Classification of Pediatric Myeloid Malignancies
French-American-British (FAB) Classification for Childhood Acute Myeloid Leukemia
The first comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the FAB Cooperative Group.[1-5] This classification system, which has been replaced by the World Health Organization (WHO) system described below, categorized AML into the following major subtypes primarily based on morphology and immunohistochemical detection of lineage markers:
- M0: Acute myeloblastic leukemia without differentiation.[6,7] M0 AML, also referred to as minimally differentiated AML, does not express myeloperoxidase (MPO) at the light microscopy level, but may show characteristic granules by electron microscopy. M0 AML can be defined by expression of cluster determinant (CD) markers such as CD13, CD33, and CD117 (c-KIT) in the absence of lymphoid differentiation.
- M1: Acute myeloblastic leukemia with minimal differentiation but with the expression of MPO that is detected by immunohistochemistry or flow cytometry.
- M2: Acute myeloblastic leukemia with differentiation.
- M3: Acute promyelocytic leukemia (APL) hypergranular type. (Refer to the Acute Promyelocytic Leukemia section of this summary for more information on treatment options under clinical evaluation.)
- M3v: APL, microgranular variant. Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. Same clinical, cytogenetic, and therapeutic implications as FAB M3.
- M4: Acute myelomonocytic leukemia (AMML).
- M4Eo: AMML with eosinophilia (abnormal eosinophils with dysplastic basophilic granules).
M5: Acute monocytic leukemia (AMoL).
- M5a: AMoL without differentiation (monoblastic).
- M5b: AMoL with differentiation.
M6: Acute erythroid leukemia (AEL).
- M6a: Erythroleukemia.
- M6b: Pure erythroid leukemia (myeloblast component not apparent).
- M6c: Presence of myeloblasts and proerythroblasts.
- M7: Acute megakaryocytic leukemia (AMKL).
Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.
World Health Organization (WHO) Classification System
In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), or MLL translocations, which collectively constituted nearly half of the cases of childhood AML, were classified as AML with recurrent cytogenetic abnormalities. This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%; an additional clarification was made so that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered AML.[8-10]
In 2008, the WHO expanded the number of cytogenetic abnormalities linked to AML classification, and for the first time included specific gene mutations (CEBPA and NPM mutations) in its classification system. Such a genetically based classification system links AML class with outcome and provides significant biologic and prognostic information. With new emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will likely evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.
WHO classification of AML
- AML with recurrent genetic abnormalities:
- AML with t(8;21)(q22;q22), RUNX1-RUNX1T1(CBFA2-AML1-ETO).
- AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11.
- APL with t(15;17)(q24;q21), PML-RARA.
- AML with t(9;11)(p22;q23), MLLT3(AF9)-MLL.
- AML with t(6;9)(p23;q34), DEK-NUP214.
- AML with inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), RPN1-EVI1.
- AML (megakaryoblastic) with t(1;22)(p13;q13), RBM15-MKL1.
- AML with mutated NPM1.
- AML with mutated CEBPA.
- AML with myelodysplasia-related features.
- Therapy-related myeloid neoplasms.
- AML, not otherwise specified:
- AML with minimal differentiation.
- AML without maturation.
- AML with maturation.
- Acute myelomonocytic leukemia.
- Acute monoblastic and monocytic leukemia.
- Acute erythroid leukemia.
- Acute megakaryoblastic leukemia.
- Acute basophilic leukemia.
- Acute panmyelosis with myelofibrosis.
- Myeloid sarcoma.
- Myeloid proliferations related to Down syndrome:
- Transient abnormal myelopoiesis.
- Myeloid leukemia associated with Down syndrome.
- Blastic plasmacytoid dendritic cell neoplasm.
The treatment for children with AML differs significantly from that for acute lymphoblastic leukemia (ALL). As a consequence, it is critical to distinguish AML from ALL. Special histochemical stains performed on bone marrow specimens of children with acute leukemia can be helpful to confirm their diagnosis, although such approaches have been mostly replaced by flow cytometric immunophenotyping. The stains most commonly used include myeloperoxidase, periodic acid-Schiff, Sudan Black B, and esterase. In most cases the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (see below).
