Acute Monocytic Leukemia

Acute monocytic leukemia

Author: Doctor Arnauld C. Verschuur1 Creation date: May 2004

Scientific Editor: Professor Gilles Vassal

1Department 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:[email protected]

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 monocytic leukemia (AML-M5) is one of the most common type of AML in young children (< 2 years). However, the condition is rare and represents approximately 2.5% of all leukemias during childhood and has an incidence of 0.8 – 1.1 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 translocation observed in AML-M5 is t(9;11). 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%. 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 monocytic leukemia, AML-M5, chloroma

Disease name and synonyms Definition • Acute monocytic leukemia AML-M5 is defined by more than 20% (WHO- • Acute monoblastic leukemia classification) or more than 30% (French- • Acute myeloid leukemia (AML) M5 American-British (FAB) classification) of (FAB-classification) myeloblasts in the bone marrow aspirate. Bone • Acute myeloid leukemia with 11q23 marrow monocytic cells comprise more than (MLL) abnormalities (WHO 80% of non-erytroid cells. In AML-M5a, more classification) than 80% of monocytic cells are monoblasts, • Acute non-lymphocytic leukemia (ANLL) whereas in AML-M5b, less than 80% of

Verschuur A. Acute monocytic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM5.pdf 1 monocytic cells are monoblasts; other cells show rectal blood loss, menorrhagia, cerebral (pro)monocytic differentiation. hemorrhage). These bleeding disorders result from thrombocytopenia that may be associated Differential diagnosis to 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). Complications due to metastases of solid tumours such as hemorrhage are more frequent in AML-M5. neuroblastoma, rhabdomyosarcoma and Ewing Pallor may be predominant, and results from the sarcoma, bone marrow invasion by non-Hodgkin decreased hemoglobin level. Pallor may be lymphoma (NHL). accompanied by dizziness, headache, tinnitus, Differential diagnosis also includes non- collaps, dyspnea and/or congestive heart failure. malignant disorders such as transient leukemoid Cutaneous leukemic infiltration may arise in reactions, transient myeloproliferative AML-M5. Gingival hyperplasia may be present, syndromes, juvenile chronic arthritis, infectious but is not typical of AML-M5. mononucleosis, viral induced bone marrow Dyspnea and/or hypoxia may also result from suppression, aplastic anemia, congenital or leukostasis, which results in a decreased blood acquired neutropenia and autoimmune flow in some organs (lungs, CNS, liver, skin) due cytopenia. to a dramatically increased White Blood Cell count (WBC) (>100.000/ml) leading to Etiology hyperviscosity. Some congenital and acquired disorders may Neurological symptoms may occur: headache, predispose to AML. nausea, vomiting, photophobia, cranial nerve The congenital predisposing factors are: palsies, papil edema and/or nuchal rigidity. • Down syndrome These symptoms may result from leukostasis, • Twin with leukemia but may also reveal meningeal invasion by • Fanconi’s anemia monoblasts or be the presenting symptoms of a • Bloom syndrome “chloroma”, which is a soft tissue mass • Ataxia teleangiectasia consisting of monoblasts. These chloromas often • Neurofibromatosis type I have an orbital or periorbital localisation, or may • Li-Fraumeni syndrome arise around the spinal cord, causing • Congenital neutropenia (Kostmann paraparesis or “cauda equina” syndrome. CNS syndrome) leukemic infiltration occurs in 6-16% of AML • Klinefelter’s syndrome (Bisschop 2001, Abbott 2003) and is frequent in AML-M5. Acquired predisposing factors include: 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 petroleum disorders is called the “tumour lysis syndrome”, where monoblasts lyse spontaneously. This • Aplastic anemia situation is an emergency since life-threatening • Myelodysplastic syndrome hyperkalemia may be associated, requiring • Paroxysmal nocturnal hemoglobinuria hemodialysis or peritoneal dialysis. • Radiation • Chemotherapy (epipodophyllotoxins, Diagnostic methods alkylating agents, anthracyclins) Routine blood analysis shows in the majority of patients a normocytic, normochromic anemia, Clinical presentation which may be as low as 3 gr/dl. Reticulocyte Children with AML in general may present with a count is low. Erythrocyte sedimentation rate broad variety of (atypical) symptoms, which may (ESR) is often increased. Thrombocyte count is range from minor symptoms to life-threatening mostly decreased (<100.000/ml). WBC count conditions. Most patients will present with fatigue may be decreased, normal or (substantially) and/or asthenia, which is often accompanied by increased. WBC differential (the percentage of (persistent) fever. Severe infections may occur each of the five types of white blood cells) may due to the diminished neutrophil count and show myeloblasts that may contain Auer rods, function. Easy bruising (petechiae and/or which are needle-shaped accumulations of purpura) may occur as well as enhanced myeloid granules. However, myeloblasts are not bleeding (epistaxis, oral or gingival bleeding, always observed in the differential, and only

