.net/data/patho/GB/uk-AMLM4.pdf 1
The M4eo variant is characterised by more than rectal blood loss, menorrhagia, cerebral
5% of abnormal eosinophilic cells. hemorrhage). These bleeding disorders result
from thrombocytopenia that may be associated
Differential diagnosis with Disseminated Intravascular Coagulopathy
Other malignancies that should be differentiated (DIC), which can lead to life-threatening
from AML are: acute lymphocytic leukemia situations. The complications due to bleeding
(ALL), myelodysplastic syndrome (MDS), chronic contribute for 7-10% to the mortality that is
myeloid leukemia (CML) including juvenile observed during the first days/weeks after
chronic myelomonocytic leukemia, bone marrow diagnosis (Creutzig, 1987). However,
metastases of solid tumours such as complications due to hemorrhage are more
neuroblastoma, rhabdomyosarcoma and Ewing frequent in promyelocytic leukemia (AML-M3)
sarcoma, bone marrow invasion by non-Hodgkin and monoblastic leukemia (AML-M5). Pallor may
lymphoma (NHL). be predominant, and results from the decreased
Differential diagnosis also includes non- hemoglobin level. Pallor may be accompanied
malignant disorders such as transient leukemoid by dizziness, headache, tinnitus, collapses,
reactions, transient myeloproliferative dyspnea and/or congestive heart failure. Gingival
syndromes, juvenile chronic arthritis, infectious hyperplasia may be present, but is not typical of
mononucleosis, viral induced bone marrow AML-M4.
suppression, aplastic anemia, congenital or Dyspnea and/or hypoxia may also result from
acquired neutropenia and autoimmune leukostasis, which results in a decreased blood
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), especially in
Acquired predisposing factors include: AML-M4.
• Prenatal exposure to tobacco, Renal insufficiency occurs seldomly. It is caused
marijuana, alcohol by hyperuricuria and/or hyperphosphaturia,
• Pesticides, herbicides, benzene, leading to obstructing tubular deposits and
petroleum 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 ( 5 cells/ml and the presence of marrow suppression, leading to prolonged
myeloblasts. anemia, leukocytopenia, neutropenia and
Radiological investigations include chest X-ray, thrombocytopenia. This is often accompanied by
abdominal ultrasound and in case of (opportunistic) bacterial or fungal infections,
neurological symptoms computed tomography which may be life threatening. Moreover, the
(CT) or magnetic resonance imaging (MRI) of chemotherapy courses result in mucositis, which
the brain using appropriate contrast. is due to a cytotoxic effect of the chemotherapy
Echocardiography should assess left ventricular on the epithelium of the intestinal tract, requiring
contractility prior to starting chemotherapy. various supportive care measures. The repeated
administration of anthracyclins may cause a
Epidemiology decrease in cardiac contractility on the short
The incidence of pediatric AML is 4.8 – 6.6 per (months) and long term (years).
million per year in children <15 years (Gurney, Supportive measures during and after treatment
1995). There is no male or female comprise:
preponderance. However, there is ethnic • Anti-emetic compounds (ondansetron,
variation in incidence, since there is a higher granisetron, domperidone,
incidence of pediatric AML in Asians and dexamethasone, metoclopramide,
Hispanics as compared to non-Hispanic alizapride, chlorpromazine).
Caucasians in the USA (Gurney, 1995). Black
• Analgetics (paracetamol, tramadol,
children have a lower incidence of AML than
morphine).
Caucasians in the USA (Parkin, 1988). There is
a peak incidence during infancy (Stiller 1995, • Prophylactic and/or therapeutic
Kaatsch 1995), but AML may occur throughout antibiotics and antifungal compounds.
childhood.
Verschuur A. Acute myelomonocytic leukemia. Orphanet Encyclopedia. May 2004.
http://www.orpha.net/data/patho/GB/uk-AMLM4.pdf 3
• Transfusions of leucocyte-depleted survival generally does not exceed 60% (38-
erythrocyte concentrates and/or 72%) (Michel, 1996). When a bone marrow
thrombocyte suspensions. donor is not available (which is the case in more
than 50% of cases), the overall survival drops to
• Enteral nutritional supplements or
35-60% (Ravindranath, 1996; Perel, 2002).
parenteral nutrition.
Several prognostic factors have been identified:
• Hematopoietic stem cell growth factors age, WBC count, response to induction therapy,
(G-CSF). FAB-type of AML, leukemic cytogenetic
abnormalities, Down syndrome.
Bone marrow transplantation The inv(16) chromosomal aberration is
Some patients may benefit from allogeneic bone associated with a better prognosis as compared
marrow transplantation (alloBMT). Whether a to the absence of cytogenetic abnormalities: 5-
patient with AML will be treated with alloBMT year overall survival of patients with inv(16) is
depends on the type of AML, the associated 61% (Grimwade, 1998).
cytogenetic abnormality, the response to Novel therapies are emerging: new nucleoside
chemotherapy and the availability of a donor. analogues (fludarabine, cladribine, cyclopentenyl
This treatment is applied when complete cytosine, clofarabine), monoclonal antibodies
remission is obtained after 2-4 courses of targeting CD33 and labelled with a radionuclide
induction and consolidation chemotherapy, and or toxic compound. Moreover, “targeted
aims at removing the minimal residual disease. therapies” such as imatinib mesylate (Glivec ®),
The treatment consists of combining high-dose flt-3 inhibitors and farnesyl transferase inhibitors,
chemotherapy with Total Body Irradiation (TBI), may act on tumour-specific cellular pathways,
which is followed by the reinfusion of HLA- resulting possibly in less toxicity than the
identical hematopoietic stem cells of a sibling or conventional chemotherapeutic compounds with
a matched unrelated donor (MUD). The anti- hopefully better anti-tumour effect.