|M0||AML, APL (M1-M3)||AMML (M4)||AMoL (M5)||AEL (M6)||AMKL (M7)||ALL|
|AEL = acute erythroid leukemia; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AMKL = acute megakaryocytic leukemia; AMML = acute myelomonocytic leukemia; AMoL = acute monocytic leukemia; APL = acute promyelocytic leukemia; PAS = periodic acid-Schiff.|
|aRefer to the French-American-British (FAB) Classification for Childhood Acute Myeloid Leukemia section of this summary for more information about the morphologic-histochemical classification system for AML.|
|bThese reactions are inhibited by fluoride.|
|Alpha-naphthol acetate||-||-||+ b||+ b||-||± b||-|
|Sudan Black B||-||+||+||-||-||-||-|
The use of monoclonal antibodies to determine cell-surface antigens of AML cells is helpful to reinforce the histologic diagnosis. Various lineage-specific monoclonal antibodies that detect antigens on AML cells should be used at the time of initial diagnostic workup, along with a battery of lineage-specific T-lymphocyte and B-lymphocyte markers to help distinguish AML from ALL and bilineal (as defined below) or biphenotypic leukemias. The expression of various cluster determinant (CD) proteins that are relatively lineage-specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIb/IIIa), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AMLs, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-associated T-lymphocytic antigens are present in 20% to 40% of AMLs.[12-14] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[12,13]
Immunophenotyping can also be helpful in distinguishing some FAB subtypes of AML. Testing for the presence of HLA-DR can be helpful in identifying APL. Overall, HLA-DR is expressed on 75% to 80% of AMLs but rarely expressed on APL. In addition, APL cases with PML-RARA were noted to express CD34/CD15 and demonstrate a heterogeneous pattern of CD13 expression. Testing for the presence of glycoprotein Ib, glycoprotein IIb/IIIa, or Factor VIII antigen expression is helpful in making the diagnosis of M7 (megakaryocytic leukemia). Glycophorin expression is helpful in making the diagnosis of M6 (erythroid leukemia).
Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[17-19] These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies, although most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[20-22] In the WHO classification, the presence of MPO is required to establish myeloid lineage. This is not the case for the EGIL classification.
|NOS = not otherwise specified; WHO = World Health Organization.|
|aBéné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009. Obtained from Haematologica/the Hematology Journal website http://www.haematologica.org.|
|Acute undifferentiated leukemia||Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage|
|Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1||Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or the BCR-ABL1 rearrangement|
|Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged||Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving the MLL gene|
|Mixed phenotype acute leukemia, B/myeloid, NOS||Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or MLL|
|Mixed phenotype acute leukemia, T/myeloid, NOS||Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or MLL|
|Mixed phenotype acute leukemia, B/myeloid, NOS—rare types||Acute leukemia meeting the diagnostic criteria for assignment to both B- and T-lineage|
|Other ambiguous lineage leukemias||Natural killer cell lymphoblastic leukemia/lymphoma|
Leukemias of mixed phenotype comprise the following two groups of patients:
- Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
- Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage.
Biphenotypic cases represent the majority of mixed phenotype leukemias. B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have a lower rate of complete remission (CR) and a significantly worse event-free survival (EFS) compared with patients with B-precursor ALL. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen,[18,19,24] although the optimal treatment for patients remains unclear.
Cytogenetic Evaluation and Molecular Abnormalities
Chromosomal analyses of leukemia should be performed on children with AML because chromosomal abnormalities are important diagnostic and prognostic markers.[25-30] Clonal chromosomal abnormalities have been identified in the blasts of about 75% of children with AML and are useful in defining subtypes with particular characteristics (e.g., t(8;21), t(15;17), inv(16), 11q23 abnormalities, t(1;22)). Leukemias with the chromosomal abnormalities t(8;21) and inv(16) are called core-binding factor leukemias; core-binding factor (a transcription factor involved in hematopoietic stem cell differentiation) is disrupted by each of these abnormalities.
Molecular probes and newer cytogenetic techniques (e.g., fluorescence in situ hybridization [FISH]) can detect cryptic abnormalities that were not evident by standard cytogenetic banding studies. This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia (Ph) chromosome in patients with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML. Molecular methods are also being used to identify recurring gene mutations in adults and children with AML, and as described below, some of these recurring mutations have prognostic significance.
A unifying concept for the role of specific mutations in AML is that mutations that promote proliferation (Type I) and mutations that block normal myeloid development (Type II) are required for full conversion of hematopoietic stem/precursor cells to malignancy.[32,33] Support for this conceptual construct comes from the observation that there is generally mutual exclusivity within each type of mutation, such that a single Type I and a single Type II mutation are present within each case. Further support comes from genetically engineered models of AML for which cooperative events rather than single mutations are required for leukemia development. Type I mutations are commonly in genes involved in growth factor signal transduction and include mutations in FLT3, KIT, NRAS, KRAS, and PTNP11. Type II genomic alterations include the common translocations and mutations associated with favorable prognosis (t(8;21), inv(16), t(16;16), t(15;17), CEBPA, and NPM1). MLL rearrangements (translocations and partial tandem duplication) are also classified as Type II mutations.