Verschuur A. Acute monocytic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM5.pdf 2 promyelocytes and/or myelocytes may be seen. Kaatsch 1995), but AML may occur throughout Neutrophil count is often decreased. childhood. A prolonged prothrombin time (PT) and or As previously mentioned, the incidence is higher activated partial thromboplastin time (APTT) may in some genetic congenital disorders. In Down reveal DIC. Additional screening then may show syndrome, the relative risk of developing AML is decreased fibrinogen levels, increased 20, and reaches 153 during the first four years of fibrinogen degradation products (FDP) or D- life (Hasle, 2000). Children with Down syndrome dimers, and decreased anti thrombin III levels. may develop all types of AML, although there is Blood chemistry analysis should include plasma a preponderance of megakaryocytic leukemia electrolytes, uric acid, lactate dehydrogenase (AML-M7), which is very rare in the normal (LDH), creatinin and Blood Urea Nitrogen (BUN). pediatric population. A bone marrow aspirate is mandatory. AML-M5 represents 18% of all pediatric cases of Morphologic analysis after May-Grünwald- AML (Raimondi, 1999). In young children (<2 Giemsa staining generally shows a majority of years) the proportion of AML-M5 is 40-50%. monoblasts: 15-25 µm large cells, with a high However, the condition is rare and represents nuclear/cytoplasmic ratio, that however contain approximately 2.5% of all leukemias during more cytoplasm than myeloblasts. The nuclei childhood and has an incidence of 0.8 – 1.1 per generally contain 1-3 nucleoli and fine million per year. AML-M5 with MLL abnormalities chromatin. Auer rods are uncommon. The may develop as secondary AML after treatment basophilic cytoplasm may contain granules with chemotherapy. and/or vacuoles. More differentiated (pro)monocytes may be even larger and have Management including treatment irregular shapes. Non-specific esterases (NSE) AML remains a disease that is difficult to treat. usually stain positive which helps to make the Treatment consists of aggressive multidrugs distinction between the various subtypes of AML. chemotherapy regimens, which are associated Immunophenotyping usually reveals positivity for with non-negligible mortality and morbidity. The CD13, CD15, CD33 and HLA-DR. Specific main drugs used for the treatment of AML are monocytic markers are: CD11b, CD14 and CD cytarabine, anthracyclins (daunorubicin, 64. idarubicin and mitoxantrone) and etoposide. A specimen of the bone marrow aspirate is also These key-drugs are repeatedly administered used for cytogenetic analysis in order to detect using various schemes of dosing and may be any of the several chromosomal abnormalities associated to drugs such as 6-thioguanine, observed in AML. The most widely observed dexamethasone and amsacrin. In most abnormality in AML-M5 is the t(9;11) (p21- chemotherapy protocols, 4-6 courses of 22;q23) translocation, resulting in the MLL/AF-9 multidrugs chemotherapy are administered with fusion product. Other MLL abnormalities on an interval of 3-4 weeks. A high dose and time- chromosome 11 have also been described. intensity may positively influence the outcome of Cerebrospinal (CSF) analysis is also mandatory the treatment. Chemotherapy is also in order to exclude CNS invasion, which is administered intrathecally in order to treat or defined as > 5 cells/ml and the presence of prevent CNS-leukemia. myeloblasts. Each course results temporarily in severe bone Radiological investigations include chest X-ray, marrow suppression, leading to prolonged abdominal ultrasound and in case of anemia, leukocytopenia, neutropenia and neurological symptoms computed tomography thrombocytopenia. This is often accompanied by (CT) or magnetic resonance imaging (MRI) of (opportunistic) bacterial or fungal infections, the brain using appropriate contrast. which may be life threatening. Moreover, the Echocardiography should assess left ventricular chemotherapy courses result in mucositis, which contractility prior to starting chemotherapy. is due to a cytotoxic effect of the chemotherapy on the epithelium of the intestinal tract, requiring Epidemiology various supportive care measures. The repeated The incidence of pediatric AML is 4.8 – 6.6 per administration of anthracyclins may cause a million per year in children <15 years (Gurney, decrease in cardiac contractility on the short 1995). There is no male nor female (months) and long term (years). preponderance. However, there is ethnic Supportive measures during and after treatment variation in incidence, since there is a higher comprise: incidence of pediatric AML in Asians and • Anti-emetic compounds (ondansetron, Hispanics as compared to non-Hispanic granisetron, domperidone, Caucasians in the USA (Gurney, 1995). Black dexamethasone, metoclopramide, children have a lower incidence of AML than alizapride, chlorpromazine). Caucasians in the USA (Parkin, 1988). There is a peak incidence during infancy (Stiller 1995,

