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Acute Megakaryoblastic Leukemia

Acute Megakaryoblastic Leukemia

Acute megakaryoblastic

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 blood cells. Acute megakaryoblastic leukemia (AML-M7) is a rare type of pediatric AML. It represents approximately 1% of all 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 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.

Keywords 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 immunoflowcytometry.

Verschuur A. Acute megakaryoblastic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM7.pdf 1

Differential diagnosis (DIC), which can lead to life-threatening Other 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), (MDS), chronic observed during the first days/weeks after (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 , Dyspnea and/or hypoxia may also result from congenital or acquired and leukostasis, which results in a decreased blood autoimmune cytopenia. flow in some organs (lungs, CNS, liver, skin) due to a dramatically increased 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 petroleum 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 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 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. http://www.orpha.net/data/patho/GB/uk-AMLM7.pdf 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 . 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 . Special stainings (, 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 morphine) 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 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. http://www.orpha.net/data/patho/GB/uk-AMLM7.pdf 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 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 a good prognosis after standard chemotherapy. Abbott BL, Rubnitz JE, Tong X, Srivastava DK, Autologous stem cell transplantations have been Pui CH, Ribeiro RC et al. Clinical significance of performed in the past, but are generally not central nervous system involvement at diagnosis recommended anymore, since it does not seem of pediatric : a single to improve the outcome as compared to the institution's experience. Leukemia current chemotherapeutic regimens 2003;17:2090-2096. (Ravindranath, 1996). Bisschop MM, Revesz T, Bierings M, van Weerden JF, van Wering ER, Hahlen K et al. Radiotherapy Extramedullary infiltrates at diagnosis have no The main indication for radiotherapy (RT) is the prognostic significance in children with acute previously mentioned TBI. Moreover, myeloid leukaemia. Leukemia 2001;15:46-49. craniospinal irradiation may be indicated when Creutzig U, Ritter J, Budde M, Sutor A, CNS is invaded by myeloblasts, although Schellong G. Early deaths due to hemorrhage repeated intrathecal chemotherapy has replaced and leukostasis in childhood acute myelogenous RT in some protocols. Finally, RT is applied for leukemia. Associations with hyperleukocytosis the emergency treatment of chloroma in case of and acute .Cancer. dural compression. 1987;60:3071-3079. Gurney JG, Severson RK, Davis S, Robison LL. Outcome Incidence of cancer in children in the United As mentioned before, AML remains a difficult States. Sex-, race-, and 1-year age-specific disease to treat. Some but little progress has rates by histologic type. Cancer 1995;75:2186- been made during the last 2-3 decades. Less 2195. than 20% of the patients with a recurrence can Hasle H, Clemmensen IH, Mikkelsen M. Risks be cured in the long term. Five year overall of leukaemia and solid tumours in individuals survival generally does not exceed 60% (38- with Down's syndrome. Lancet 2000;355:165- 72%) (Michel, 1996). When a bone marrow 169. donor is not available (which is the case in > Kaatsch P, Haaf G, Michaelis J. Childhood 50%), the overall survival drops to 35-60% malignancies in Germany--methods and results (Ravindranath, 1996; Perel, 2002). Several of a nationwide registry. Eur J Cancer prognostic factors have been identified: age, 1995;31A:993-999. WBC count, response to induction therapy, FAB- Michel G, Leverger G, Leblanc T, Nelken B, type of AML, leukemic cytogenetic abnormalities, Baruchel A, Landman-Parker J, et al. Allogeneic Down syndrome. The outcome of AML-M7 in bone marrow transplantation vs aggressive post- patients with Down syndrome is ± 70%. remission chemotherapy for children with acute Novel therapies are emerging: new nucleoside myeloid leukemia in first complete remission. A analogues (fludarabine, , cyclopentenyl prospective study from the French Society of cytosine, clofarabine), monoclonal antibodies

Verschuur A. Acute megakaryoblastic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM7.pdf 4

Pediatric and Immunology (SHIP). Stevens RF, Hann IM, Wheatley K, Gray RG. Bone Marrow Transplant 1996;17:191-196. Marked improvements in outcome with Parkin DM, Stiller CA, Draper GJ, Bieber CA. chemotherapy alone in paediatric acute myeloid The international incidence of childhood cancer. leukemia: results of the United Kingdom Medical Int J Cancer 1988;42:511-520. Research Council's 10th AML trial. MRC Perel Y, Auvrignon A, Leblanc T, Vannier JP, Childhood Leukaemia Working Party. Br J Michel G, Nelken B, et al. Impact of addition of Haematol 1998;101:130-140. maintenance therapy to intensive induction and Stiller CA, Allen MB, Eatock EM. Childhood consolidation chemotherapy for childhood acute cancer in Britain: the National Registry of myeloblastic leukemia: results of a prospective Childhood Tumours and incidence rates 1978- randomized trial, LAME 89/91. J Clin Oncol 1987. Eur J Cancer 1995;31A:2028-2034. 2002;20:2774-2782. Woods WG, Neudorf S, Gold S, Sanders J, Ravindranath Y, Yeager AM, Chang MN, Buckley JD, Barnard DR et al. A comparison of Steuber CP, Krischer J, Graham-Pole J et al. allogeneic bone marrow transplantation, Autologous bone marrow transplantation versus autologous bone marrow transplantation, and intensive consolidation chemotherapy for acute aggressive chemotherapy in children with acute myeloid leukemia in childhood. Pediatric myeloid leukemia in remission. Blood Oncology Group. N Engl J Med 1996; 334:1428- 2001;97:56-62. 1434.

Verschuur A. Acute megakaryoblastic leukemia. Orphanet Encyclopedia. May 2004. http://www.orpha.net/data/patho/GB/uk-AMLM7.pdf 5

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