tumour effect is obtained by the cytotoxic effects
of the chemotherapy and radiotherapy and by Unresolved questions and conclusion
immunological effects (“Graft-versus-leukemia” The mechanisms underlying AML and the
effect) caused by minor immunological reasons for the difficulties of treating patients
disparities between donor and recipient. with AML have only partly been unravelled. The
Although alloBMT has improved the outcome of large difference in outcome between patients
AML patients, it remains a highly specialized with/without Down syndrome suffering from
treatment with high treatment-related mortality AML-M7 remains to be understood. The various
(10-15%) and morbidity (Stevens, 1998). mechanisms of drug resistance certainly play a
Patients with AML-M4 carrying the inv(16) are role in the moderate outcome of patients with
generally not treated by alloBMT, since their AML after intensive chemotherapy. Novel
disease is often curable by standard AML targeted therapies may hopefully improve
chemotherapy regimens. treatment when combined with the conventional
Autologous stem cell transplantations have been chemotherapeutic approaches.
performed in the past, but are generally not
recommended anymore, since they do not seem References
to improve the outcome as compared to the Abbott BL, Rubnitz JE, Tong X, Srivastava DK,
current chemotherapeutic regimens Pui CH, Ribeiro RC et al. Clinical significance of
(Ravindranath, 1996). central nervous system involvement at diagnosis
of pediatric acute myeloid leukemia: a single
Radiotherapy institution's experience. Leukemia
The main indication for radiotherapy (RT) is the 2003;17:2090-2096.
previously mentioned TBI. Moreover, Bisschop MM, Revesz T, Bierings M, van
craniospinal irradiation may be indicated when Weerden JF, van Wering ER, Hahlen K et al.
CNS is invaded by myeloblasts, although Extramedullary infiltrates at diagnosis have no
repeated intrathecal chemotherapy has replaced prognostic significance in children with acute
RT in some protocols. Finally, RT is applied for myeloid leukemia. Leukemia 2001;15:46-49.
the emergency treatment of chloroma in case of Creutzig U, Ritter J, Budde M, Sutor A,
dural compression. Schellong G. Early deaths due to hemorrhage
and leukostasis in childhood acute myelogenous
Outcome leukemia. Associations with hyperleukocytosis
As mentioned before, AML remains a difficult and acute monocytic leukemia.Cancer.
disease to treat. Some but small progress has 1987;60:3071-3079.
been made during the last 2-3 decades. Less Grimwade D, Walker H, Oliver F, Wheatley K,
than 20% of the patients with a recurrence can Harrison C, Harrison G et al. The importance of
be cured in the long term. Five year overall diagnostic cytogenetics on outcome in AML:
Verschuur A. Acute myelomonocytic leukemia. Orphanet Encyclopedia. May 2004.
http://www.orpha.net/data/patho/GB/uk-AMLM4.pdf 4
analysis of 1,612 patients entered into the MRC maintenance therapy to intensive induction and
AML 10 trial. The Medical Research Council consolidation chemotherapy for childhood acute
Adult and Children's Leukaemia Working myeloblastic leukemia: results of a prospective
Parties. Blood 1998;92:2322-2333. randomized trial, LAME 89/91. J Clin Oncol
Gurney JG, Severson RK, Davis S, Robison LL. 2002;20:2774-2782.
Incidence of cancer in children in the United Ravindranath Y, Yeager AM, Chang MN,
States. Sex-, race-, and 1-year age-specific Steuber CP, Krischer J, Graham-Pole J et al.
rates by histologic type. Cancer 1995;75:2186- Autologous bone marrow transplantation versus
2195. intensive consolidation chemotherapy for acute
Hasle H, Clemmensen IH, Mikkelsen M. Risks myeloid leukemia in childhood. Pediatric
of leukaemia and solid tumours in individuals Oncology Group. N Engl J Med 1996; 334:1428-
with Down's syndrome. Lancet 2000;355:165- 1434.
169. Stevens RF, Hann IM, Wheatley K, Gray RG.
Kaatsch P, Haaf G, Michaelis J. Childhood Marked improvements in outcome with
malignancies in Germany--methods and results chemotherapy alone in paediatric acute myeloid
of a nationwide registry. Eur J Cancer leukemia: results of the United Kingdom Medical
1995;31A:993-999. Research Council's 10th AML trial. MRC
Michel G, Leverger G, Leblanc T, Nelken B, Childhood Leukaemia Working Party. Br J
Baruchel A, Landman-Parker J, et al. Allogeneic Haematol 1998;101:130-140.
bone marrow transplantation vs aggressive post- Stiller CA, Allen MB, Eatock EM. Childhood
remission chemotherapy for children with acute cancer in Britain: the National Registry of
myeloid leukemia in first complete remission. A Childhood Tumours and incidence rates 1978-
prospective study from the French Society of 1987. Eur J Cancer 1995;31A:2028-2034.
Pediatric Hematology and Immunology (SHIP). Woods WG, Neudorf S, Gold S, Sanders J,
Bone Marrow Transplant 1996;17:191-196. Buckley JD, Barnard DR et al. A comparison of
Parkin DM, Stiller CA, Draper GJ, Bieber CA. allogeneic bone marrow transplantation,
The international incidence of childhood cancer. autologous bone marrow transplantation, and
Int J Cancer 1988;42:511-520. aggressive chemotherapy in children with acute
Perel Y, Auvrignon A, Leblanc T, Vannier JP, myeloid leukemia in remission. Blood
Michel G, Nelken B, et al. Impact of addition of 2001;97:56-62.
Verschuur A. Acute myelomonocytic leukemia. Orphanet Encyclopedia. May 2004.
http://www.orpha.net/data/patho/GB/uk-AMLM4.pdf 5