Elsevier

Blood Reviews

Volume 29, Issue 2, March 2015, Pages 101-125
Blood Reviews

REVIEW
Global characteristics of childhood acute promyelocytic leukemia

https://doi.org/10.1016/j.blre.2014.09.013Get rights and content

Abstract

Acute promyelocytic leukemia (APL) comprises approximately 5–10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning > 60 countries) identified, variation was apparent—de novo APL represented from 2% (Switzerland) to > 50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed.

Introduction

Leukemia, the most common type of cancer in children [1], accounts for 25–35% of cases of childhood cancer in most populations [1], [2]. Acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) comprise the two major subtypes of childhood leukemia, with ALL accounting for 76% of childhood leukemia cases [3], [4]. AML, the second largest subgroup in children but the most common leukemia type among adults [3], represents 15–20% of leukemia cases in children, and is responsible for up to 30% of pediatric leukemia related deaths [4], [5].

De novo acute promyelocytic leukemia (APL), a subtype of AML, represents about 5–10% of childhood AML cases in the United States [6]. Previous studies, in which the majority of cases were reported from clinical trials or treatment protocols, rather than population-based analyses, have suggested that in certain Latin American, European and African populations, APL comprises relatively higher percentages of childhood AML [7]. However, variation in incidence among geographic regions has not been formally explored at a global level.

This review not only provides an overview of childhood APL, but also aims to: 1) examine childhood APL as a proportion of AML in countries around the world in order to gain insight into potential global geographic patterns; 2) analyze whether a previously hypothesized gender predominance in childhood APL cases exists; and, 3) discuss the potential contribution of environmental risk factors to the development of APL, using the example of exposure to previous therapy for primary diseases.

AML encompasses a heterogeneous group of leukemias characterized by increased proliferation of myeloid cells in the bone marrow [8]. Among the subtypes of AML, APL is of particular interest due to its well-characterized etiology. With targeted treatment involving chemotherapy and all-trans retinoic acid (ATRA), the survival rate of APL in children is relatively high (75–80%) [9]. Additionally, variation in the incidence of APL as a percentage of total childhood AML across certain racial/ethnic groups and geographic regions has been previously observed, and is potentially attributable to certain environmental exposures.

The etiology, molecular mechanisms, and treatment of APL have been comprehensively studied. In 1990, based on the observation that retinoic acid, a vitamin A derivative, is able to induce in vivo differentiation of APL cells into mature granulocytes, a French team of researchers examined the retinoic acid receptor gene (RARα) and discovered that the t(15;17) translocation, characteristic of the majority of APL cases, involved the RARα gene (located on chromosome 17) and the PML locus on chromosome 15, resulting in PML/RARα fusion products [10], [11].

Under the French–American–British (FAB) classification system, AML is categorized into eight subtypes (AML-M0 to M7) based on morphological features, as well as percentage and maturation of myeloblasts [12]. Under the FAB system, APL is characterized as subtype AML-M3, in which the predominant cells are promyelocytes with heavy granules and Auer rods. Diagnosing the microgranular variant of APL (AML-M3v) can be difficult because its morphological and cytochemical features are often non-specific, leading to misdiagnosis as AML-M4 or AML-M5 [13]. For these reasons, APL diagnosis by morphology alone has its limitations.

Random somatic chromosomal abnormalities resulting in fusion gene rearrangements are common in the malignant cells of patients with AML. About 95% of APL cases are characterized by recurrent chromosomal rearrangements of the RARα gene located on chromosome 17 [14], with the majority involved in a t(15;17)(q24;q21) translocation where the RARα gene fuses to the PML gene on chromosome 15. Eight rare partner genes (in addition to PML) which fuse to RARα have been previously described: NPM1, NUMA1, PLZF, PRKAR1A, FIP1L1, BCOR, STAT5B and a yet unidentified gene. These are represented by cytogenetic abnormalities t(5;17)(q35;q21), t(11;17)(q13;q21), t(11;17)(q23;q21), del(17)(q21;q24)/t(17;17)(q21;q24), t(4;17)(q12;q21), t(X;17)(p11;q12), der(17) and t(3;17)(p25;q21), respectively [15], [16], [17], [18], [19], [20], [21], [22].