Verschuur A. Acute monocytic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM5.pdf 3

• Analgetics (paracetamol, tramadol, survival generally does not exceed 60% (38- morphine). 72%) (Michel, 1996). When a bone marrow donor is not available (which is the case in more • Prophylactic and/or therapeutic than 50% of cases), the overall survival drops to antibiotics and antifungal compounds. 35-60% (Ravindranath, 1996; Perel, 2002). • Transfusions of leucocyte-depleted Several prognostic factors have been identified: erythrocyte concentrates and/or age, WBC count, response to induction therapy, thrombocyte suspensions. FAB-type of AML, leukemic cytogenetic • Enteral nutritional supplements or abnormalities, Down syndrome parenteral nutrition. The t(9;11) translocation is associated with a • Hematopoietic stem cell growth factors better prognosis in some series, although it (G-CSF). remains controversial (Grimwade, 1998; Raimondi, 1999). Secondary AML occurring after Bone marrow transplantation chemotherapy has a poor prognosis. 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 mechanisms underlying 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 patients effect) caused by minor immunological AML 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 Autologous stem cell transplantations have been Abbott BL, Rubnitz JE, Tong X, Srivastava DK, performed in the past, but are generally not Pui CH, Ribeiro RC et al. Clinical significance of recommended anymore, since they do not seem central nervous system involvement at diagnosis to improve the outcome as compared to the of pediatric acute myeloid leukemia: a single current chemotherapeutic regimens institution's experience. Leukemia (Ravindranath, 1996). 2003;17:2090-2096. Bisschop MM, Revesz T, Bierings M, van Radiotherapy Weerden JF, van Wering ER, Hahlen K et al. The main indication for radiotherapy (RT) is the Extramedullary infiltrates at diagnosis have no previously mentioned TBI. Moreover, prognostic significance in children with acute craniospinal irradiation may be indicated when myeloid leukaemia. Leukemia 2001;15:46-49. CNS is invaded by myeloblasts, although Creutzig U, Ritter J, Budde M, Sutor A, repeated intrathecal chemotherapy has replaced Schellong G. Early deaths due to hemorrhage RT in some protocols. Finally, RT is applied for and leukostasis in childhood acute myelogenous the emergency treatment of chloroma in case of leukemia. Associations with hyperleukocytosis dural compression. and acute monocytic leukemia.Cancer. 1987;60:3071-3079. Outcome Grimwade D, Walker H, Oliver F, Wheatley K, As mentioned before, AML remains a difficult Harrison C, Harrison G et al. The importance of disease to treat. Some but small progress has diagnostic cytogenetics on outcome in AML: been made during the last 2-3 decades. Less analysis of 1,612 patients entered into the MRC than 20% of the patients with a recurrence can AML 10 trial. The Medical Research Council be cured in the long term. Five year overall

Verschuur A. Acute monocytic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM5.pdf 4

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Verschuur A. Acute monocytic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM5.pdf 5