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Childhood Acute Myeloid Leukemia Treatment (Professional) (cont.)

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.[1,2,3,4,5] This classification system categorizes 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. To be categorized as M0, the leukemic blasts must not display specific morphologic or histochemical features of either AML or acute lymphoblastic leukemia (ALL). M0 AML appears to be associated with an inferior prognosis in non-Down syndrome patients.[8]
  • 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.Identifying this subtype is critical since the risk of fatal hemorrhagic complication prior to or during induction is high and the appropriate therapy is different than for other subtypes of AML. (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.
  • M7: acute megakaryocytic leukemia (AMKL). Diagnosis of M7 can be difficult without the use of flow cytometry as the blasts can be morphologically confused with lymphoblasts. Characteristically, the blasts display cytoplasmic blebs. Marrow aspiration can be difficult due to myelofibrosis, and marrow biopsy with reticulin stain can be helpful.

Other extremely rare subtypes of AML include acute eosinophilic leukemia and acute basophilic leukemia.

Fifty percent to 60% of children with AML can be classified as having M1, M2, M3, M6, or M7 subtypes; approximately 40% have M4 or M5 subtypes. About 80% of children younger than 2 years with AML have an M4 or M5 subtype. The response to cytotoxic chemotherapy among children with the different subtypes of AML is relatively similar. One exception is FAB subtype M3, for which all-trans retinoic acid plus chemotherapy achieves remission and cure in approximately 70% to 80% of affected children.

World Health Organization (WHO) Classification System

In 2002, 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), and those with 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.[9,10,11] In 2008, 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.[12] (Refer to the WHO classification of myeloid leukemias section of this summary for more information.) 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(CBFA/ETO).
    • AML with inv(16)(p13;q22) or t(16;16)(p13;q22), CBFB-MYH11.
    • APL with t(15;17)(q22;q11-12), PML-RARA.
    • AML with t(9;11)(p22;q23), MLLT3-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.

Histochemical Evaluation

The treatment for children with AML differs significantly from that for ALL. As a consequence, it is crucial 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. The stains most commonly used include myeloperoxidase, periodic acid-Schiff (PAS), Sudan Black B, and esterase. In most cases the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (see below). This approach is being replaced by immunophenotyping using flow cytometry.

Table 1. Histochemical Staining Patternsa

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.
a Refer 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.
b These reactions are inhibited by fluoride.
M0AML, APL (M1-M3) AMML (M4)AMoL (M5)AEL (M6)AMKL (M7)ALL
Myeloperoxidase-++----
Nonspecific esterases
Chloracetate -++±---
Alpha-naphthol acetate--+ b+ b-± b-
Sudan Black B-++----
PAS --±±+-+

Immunophenotypic Evaluation

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 above) or biphenotypic leukemias. The expression of various 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.[13,14,15] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[13,14]

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 heterogenous pattern of CD13 expression.[16] 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).[17]

Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[18,19,20] 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.[21,22,23] In the WHO classification, the presence of MPO is required to establish myeloid lineage. This is not the case for the EGIL classification. Leukemias of mixed phenotype comprise two groups of patients: (1) bilineal leukemias in which there are two distinct population of cells, usually one lymphoid and one myeloid, and (2) biphenotypic leukemias where individual blast cells display features of both lymphoid and myeloid lineage. Biphenotypic cases represent the majority of mixed phenotype leukemias.[18] B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have a lower rate of complete remission and a significantly worse event-free survival compared with patients with B-precursor ALL.[18] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen,[19,20,24] 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.[25,26,27,28,29,30] 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) with M2, t(15;17) with M3, inv(16) with M4Eo, 11q23 abnormalities with M4 and M5, t(1;22) with M7). 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.[31] 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): In leukemias with t(8;21), the AML1 (RUNX1) gene on chromosome 21 is fused with the ETO (RUNX1T1) gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas.[34,35] Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.[25,36] These children have a more favorable outcome compared with children with AML characterized by normal or complex karyotypes [25,37,38,39] with 5-year overall survival (OS) of 80% to 90%.[28,29]
  • inv(16): In leukemias with inv(16), the CBF beta gene 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.[40] Inv(16) confers a favorable prognosis for both adults and children with AML [25,37,38,39] 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): 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.[41] Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t(11;17) involving the PLZF gene).[42] Identification of cases with the t(11;17) is important because of their decreased sensitivity to all-trans retinoic acid.[41,42] APL represents about 7% of children with AML.[29,43]
  • 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.[44] 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,[45] and an improved prognosis in the absence of FLT3-internal tandem duplication (ITD) mutations in adults and younger adults.[45,46,47,48,49,50]

    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.[33,51,52,53]NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[33,52,53] For the pediatric population, conflicting reports have been published regarding the prognostic significance of a NPM1 mutation when a FLT3-ITD mutation is also present, with one study reporting that a NPM1 mutation did not completely abrogate the poor prognosis associated with having a FLT3-ITD mutation,[52] but with other studies showing no impact of a FLT3-ITD mutation on the favorable prognosis associated with a NPM1 mutation.[33,53]