Recently, the AML committee of the International BFM Study Group published guidelines for the diagnosis and management of AML in children and adolescents with recommendations that cytogenetic and molecular methods should be performed in order to stratify AML subgroups by risk [23]. The advent of cytogenetic analysis has allowed the identification and categorization of recurring chromosomal aberrations associated with some AML subtypes, leading to the World Health Organization (WHO) classification system [24], [25]. Under the WHO classification system [26], AML subtypes are defined using more comprehensive information sources, including genetic, immunophenotypic, biological and clinical features, rather than morphology alone [27]. Under this system, APL (ICD-10 C92.4) falls into a category of myeloid leukemia with recurrent genetic abnormalities [28].

A notable epidemiologic feature of pediatric APL is that observed incidence rates, based on data from hospital-based registries and clinical trials, differ markedly among certain ethnic groups and geographic regions [14], [29]. Previous studies reported a high frequency of APL in certain Latin American, European and African populations, accounting for 17–58% of pediatric AML cases and 22–37% of adult AML cases [7]. APL incidence in studies like these traditionally has been estimated based on its relative frequency among other AML subtypes in large clinical trials because population-based registries did not distinguish APL from other AML subtypes until recently, and as a result, the true incidence rate of APL is nearly unknown [29].

The geographic variation in relative frequency of childhood APL potentially suggests that genetic predisposition towards APL and/or environmental exposures to specific risk factors may be involved [14]. Genetic predisposition may influence susceptibility to breakage at the site involved in chromosomal translocations, such as t(15;17), in APL [7]. In addition, nutritional and environmental factors [30], obesity at diagnosis [31], as well as dietary or metabolic patterns of ingested vitamin A (or its derivatives) [7], [32] have suggested associations with APL. Besides suggested genetic and environmental factors, exposure to chemotherapeutic drugs and other toxins may also contribute to APL development.

Development of therapy-related AML (t-AML) and APL (t-APL) is a potential long-term complication of exposure to high doses of chemotherapy and/or radiation involved in treatment of primary diseases, and leukemia that arises following exposure to chemotherapy is primarily AML [33]. Previous studies have suggested that radiation and chemotherapy with alkylating agents and topoisomerase II inhibitors are potentially implicated in the development of t-APL specifically [34], [35], [36]. In recent years, the development of t-AMLs has been a cause of increasing concern due to the increase in the number of individuals surviving primary malignancies [37]. Under the WHO classification of AML (ICD-10 C92.0), t-AMLs following chemotherapy are considered to be distinct diagnostic entities [38], and the system recognizes two types of t-AML based on causative therapy: an alkylating agent/radiation-related type and a topoisomerase II inhibitor-related type [27]. Similar to therapy-related leukemias with MLL translocations, t-APL following treatment with topoisomerase II inhibitors has distinct breakpoints at chromosomal translocations involving the RARα gene, which appear to be caused by the drug-topoisomerase ‘cleavable complexes’ [39], [40]. Such breakpoint features are a direct link between a causal exposure and leukemia, which hopefully could be extended to de novo or idiopathic APL in the future.

Other than exposure to radiation and drugs associated with therapy for a primary disease, AML development has also been associated with a variety of different environmental risk factors in both adults and children. In adults, an increased risk of AML has been strongly associated with exposure to ionizing radiation and benzene [41]. Additionally, exposures to other toxic chemicals and occupational hazards have been associated with AML in adults [3]. Due to the relative rarity of childhood AML and APL, fewer epidemiological studies addressing environmental exposure have been conducted [41]. Childhood exposure to petroleum solvents [42], as well as in utero exposure to ionizing radiation [43], and parental smoking [44], are a few among a range of risk factors reported as being potentially associated with development of childhood AML. In a recent case–control study of California children, Heck et al. examined associations between air toxics exposures in pregnancy and early life in relation to leukemia in young children, and found that risk of AML was increased with 3rd trimester exposures to chloroform, benzene, and two other traffic-related chemicals (meta/para-xylene and toluene) [45]. There appear to be a limited number of studies that have previously examined childhood exposure and the development of childhood APL specifically.