Specific recurring cytogenetic and molecular abnormalities are briefly described below. The abnormalities are listed by those in clinical use that identify patients with favorable or unfavorable prognosis, followed by other abnormalities.
Molecular abnormalities associated with favorable prognosis include the following:
- t(8;21) (RUNX1-RUNX1T1): In leukemias with t(8;21), the RUNX1(AML1) gene on chromosome 21 is fused with the RUNX1T1 (ETO) gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas.[35,36] Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.[25,37] These children have a more favorable outcome compared with children with AML characterized by normal or complex karyotypes [25,38-40] with 5-year overall survival (OS) of 80% to 90%.[28,29] The t(8;21) translocation occurs in approximately 12% of children with AML.[28,29]
- inv(16) (CBFB-MYH11): In leukemias with inv(16), the CBF beta gene (CBFB) at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype. Inv(16) confers a favorable prognosis for both adults and children with AML [25,38-40] with a 5-year OS of about 85%.[28,29] Inv(16) occurs in 7% to 9% of children with AML.[28,29]
- t(15;17) (PML-RARA): AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently than other types of AML because of its marked sensitivity to the differentiating effects of all-trans retinoic acid. The t(15;17) translocation leads to the production of a fusion protein involving the retinoid acid receptor alpha and PML. Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t(11;17)(q23;q21) involving the PLZF gene). Identification of cases with the t(11;17)(q23;q21) is important because of their decreased sensitivity to all-trans retinoic acid.[42,43] APL represents about 7% of children with AML.[29,44]
Nucleophosmin (NPM1) mutations: NPM1 is a protein that has been linked to ribosomal protein assembly and transport as well as being a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 mutations by the demonstration of cytoplasmic localization of NPM. Mutations in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression, and an improved prognosis in the absence of FLT3-internal tandem duplication (ITD) mutations in adults and younger adults.[46-51]
Studies of children with AML suggest a lower rate of occurrence of NPM1 mutations in children compared with adults with normal cytogenetics. NPM1 mutations occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[33,52-54] NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[33,53,54] For the pediatric population, conflicting reports have been published regarding the prognostic significance of an NPM1 mutation when a FLT3-ITD mutation is also present, with one study reporting that an NPM1 mutation did not completely abrogate the poor prognosis associated with having a FLT3-ITD mutation,[53,55] but with other studies showing no impact of a FLT3-ITD mutation on the favorable prognosis associated with an NPM1 mutation.[33,54]
CEBPA mutations: Mutations in the CCAAT/Enhancer Binding Protein Alpha gene (CEBPA) occur in a subset of children and adults with cytogenetically normal AML. In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[50,56] Outcome for adults with AML with CEBPA mutations appears to be relatively favorable and similar to that of patients with core-binding factor leukemias.[50,56] Studies in adults with AML have demonstrated that CEBPA double-mutant, but not single-allele mutant, AML was independently associated with a favorable prognosis.[57-60]
CEBPA mutations occur in 5% to 8% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2; 70% to 80% of pediatric patients have double-mutant alleles, which is predictive of a significantly improved survival and similar to the effect observed in adult studies.[61,62] Although both double- and single-mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study, a second study observed inferior outcome for patients with single CEBPA mutations. However, very low numbers of children with single-allele mutants were included in these two studies (only 13 in toto), making a conclusion regarding the prognostic significance of single-allele CEBPA mutations in children premature.
Molecular abnormalities associated with an unfavorable prognosis include the following:
Chromosomes 5 and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 5 (monosomy 5 and del(5q)) and chromosome 7 (monosomy 7).[25,37,63] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[28,37,63-66]
In the past, patients with del(7q) were also considered to be at high risk of treatment failure and data from adults with AML support a poor prognosis for both del(7q) and monosomy 7. However, outcome for children with del(7q), but not monosomy 7, appears to be comparable to that of other children with AML.[29,66] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[25,66,67]
Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are 4 years of age and younger.
