Biology and outcome of childhood acute megakaryoblastic leukemia: A single institution's experience

Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Blood (Impact Factor: 10.43). 06/2001; 97(12):3727-32. DOI: 10.1182/blood.V97.12.3727
Source: PubMed

ABSTRACT To describe the clinical and biologic features of pediatric acute megakaryoblastic leukemia (AMKL) and to identify prognostic factors, experience at St Jude Children's Research Hospital was reviewed. Of 281 patients with acute myeloid leukemia treated over a 14-year period, 41 (14.6%) had a diagnosis of AMKL. Six patients had Down syndrome and AMKL, 6 had secondary AMKL, and 29 had de novo AMKL. The median age of the 22 boys and 19 girls was 23.9 months (range, 6.7-208.9 months). The rate of remission induction was 60.5%, with a 48% rate of subsequent relapse. Patients with Down syndrome had a significantly higher 2-year event-free survival (EFS) estimate (83%) than did other patients with de novo AMKL (14%) or with secondary AMKL (20%; P < or =.038). Among patients who had de novo AMKL without Down syndrome, 2-year EFS was significantly higher after allogeneic bone marrow transplantation (26%) than after chemotherapy alone (0%; P =.019) and significantly higher when performed during remission (46%) than when performed during persistent disease (0%; P =.019). The 5-year survival estimates were significantly lower for de novo AMKL (10%) than for other forms of de novo AML (42%; P <.001). Treatment outcome is very poor for patients with AMKL in the absence of Down syndrome. Remission induction is the most important prognostic factor. Allogeneic transplantation during remission offers the best chance of cure; in the absence of remission, transplantation offers no advantage over chemotherapy alone. (Blood. 2001;97:3727-3732)

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Available from: Bassem I Razzouk, Aug 10, 2015
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    • "AMKL is divided into two subgroups: AMKL arising in patients with Down syndrome (DS-AMKL), and leukemia arising in patients without Down syndrome (non-DS- AMKL). Although DS-AMKL patients have an excellent prognosis with an $80% survival, non-DS-AMKL patients do not fare as well, with a reported survival of only 14%–34% despite highintensity chemotherapy (Athale et al., 2001; Barnard et al., 2007; Creutzig et al., 2005). With the exception of the t(1;22) seen in infant non-DS-AMKL, little is known about the molecular lesions that underlie this leukemia subtype (Carroll et al., 1991; Lion et al., 1992; Ma et al., 2001; Mercher et al., 2001). "
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    ABSTRACT: To define the mutation spectrum in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL samples. Our analysis identified a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.
    Cancer cell 11/2012; 22(5):683-97. DOI:10.1016/j.ccr.2012.10.007 · 23.89 Impact Factor
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    • "AMKL in DS patients is distinguished by an unusually favorable clinical prognosis, first recognized by POG over a decade ago, and confirmed by the Nordic Society for Pediatric Hematology and Oncology and the Children's Cancer Group (CCG).[7] [27] [28] Current eventfree survival (EFS) for DS AMKL is about 80%, whereas EFS in the rarer subgroup of non- DS AMKL is considerably worse than other AML subtypes at 15-20%.[29] Young age is an important positive prognostic factor in DS AML. "
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    ABSTRACT: Patients with Down syndrome (DS) display a unique spectrum of malignancies, with a 10- to 20-fold higher risk of acute leukemias, and a markedly lower incidence of solid tumors. This review discusses the current understanding of the basis for this distinctive pattern of cancer incidence and the clinical and biologic features of the malignant disorders most frequent in DS individuals: transient myeloproliferative disease, acute megakaryoblastic leukemia, and acute lymphoblastic leukemia. We also review distinctive pharmacogenetic issues, highlighting the differential chemosensitivity and toxicity profiles of DS patients compared with the general population, and epidemiologic studies of protective and adverse environmental risk factors for the development of leukemia.
    The Oncologist 02/2009; 14(2):164-73. DOI:10.1634/theoncologist.2008-0217 · 4.54 Impact Factor
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    • "In a study conducted by Athale et al. in 2001, two findings were identified as highly diagnostic for AMKL: leukemic cells isolated from the BM had distinct morphologic features, such as surface blebs, cell clumping, and binucleation, and the presence of multifocal punctate cytoplasmic alpha naphthyl acetate esterase cytochemical staining that is inhibited by sodium fluoride. As aforementioned Trisomy 21-AMKL has a much better outcome than AMKL not associated with Trisomy 21 or GATA-1 mutations, and the same study found an estimated 83% two year event free survival rate for Trisomy 21-AMKL, versus 14% and 20% for de novo and secondary AMKL not associated with Trisomy 21 or spontaneous GATA-1 mutations (Athale et al., 2001). "
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    ABSTRACT: GATA-1 is one of the six members of the GATA gene family, a group of related transcription factors discovered in the 1980s. In the past few decades, the crucial role of GATA-1 in normal human hematopoiesis has been delineated. As would be expected, mutations in GATA-1 have subsequently been found to have important clinical significance, and are directly linked to deregulated formation of certain blood cell lineages. This paper reviews the functional consequences of GATA-1 mutations by linking specific errors in the gene, or its downstream protein products, to documented human diseases. These five human diseases are: X-linked thrombocytopenia (XLT), X-linked thrombocytopenia with thalassemia (XLTT), congenital erythropoietic porphyria (CEP), transient myeloproliferative disorder (TMD) and acute megarakaryoblastic leukemia (AMKL) associated with Trisomy 21, and, lastly, a particular subtype of anemia associated with the production of GATA-1s, a shortened, mutant isoform of the wild-type GATA-1. The different phenotypic expressions associated with GATA-1 mutations illustrate the integral function of the transcription factor in overall body homeostasis. Furthermore, these direct genotype-phenotype correlations reinforce the importance of unraveling the human genome, as such connections may lead to important therapeutic or preventive therapies.
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