In this review, we aim to examine regional variation in the global geographic pattern of childhood APL. If the variation exists, it could potentially reflect the involvement of genetic, cultural, and environmental exposure related factors. Therefore, comprehensive characterization of such variation could help with the design of studies to examine the contribution of these factors. Data on childhood APL incidence is lacking for many global regions, however. Ribeiro and Rego have reported previously that a lack of population-based registries in developing countries makes determining the true frequency of APL difficult [29]. Recently, a population-based study of childhood leukemia in Brazil demonstrated that substantial regional differences in the incidence of AML; this finding, which corroborates hospital-based data described previously, warrants further ecological study [46]. Because the vast majority of the published data in APL came from clinical and/or descriptive epidemiologic data, the real incidence rate of APL is still unknown even in well-developed countries.

In the current study, we measured the frequency of childhood APL cases as a percentage of childhood AML, based on data from hospital-, study- or registry-based populations around the world. We sought to examine geographic variation and potential contributions, and to highlight regions of the world where data are not available so further studies including these areas can be conducted to increase the scope of the current understanding of this disease.

Section snippets

Study selection and criteria

Broad literature searches were conducted from June 2011 to February 2014 using PubMed and Google Scholar databases to locate original, peer-reviewed research and review articles related to childhood AML, APL, t-APL, geographic distributions, and potential risk factors. Initially, combinations of relevant key words were used to search for relevant studies, and terms used included: acute myeloid leukemia (leukaemia), pediatric (paediatric) acute promyelocytic leukemia, childhood leukemia,

Geographic area

The 142 studies included in the current review that had relevant data on de novo APL and AML cases represented 61 individual countries or regions spanning multiple countries (Table 2, Fig. 2). Information regarding the numbers of childhood AML and APL cases was available for countries in North America (Table 2a), South and Central America (Table 2b), Europe (Table 2c), Africa and the Middle East (Table 2d), Asia (Table 2e), and Oceania (Table 2f). The available data were mostly from Western

Conclusions

This study provides the first comprehensive overview of global variation in the proportion of childhood APL among AML cases. In the 142 studies gathered, we found the lowest percent of APL among AML in Switzerland (2.4%) and the highest in Nicaragua (58.8%). Compared to North America, the assessed APL risk among AML cases was more than two times higher in South/Central America (OR = 2.43, 95% CI = 1.70–3.47). A goal of this study was to examine whether known or potential environmental exposures and

Future directions

More studies examining both the incidence of APL, in countries and regions for which information is lacking, and the association of APL with specific risk factors are needed. In this review, we have examined the distribution of APL mostly in hospital- and study-based populations; further studies examining the distribution of APL using population-based data like national and/or regional cancer registries are needed. Since APL is a relatively rare subtype of acute childhood leukemia, studying

Practice points

  • Geographic patterns may potentially reflect specific genetic and environmental factors involved in development of APL.

  • In light of increasing globalization, where patients have lived previously may have increasing relevance to their risk of APL.

  • A predominance of either gender in de novo childhood APL was unclear. Although in the t-APL cases gathered a female predominance was observed, the number of cases was too few to draw conclusions about a potential gender difference.

  • Development of t-APL in

Research agenda

  • Geographic distribution of childhood APL using population-based data from registries

  • Contribution of specific environmental factors to childhood APL risk

  • Association between obesity and APL in children

The following are the supplementary data related to this article.

. Childhood APL gender ratios from AML studies.

. Childhood APL gender ratios from APL only studies.

. Therapy-related childhood APL case studies.

. Therapy-related APL in adults.