- Chromosome 3 (inv(3)(q21;q26) or t(3;3)(q21;q26)) and EVI1 overexpression: The inv(3) and t(3;3) abnormalities involving the EVI1 gene located at chromosome 3q26 are associated with poor prognosis in adults with AML,[25,37,69] but are very uncommon in children (<1% of pediatric AML cases).[28,39,70]
FLT3 mutations: Presence of a FLT3-ITD mutation appears to be associated with poor prognosis in adults with AML, particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[72,73] FLT3-ITD mutations also convey a poor prognosis in children with AML.[55,74-78] The frequency of FLT3-ITD mutations in children is lower than that observed in adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% for adults).[76,77,79] The prevalence of FLT3-ITD is increased in certain genomic subtypes of pediatric AML, including those with the NUP98-NSD1 fusion gene, of which 80% to 90% have FLT3-ITD.[80,81] Approximately 15% of patients with FLT3-ITD have NUP98-NSD1, and patients with both FLT3-ITD and NUP98-NDS1 have a poorer prognosis than do patients with FLT3-ITD and without NUP98-NDS1.
For APL, FLT3-ITD and point mutations occur in 30% to 40% of children and adults.[72,75,76,82-85] Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[75,84,86,87] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid and arsenic trioxide.[82,83,86,88,89]
Activating point mutations of FLT3 have also been identified in both adults and children with AML, though the clinical significance of these mutations is not clearly defined.
Other molecular abnormalities observed in pediatric AML include the following:
MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most AMLs secondary to epipodophyllotoxin, are associated with monocytic differentiation (FAB M4 and M5). The most common translocation,
representing approximately 50% of MLL-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23) in which the MLL gene is fused with the MLLT3(AF9) gene. An MLL gene rearrangement occurs in approximately 20% of children with AML.[28,29] However, more than 50 different fusion partners have been identified for the MLL gene in patients with AML. The median age for 11q23/MLL-rearranged cases in the pediatric AML setting is approximately 2 years, and most translocation subgroups have a median age at presentation of younger than 5 years. However, pediatric cases with t(6;11)(q27;q23) and t(11;17)(q23;q21) have significantly older median ages at presentation (12 years and 9 years, respectively).
Outcome for patients with de novo AML and MLL gene rearrangement is generally reported as being similar to that for other patients with AML.[25,28,91,92] However, as the MLL gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis, as demonstrated by a large international retrospective study evaluating outcome for 756 children with 11q23- or MLL-rearranged AML. For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/MLL-rearranged AML, showed a highly favorable outcome with 5-year EFS of 92%. While reports from single clinical trial groups have variably described more favorable prognosis for cases with t(9;11), in which the MLL gene is fused with the AF9 gene, the international retrospective study did not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup.[25,28,91,93-95]
Several 11q23/MLL-rearranged AML subgroups appear to be associated with poor outcome. For example, cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the central nervous system (CNS).[25,29,96] Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10-MLLT10 at 10p12, while others have fusion of MLL with ABI1 at 10p11.2.[97,98] The international retrospective study found that these cases, which present at a median age of approximately 1 year, have a 5-year EFS in the 20% to 30% range. Patients with t(6;11)(q27;q23) and with t(4;11)(q21;q23) also have a poor outcome, with a 5-year EFS of 11% and 29%, respectively, in the international retrospective study. A follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with MLL translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.
- t(6;9) (DEK-NUP214): t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214.[100,101] This subgroup of AML has been associated with a poor prognosis in adults with AML,[100,102,103] and occurs infrequently in children (less than 1% of AML cases). The median age of children with DEK-NUP214 AML is 10 to 11 years, and approximately 40% of pediatric patients have FLT3-ITD.[104,105] t(6;9) AML appears to be associated with a high risk of treatment failure in children, particularly for those not proceeding to allogeneic stem cell transplantation.[28,101,104,105]
t(1;22) (RBM15-MKL1): The t(1;22)(p13;q13) translocation is uncommon (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia (AMKL).[28,106-108] Most AMKL cases with t(1;22) occur in infants, with the median age at presentation (4–7 months) being younger than that for other children with AMKL.[109,110] The translocation is uncommon in children with Down syndrome who develop AMKL.[106,108] In leukemias with t(1;22), the RBM15 (OTT) gene
on chromosome 1 is fused to the MKL1 (MAL) gene on chromosome 22.[111,112] Cases with detectable RBM15-MKL1 fusion transcripts in the absence of t(1;22) have also been reported.
