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Acute Myelomonocytic Leukemia

Acute Myelomonocytic Leukemia

Acute myelomonocytic

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

Scientific Editor: Professor Gilles Vassal

1Department of Pediatric , 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 neoplasms of myeloid precursors of white cells. Acute myelomonocytic leukemia (AML-M4) is a common type of pediatric AML. However, the condition is rare and represents approximately 3 % of all during childhood and has an incidence of 1.1 – 1.7 per million per year. The symptoms may be aspecific: asthenia, pallor, , 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 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 (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 with 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 that may be associated Differential diagnosis with Disseminated Intravascular Coagulopathy Other that should be differentiated (DIC), which can lead to life-threatening from AML are: acute lymphocytic leukemia situations. The complications due to bleeding (ALL), (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 , congenital or Dyspnea and/or hypoxia may also result from acquired and autoimmune , which results in a decreased blood cytopenia. flow in some organs (lungs, CNS, liver, skin) due to a dramatically increased White 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 • 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, , 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 mostly decreased (<100.000/ml). WBC count and/or asthenia, which is often accompanied by may be decreased, normal or (substantially) (persistent) fever. Severe 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

Verschuur A. Acute myelomonocytic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM4.pdf 2 always observed in the differential, and only As previously mentioned, the incidence is higher and/or may be seen. in some genetic congenital disorders. In Down Neutrophil count is often decreased. syndrome, the relative risk of developing AML is A prolonged prothrombin time (PT) and or 20, and reaches 153 during the first four years of activated partial thromboplastin time (APTT) may life (Hasle, 2000). Children with Down syndrome reveal DIC. Additional screening then may show may develop all types of AML, although there is decreased fibrinogen levels, increased a preponderance of megakaryocytic leukemia fibrinogen degradation products (FDP) or D- (AML-M7), which is very rare in the normal dimers, and decreased anti thrombin III levels. pediatric population. Blood chemistry analysis should include plasma AML-M4 represents ± 20% of all pediatric cases electrolytes, uric acid, of AML, and is more frequent among young (LDH), creatinin and Blood Urea Nitrogen (BUN). children (<2 years). However, the condition is A bone marrow aspirate is mandatory. rare and represents approximately 3 % of all Morphologic analysis after May-Grünwald- leukemias during childhood and has an Giemsa generally shows a mixture of incidence of 1.1 – 1.7 per million per year. myeloblasts, monoblasts and promonocytes. The M4eo and M4baso subtypes are Management including treatment characterized by an excess of abnormal AML remains a disease that is difficult to treat. eosinophilic or basophilic cells. Special stainings Treatment consists of aggressive multidrug (, Sudan black B, chloroacetate chemotherapy regimens, which are associated esterase, α-naphtyl acetate esterase) may help with non-negligible mortality and morbidity. The to make the distinction between the various main drugs used for the treatment of AML are subtypes of AML and ALL. Immunophenotyping , anthracyclins (, usually reveals positivity for MPO, CD13, CD14, and ) and . CD15, CD33, CD34, CD64, CD65, CD117 and These key-drugs are repeatedly administered HLA-DR. using various schemes of dosing and may be A specimen of the bone marrow aspirate is also associated to drugs such as 6-thioguanine, used for cytogenetic analysis in order to detect dexamethasone and amsacrin. In most any of the several chromosomal abnormalities chemotherapy protocols, 4-6 courses of observed in AML. The most widely observed multidrug chemotherapy are administered with chromosomal abnormality in AML-M4 is the an interval of 3-4 weeks. A high dose and time- inv(16) aberration, which is typical of the M4eo intensity may positively influence the outcome of variant. Inv(16) is associated with a good the treatment. Chemotherapy is also prognosis (Grimwade, 1988). administered intrathecally in order to treat or Cerebrospinal (CSF) analysis is also mandatory prevent CNS-leukemia. in order to exclude CNS invasion, which is Each course results temporarily in severe bone defined as > 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 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 (, cladribine, cyclopentenyl This treatment is applied when complete cytosine, ), monoclonal antibodies 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 . therapies” such as 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 : 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 .. 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 on outcome in AML:

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Verschuur A. Acute myelomonocytic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM4.pdf 5

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