Conflict of interest

Dr. Smith has received consulting and expert testimony fees from lawyers representing both plaintiffs and defendants in cases involving claims related to exposure to chemicals and leukemia. The remaining authors declare that there are no conflicts of interest.

Acknowledgment

This study was supported in part by the National Institute of Environmental Health Sciences, NIEHS, and National Cancer Institute, NCI, (grant R01ES009137), NIEHS (grants P42ES04705 and P01ES018172), and the U.S. Environmental Protection Agency, US EPA (grant RD83451101). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIEHS, NCI and US EPA. Aaida Samad, an undergraduate, and a summer intern of STEER program (2011) at UC

References (272)

  • S.C. Raimondi et al.

    Cytogenetics of childhood acute nonlymphocytic leukemia

    Cancer Genet Cytogenet

    (1989)
  • G.M. Brodeur et al.

    Cytogenetic features of acute nonlymphoblastic leukemia in 73 children and adolescents

    Cancer Genet Cytogenet

    (1983)
  • M. Abdelhaleem

    Frequent but nonrandom expression of lymphoid markers on de novo childhood acute myeloid leukemia

    Exp Mol Pathol

    (2007)
  • T. Onsten et al.

    Cytogenetic and morphological findings in 166 patients with de novo acute myeloid leukemia in southern Brazil

    Cancer Genet Cytogenet

    (2006)
  • S. Strehl et al.

    Multiplex reverse transcriptase-polymerase chain reaction screening in childhood acute myeloblastic leukemia

    Blood

    (2001)
  • N.V. Lipay et al.

    Epidemiology of venous thromboembolism in children with malignant diseases: a single-center study of the Belarusian Center for Pediatric Oncology and Hematology

    Thromb Res

    (2011)
  • U. Creutzig et al.

    Improved Treatment results in childhood acute myelogenous leukemia—a report of the German cooperative study AML-BFM-78

    Blood

    (1985)
  • K.N. Manola et al.

    Cytogenetic abnormalities and monosomal karyotypes in children and adolescents with acute myeloid leukemia: correlations with clinical characteristics and outcome

    Cancer Genet

    (2013)
  • P. Monge et al.

    Childhood leukaemia in Costa Rica, 1981–96

    Paediatr Perinat Epidemiol

    (2002)
  • B. Deschler et al.

    Acute myeloid leukemia: epidemiology and etiology

    Cancer

    (2006)
  • J.F. Margolin

    Molecular diagnosis and risk-adjusted therapy in pediatric hematologic malignancies: a primer for pediatricians

    Eur J Pediatr

    (2011)
  • J. Quintana et al.

    Acute myelogenous leukemia in Chile PINDA protocols 87 and 92 results

    Leukemia

    (2005)
  • J. Gregory et al.

    Acute promyelocytic leukemia in childhood

    Curr Oncol Rep

    (2009)
  • B. Lowenberg et al.

    Acute myeloid leukemia

    N Engl J Med

    (1999)
  • Leukemias/Lymphomas: Acute Promyelocytic Leukemia (APL)

  • H. de The et al.

    The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus

    Nature

    (1990)
  • L. Longo et al.

    Rearrangements and aberrant expression of the retinoic acid receptor alpha gene in acute promyelocytic leukemias

    J Exp Med

    (1990)
  • B.J. Bain

    The Nature of Leukaemia, Cytology, Cytochemistry and the FAB Classification of Acute Leukaemia

    Leukaemia Diagnosis

    (2010)
  • S. Nagendra et al.

    Leukemias resembling acute promyelocytic leukemia, microgranular variant

    Am J Clin Pathol

    (2002)
  • C. Rizzari et al.

    Tailoring treatment strategy for acute promyelocytic leukemia in low-income countries

    Pediatr Blood Cancer

    (2009)
  • J. Huret

    t(17;17)(q21;q24) PRKAR1A/RARA; del(17)(q21q24) PRKAR1A/RARA

    Atlas Genet Cytogenet Oncol Haematol

    (2011)
  • R.L. Redner

    Variations on a theme: the alternate translocations in APL

    Leukemia

    (2002)
  • R.L. Redner et al.