A report of 39 cases of AMKL with t(1;22) described a relatively poor outcome (survival rate of approximately 30%), similar to that of other patients with non–Down syndrome AMKL. Further experience has suggested that within the context of intensive chemotherapy and adequate supportive care, infants with t(1;22) can have a relatively favorable outcome that is superior to that of children with AMKL whose leukemia lacks t(1;22), with only 3 of 16 children with t(1;22) relapsing in two series.[108,109,113]
- t(8;16) (MYST3-CREBBP): The t(8;16) translocation fuses the MYST3 gene on chromosome 8p11 to CREBBP on chromosome 16p13. t(8;16) AML occurs rarely in children, and in an international Berlin-Frankfurt-Münster AML study of 62 children, presence of this translocation was associated with younger age at diagnosis (median, 1.2 years), FAB M4/M5 phenotype, erythrophagocytosis, leukemia cutis, and disseminated intravascular coagulation. Outcome for children with t(8;16) AML appears similar to other types of AML. A substantial proportion of infants diagnosed with t(8;16) AML in the first month of life show spontaneous remission, although AML recurrence may occur months to years later.[114-120] These observations suggest that a watch and wait policy could be considered in cases of t(8;16) AML diagnosed in the neonatal period if close long-term monitoring can be ensured.
- t(7;12)(q36;p13): The t(7;12)(q36;p13) translocation involves ETV6 on chromosome 12p13 and variable breakpoints on chromosome 7q36 in the region of MNX1 (HLXB9). The translocation may be cryptic by conventional karyotyping and in some cases may be confirmed only by fluorescence in situ hybridization (FISH).[122-124] This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with MLL rearrangement, and is associated with a high risk of treatment failure.[28,29,33,122,123,125]
NUP98 gene fusions: NUP98 has been reported to form leukemogenic gene fusions with more than 20 different partners. In the pediatric AML setting, the two most common fusion genes are NUP98-NSD1 and NUP98-JARID1A, with the former observed in one report in approximately 15% of cytogenetically normal pediatric AML and the latter observed in approximately 10% of pediatric AMKL.[80,109] AML cases with either NUP98 fusion gene show high expression of HOXA and HOXB genes, indicative of a stem cell phenotype.[101,109]
- NUP98-NSD1: The NUP98-NSD1 fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[80,81,101,127-130] This alteration occurs in approximately 4% to 5% of pediatric AML cases.[80,101,129] The highest frequency in the pediatric population is in the 5- to 9-year age group (approximately 8%), with lower frequency in younger children (approximately 2% in children younger than 2 years). NUP98-NSD1 cases present with high white blood cell (WBC) count (median, 147 × 109/L in one study).[80,81] Most NUP98-NSD1 AML cases do not show cytogenetic aberrations.[80,101,127] A high percentage of NUP98-NSD1 cases (80% to 90%) have FLT3-ITD.[80,81] A study that included 12 children with NUP98-NSD1 AML reported that although all patients achieved CR, presence of NUP98-NSD1 independently predicted for poor prognosis, and children with NUP98-NSD1 AML had a high risk of relapse, with a resulting 4-year EFS of approximately 10%. In another study that included children (n = 38) and adults (n = 7) with NUP98-NSD1 AML, presence of both NUP98-NSD1 and FLT3-ITD independently predicted for poor prognosis; patients with both lesions had a low CR rate (approximately 30%) and a low 3-year EFS rate (approximately 15%).
- NUP98-JARID1A:NUP98-JARID1A is a recurrent cryptic translocation in pediatric AMKL, accounting for approximately 10% of AMKL cases and having a median age at presentation of approximately 2 years. Risk of treatment failure appears high for patients with NUP98-JARID1A, although the number of patients studied is small.
- CBFA2T3-GLIS2: Initial reports have demonstrated that CBFA2T3-GLIS2 is a fusion product present in approximately 2% of pediatric AML; has a predominance in cytogenetically normal AML; and is associated with a poor prognosis in pediatric AML patients, with EFS and OS rates of approximately 30%.[109,131-133] The CBFA2T3-GLIS2 fusion protein results from a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)).[132,134] It was initially reported in patients with AMKL and was observed in approximately 30% of pediatric non–Down syndrome AMKL cases but was not observed in adults with AMKL.[132,134] A report of 105 cases of non–Down syndrome AMKL identified CBFA2T3-GLIS2 in 13% of cases. Subsequently, the CBFA2T3-GLIS2 fusion has been identified in non-AMKL pediatric patients, with 20 patients (10 with AMKL) positive for the fusion of 237 patients with cytogenetically normal AML investigated (8.4%).
- RAS mutations: Although mutations in RAS have been identified in 20% to 25% of patients with AML, the prognostic significance of these mutations has not been clearly shown.[33,135-137] Mutations in NRAS are observed more commonly than KRAS mutations in pediatric AML cases.[33,34] RAS mutations occur with similar frequency for all Type II alteration subtypes with the exception of APL, for which RAS mutations are seldom observed.
- KIT mutations: Mutations in KIT occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[33,34,138,139] The presence of activating KIT mutations in adults with this AML subtype appears to be associated with a poorer prognosis compared with core-binding factor AML without KIT mutation.[139-141] The prognostic significance of KIT mutations occurring in pediatric core-binding factor AML remains unclear,[138,142-144] although the largest pediatric study reported to date observed no prognostic significance for KIT mutations.
- GATA1 mutations: GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease or AMKL.[146-149] GATA1 mutations are not observed in non-Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.[148,149] GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells. GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.
- WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[152-155] The WT1 mutation has been shown in some,[152,153,155] but not all, studies to be an independent predictor of worse disease-free, event-free, and overall survival of adults. In children with AML, WT1 mutations are observed in approximately 10% of cases.[156,157] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3-ITD, but are less common among children younger than 3 years.[156,157] AML cases with NUP98-NSD1 are enriched for both FLT3-ITD and WT1 mutations. In univariate analyses, WT1 mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1 mutation status is unclear because of its strong association with FLT3-ITD and its association with NUP98-NSD1.[80,156,157] The largest study of WT1 mutations in children with AML observed that children with WT1 mutations in the absence of FLT3-ITD had outcomes similar to that of children without WT1 mutations, while children with both WT1 mutation and FLT3-ITD had survival rates less than 20%.
- DNMT3A mutations: Mutations of the DNA cytosine methyltransferase gene (DNMT3A) have been identified in approximately 20% of adult AML patients, being virtually absent in patients with favorable cytogenetics but occurring in one-third of adult patients with intermediate-risk cytogenetics. Mutations in this gene are independently associated with poor outcome.[158-160] DNMT3A mutations appear to be very uncommon in children.
- IDH1 and IDH2 mutations: Mutations in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[162-166] and they are enriched in patients with NPM1 mutations.[163,164,167] The specific mutations that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[168,169] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in TET2. Mutations in IDH1 and IDH2 are uncommon in pediatric AML, occurring in 0% to 4% of cases.[161,170-174] There is no indication of a negative prognostic effect for IDH1 and IDH2 mutations in children with AML.
Classification of Myelodysplastic Syndromes in Children
The FAB classification of myelodysplastic syndromes (MDS) was not completely applicable to children.[175,176] Traditionally, MDS classification systems have been divided into several distinct categories based on the presence of the following:[176-179]
- Types of cytopenia.
- Specific chromosomal abnormalities.
- Percentage of myeloblasts.
A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by the WHO in 2008 and included subsections that focused on pediatric MDS and MPD. The bone marrow and peripheral blood findings for the myelodysplastic syndromes according to the 2008 WHO classification schema  are summarized in Tables 3 and 4.
A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was published in 2003. A retrospective comparison of the WHO classification to the Category, Cytology, and Cytogenetics system (CCC) and to a Pediatric WHO adaptation for MDS/MPD, has shown that the latter two systems appear to effectively classify childhood MDS better than the more general WHO system. For instance, while refractory anemia with ring sideroblasts is rare in children, refractory anemia and refractory anemia with excess blasts are more common. When such refractory cytopenias with excess blasts (5%–20%) are associated with recurrent cytogenetic abnormalities usually associated with AML, a diagnosis of the latter should be made and treated accordingly.
The WHO classification schema has a subgroup that includes JMML (formerly juvenile chronic myeloid leukemia), CMML, and Ph chromosome–negative CML. This group can show mixed myeloproliferative and sometimes myelodysplastic features. JMML shares some characteristics with adult CMML [182-184] but is a distinct syndrome (see below). A subgroup of children younger than 4 years at diagnosis with JMML associated with monosomy 7, are considered to have a subtype of JMML characterized by lower WBC, higher percentage of circulating monocytes, higher mean cell volume for red blood cells, a lower bone marrow myeloid to erythroid ratio and often, normal to moderately increased fetal hemoglobin.
The International Prognostic Scoring System is used to determine the risk of progression to AML and the outcome in adult patients with MDS. When this system was applied to children with MDS or JMML, only a blast count of less than 5% and a platelet count of more than 100 x 109/L were associated with a better survival in MDS, and a platelet count of more than 40 x 109/L predicted a better outcome in JMML. These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS.