    A novel t(3;17)(p25;q21) variant translocation of acute promyelocytic leukemia with rearrangement of the RARA locus

    Leukemia

    (2006)
  • S. Strehl et al.

    All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene

    Leukemia

    (2013)
  • T. Kondo et al.

    The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia

    Haematologica

    (2008)
  • S. Acevedo et al.

    Cytogenetic study of 50 de-novo cases of ANLL from Argentina

    Haematologica

    (1994)
  • S. Swerdlow et al.

    WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue World Health Organization

    (2008)
  • P. Imbach

    Acute myeloid leukemia

  • E. Mantadakis et al.

    A comprehensive review of acute promyelocytic leukemia in children

    Acta Haematol

    (2008)
  • R.C. Ribeiro et al.

    Management of APl in developing countries: epidemiology, challenges and opportunities for international collaboration

    Hematology Am Soc Hematol Educ Program

    (2006)
  • J. Feusner et al.

    Obesity in Newly Diagnosed Childhood Acute Promyelocytic Leukemia

  • A. Biondi et al.

    Acute Promyelocytic Leukaemia

    (2010)
  • D.W. Pyatt et al.

    Is age an independent risk factor for chemically induced acute myelogenous leukemia in children?

    J Toxicol Environ Health B

    (2007)
  • C. Sandoval et al.

    Secondary acute myeloid leukmeia in children perviously treated with alkylating agents, interclating topoisomeraise II inhibitors and irradiation

    J Clin Oncol

    (1993)
  • E. Jantunen et al.

    Secondary acute promyelocytic leukemia: an increasingly common entity

    Leuk Lymphoma

    (2007)
  • L. Detourmignies et al.

    Therapy-related acute promyelocytic leukemia: a report on 16 cases

    J Clin Oncol

    (1992)
  • K. Kudo et al.

    Etoposide-related acute promyelocytic leukemia

    Leukemia

    (1998)
  • W. Au et al.

    Two cases of therapy-related acute promyelocytic leukemia (t-APL) after mantle cell lymphoma and gestational trophoblastic disease

    Ann Hematol

    (2002)
  • M. Joannides et al.

    Molecular pathogenesis of secondary acute promyelocytic leukemia

    Mediterr J Hematol Infect Dis

    (2011)
  • A.R. Mistry et al.

    DNA topoisomerase II in therapy-related acute promyelocytic leukemia

    N Engl J Med

    (2005)
  • Cited by (0)

    1

    These authors contributed equally to this work.

    2

    Genes and Environment Laboratory, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, 388 Li-Ka Shing Center, Berkeley, CA 94720, USA. Tel.: + 1 510 643 5189; fax: + 1 510 642 0427.

    3

    Pediatric Hematology–Oncology Program Research Center-Instituto Nacional de Câncer, Rua André Cavalcanti, 37; 6° andar, CEP 20231050-Rio de Janeiro, Brazil. Tel.: + 55 21 32076532; fax: + 55 21 32076566.

    4

    International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France. Tel.: + 33 4 7273 8173; fax: + 33 4 7273 8342.

    5

    Berkeley Institute of the Environment and Superfund Research Program, Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, 386 Li Ka-Shing Center, Berkeley, CA 94720-3370, USA. Tel.: + 1 510 642 8770; fax: + 1 510 642 0427.

    6

    Children's Hospital Oakland, 747 52nd Street, Oakland, CA 94609, USA. Tel.: + 1 510 428 3689; fax: + 1 510 601 3916.

    7

    Department of Epidemiology and Biostatistics, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA. Tel.: + 1 415 514 0577; fax: + 1 415 502 7411.

    8

    School of Public Health, University of California, Berkeley, 1995 University Avenue, Suite 460, Berkeley, CA 94704-7392, USA. Tel.: + 1 510 643 1156; fax: + 1 510 642 9319.

    View full text