MDS in children with monosomy 7 and high-grade MDS behaves more like MDS in adults and are best classified as adult MDS, as well as treated with allogeneic hematopoietic stem cell transplantation.[186,187] The risk group or grade of MDS is defined according to International Prognostic Scoring System guidelines.
|Type of MDS||Bone Marrow||Peripheral Blood|
|aAdapted from Arber et al.|
|bNote that cases with pancytopenia would be classified as MDS-U.|
|cWhen the marrow has <5% myeloblasts, but the peripheral blood has 2%–5% myeloblasts, RAEB-1 should be diagnosed.|
|dIf Auer rods are present and there are <5% myeloblasts in the peripheral blood and the marrow has <10% myeloblasts, the diagnosis should be RAEB-2.|
|eRecurring chromosomal abnormalities in MDS: Unbalanced: +8, -7 or del(7q), -5 or del(5q), del(20q), -Y, i(17q) or t(17p), -13 or del(13q), del(11q), del(12p) or t(12p), de(9q), idic(X)(q13); Balanced: t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21.2), t(2;11)(p21;q23), inv(3)(q21q26.2), t(6;9)(p23;q34). The WHO classification notes that the presence of these chromosomal abnormalities in presence of persistent cytopenias of undetermined origin should be considered to support a presumptive diagnosis of MDS when morphological characteristics are not observed.|
|Refractory cytopenias with unilineage dysplasia (RCUD)||Unilineage dysplasia:||Unicytopenia or bicytopeniab|
|—Refractory anemia (RA)||— ≥10% in one myeloid lineage||Blasts (none or <1%)c|
|—Refractory neutropenia (RN)||— <5% blasts|
|—Refractory thrombocytopenia (RT)||— <15% ring sideroblasts|
|Refractory anemia with ring sideroblasts (RARS)||Erythroid dysplasia only||Anemia|
|<5% blasts||No blasts|
|≥15% ring sideroblasts|
|Refractory cytopenia with multilineage dysplasia (RCMD)||Dysplasia in ≥10% of cells in ≥2 myeloid lineages||Cytopenia(s)|
|<5% blasts||Blasts (none or <1%)c|
|±15% ring sideroblasts||No Auer rods|
|No Auer rods||<1×109 monocytes/L|
|Refractory anemia with excess blasts-1 (RAEB-1)||Unilineage or multilineage dysplasia||Cytopenia(s)|
|5%–9% blastsc||<5% blastsc|
|No Auer rods||No Auer rods|
|Refractory anemia with excess blasts-2 (RAEB-2)||Unilineage or multilineage dysplasia||Cytopenia(s)|
|10%–19% blasts||<5%–19% blasts|
|Auer rods ±d||Auer rods ±d|
|MDS associated with isolated del(5q)||Normal to increased megakaryocytes (hypolobulated nuclei)||Anemia|
|<5% blasts||Normal to increased platelet count|
|No Auer rods||Blasts (none or <1%)|
|Myelodysplastic syndrome-unclassified (MDS-U)||Dysplasia in <10% of cells in ≥1 myeloid cell lineage||Cytopenias|
|Cytogenetic abnormality associated with diagnosis of MDSe||≤1% blastsc|
|Childhood myelodysplastic syndrome||Refer to Table 4 for more information.|
|—Provisional entity: Refractory cytopenia of childhood (RCC)f|
The diagnostic criteria for childhood myelodysplastic syndrome (refractory cytopenia of childhood [RCC]–provisional entry) include the following:
- Persistent cytopenia with <5% bone marrow blasts and <2% peripheral blood blasts.
- Dysplastic changes should be present.
|Erythroid Lineage||Myeloid Lineage||Megakaryocyte Lineage|
|aAdapted from Baumann et al.|
|bBone marrow trephine/biopsy may be required as bone marrow in childhood RCC is often hypocellular.|
|cCharacteristics include abnormal nuclear lobulation, multinuclear cells, presence of nuclear bridges.|
|dPresence of pseudo–Pelger-Huet cells, hypo- or agranular cytoplasm, giant band forms.|
|eMegakaryocytes have variable size and often round or separated nuclei; the absence of megakaryocytes does not exclude the diagnosis of RCC.|
|Bone Marrow Aspirateb||Dysplasia and/or megablastoid changes in ≥10% of erythroid precursorsc||Dysplasia in ≥10% of granulocytic precursors and neutrophils||Micromegakaryocytes plus other dysplastic featurese|
|Bone Marrow Biopsy||Presence of erythroid precursors||No additional criteria||Micromegakaryocytes plus other dysplastic featurese|
|Increased proerythroblasts||Immunohistochemistry positive for CD61 and CD41|
|Increased number of mitoses|
|Peripheral Blood||Dysplasia in ≥10% of neutrophils|
Diagnostic Classification of Juvenile Myelomonocytic Leukemia
JMML is a rare leukemia that occurs approximately ten times less frequently than AML in children, with an annual incidence of about 1 to 2 cases per 1 million people. JMML typically presents in young children (a median age of approximately 1.8 years) and occurs more commonly in boys (male to female ratio approximately 2.5:1). Common clinical features at diagnosis include hepatosplenomegaly (97%), lymphadenopathy (76%), pallor (64%), fever (54%), and skin rash (36%). In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are described in Table 5.
|Category 1 (all of the following)a||Category 2 (at least one of the following)b,c||Category 3 (two of the following if no category 2 criteria are met)a,d|
|GM-CSF = granulocyte-macrophage colony-stimulating factor; NF1 = neurofibromatosis type 1.|
|aCurrent World Health Organization (WHO) criteria.|
|bProposed additions to the WHO criteria that were discussed by participants attending the JMML Symposium in Atlanta, Georgia in 2008. CBL mutations were discovered subsequent to the symposium and should be screened for in the workup of a patient with suspected JMML.|
|cPatients who are found to have a category 2 lesion need to meet the criteria in category 1 but do not need to meet the category 3 criteria.|
|dPatients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria.|
|eNote that only 7% of patients with JMML will NOT present with splenomegaly but virtually all patients develop splenomegaly within several weeks to months of initial presentation.|
|Absence of the BCR-ABL1 fusion gene||Somatic mutation in RAS or PTPN11||White blood cell count >10 × 109/L|
|>1 × 109/L circulating monocytes||Clinical diagnosis of NF1 or NF1 gene mutation||Circulating myeloid precursors|
|<20% blasts in the bone marrow||Monosomy 7||Increased hemoglobin F for age|
|Splenomegalyb,e||Clonal cytogenetic abnormality excluding monosomy 7b|
Characteristics of JMML cells include in vitro hypersensitivity to granulocyte-macrophage colony-stimulating factor and activated RAS signaling secondary to mutations in various components of this pathway including NF1, KRAS,NRAS, and PTPN11.[194-196] Mutations of the E3 ubiquitin ligase CBL are observed in 10% to 15% of JMML cases,[197,198] with many of these cases occurring in children with germline CBL mutations.[199,200] CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML. Some individuals with CBL germline mutations experience spontaneous regression of their JMML, but develop vasculitis later in life. CBL mutations are mutually exclusive with RAS and PTPN11 mutations. While most children with JMML have no detectable cytogenetic abnormalities, 20% to 25% show loss of chromosome 7 in bone marrow cells.[183,190,199,201,202]
Recurrent mutations in SETBP1 or JAK3 have also been identified in addition to RAS pathway mutations in about 16% of JMML cases. These mutations were generally subclonal and, thus, thought to be secondary mutations. It has been suggested that the presence of these mutations leads to a decreased OS. For instance, the subclonal presence of SETBP1 mutations have been reported to be associated with an 18% ± 9% 5-year EFS, compared with a 51% ± 8% EFS for those without such mutations.
There is presently no therapeutically or prognostically meaningful staging system for these myeloid malignancies. Leukemia is considered to be disseminated in the hematopoietic system at diagnosis, even in children with AML who present with isolated chloromas (also called granulocytic sarcomas). If these children do not receive systemic chemotherapy, they invariably develop AML in months or years. AML may invade nonhematopoietic tissue such as meninges, brain parenchyma, testes or ovaries, or skin (leukemia cutis). Extramedullary leukemia is more common in infants than in older children with AML.
Childhood AML is diagnosed when bone marrow has greater than 20% blasts. The blasts have the morphologic and histochemical characteristics of one of the FAB subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, patients with clonal cytogenetic abnormalities typically associated with AML, such as t(8:21) (RUNX1-RUNX1T1), inv(16)(CBFB-MYH11), t(9;11)(MLL-MLLT3(AF9)) or t(15;17)(PML-RARA) and who have less than 20% bone marrow blasts, are considered to have AML rather than myelodysplastic syndrome.
Remission is defined in the United States as peripheral blood counts (WBC count, differential, and platelet count) rising toward normal, a mildly hypocellular to normal cellular marrow with fewer than 5% blasts, and no clinical signs or symptoms of the disease, including in the CNS or at other extramedullary sites. Achieving a hypoplastic bone marrow is usually the first step in obtaining remission in AML with the exception of the M3 (acute promyelocytic leukemia [APL]); a hypoplastic marrow phase is often not necessary before the achievement of remission in APL. Additionally, early recovery marrows in any of the subtypes of AML may be difficult to distinguish from persistent leukemia, although the application of flow cytometric immunophenotyping and cytogenetic/molecular testing have made this less problematic. Correlation with blood cell counts and clinical status is imperative in passing final judgment on the results of early bone marrow findings in AML. If the findings are in doubt, the bone marrow aspirate should be repeated in 1 to 2 weeks.
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