  • 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.[49,54] Outcome for adults with AML with CEBPA mutations appears to be relatively favorable and similar to that of patients with core-binding factor leukemias.[49,54] Studies in adults with AML have demonstrated that CEBPA double-mutant, but not single-allele mutant, AML was independently associated with a favorable prognosis.[55,56,57]

    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.[58,59] Although both double- and single-mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study,[58] a second study observed inferior outcome for patients with single CEBPA mutations.[59] 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.[58]

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).[25,36] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[28,36,60,61,62] 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.[30] However, outcome for children with del(7q), but not monosomy 7, appears to be comparable to that of other children with AML.[29,62] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[25,62,63]
  • 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,[25,36,64] but are very uncommon in children (<1% of pediatric AML cases).[28,38,65]
  • FLT3 mutations: Presence of a FLT3-ITD mutation appears to be associated with poor prognosis in adults with AML,[66] particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[67,68]FLT3-ITD mutations also convey a poor prognosis in children with AML.[69,70,71,72,73] 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).[71,72,74] A longer length of the ITD segment of FLT3-ITD has been reported to be associated with a poorer outcome.[75]

    Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[70,76,77] 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.[77,78,79,80]

    Activating point mutations of FLT3 have also been identified in both adults and children with AML,[67,71,81] though the clinical significance of these mutations is not clearly defined. FLT3-ITD and point mutations occur in 30% to 40% of children and adults with APL.[70,76,78,79] The prognostic significance of this mutation in APL is unclear, although a mutant to wild type allelic ratio of greater than or equal to 0.5 may be associated with a worse outcome.[82]

Other molecular abnormalities observed in pediatric AML include the following:

  • MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most AML secondary to epipodophyllotoxin,[83] 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 AF9 gene.[84] 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.[84] 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).[84]

    Outcome for patients with de novo AML and MLL gene rearrangement are generally reported as being similar to that for other patients with AML.[25,84,85] 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.[84] 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 event-free survival (EFS) of 92%. While several reports have 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.[25,84,86,87,88] A similarly inferior outcome for patients with t(9;11) AML was reported from the AML-BFM 98 study.[29]

    Several 11q23/MLL-rearranged AML subgroups are associated with poor outcome. For example, cases with the t(10;11) translocation are a group at particularly high risk of relapse in bone marrow and the central nervous system (CNS).[25,29,89] 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.[90,91] 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.[84] Patients with t(6;11)(q27;q23) and with t(4;11)(q21;q23) also show poor outcome, with a 5-year EFS of 11% and 29%, respectively.[84]

  • t(6;9): t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214.[92] This subgroup of AML has been associated with a poor prognosis in adults with AML,[92,93,94] and occurs infrequently in children (approximately 2% of AML cases). This subtype appears to be associated with a high risk of treatment failure in children.[28]
  • t(1;22): The t(1;22)(p13;q13) translocation is uncommon (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia (AMKL).[28,95,96,97] Most AMKL cases with t(1;22) occur in infants, and the translocation is uncommon in children with Down syndrome who develop AMKL.[95,97] In leukemias with t(1;22), the OTT (RBM15) gene on chromosome 1 is fused to the MAL (MLK1) gene on chromosome 22.[98,99] Cases with detectable OTT/MAL fusion transcripts in the absence of t(1;22) have been reported, as well.[97] In the small number of children reported, the presence of the t(1;22) appears to be associated with poor prognosis, though long-term survivors have been noted following intensive therapy.[97,100]
  • 12p: Cytogenetically detectable aberrations on the short arm of chromosome 12 are uncommon in unselected pediatric AML patients (2%–4%) and appear to predict poor outcome.[28,29]

    A subset of patients with 12p abnormalities have the t(7;12)(q36;p13) translocation involving ETV6 on chromosome 12p13 and HLXB9 on chromosome 7q36.[101] 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.[28,29,33,102,103]

  • NUP98/NSD1 translocation: The NUP98/NSD1 translocation, which is often cytogenetically cryptic, results in the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[104,105,106,107,108] This alteration occurs in approximately 4% of pediatric AML cases.[106,108] NUP98/NSD1 cases have not been observed in children younger than 2 years,[104,105,106,107,108] and they present with high WBC (median 147 × 109 /L in one study).[108] Most NUP98/NSD1 AML cases do not show cytogenetic aberrations,[104,108] although del(5q) is noted in some.[106,107] A high percentage of NUP98/NSD1 cases (91% in one study) have FLT3-ITD.[108] 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%.[108]
  • 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.[33,109,110] Mutations in NRAS are observed more commonly than KRAS mutations in pediatric AML cases.[33]RAS mutations occur with similar frequency for all Type II alteration subtypes with the exception of APL, for which RAS mutations are seldom observed.[33]
  • KIT mutations: Mutations in KIT occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[33,111,112] 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.[112,113,114] The prognostic significance of KIT mutations occurring in pediatric core-binding factor AML remains unclear,[111,115,116,117] although the largest pediatric study reported to date observed no prognostic significance for KIT mutations.[118]
  • GATA1 mutations: GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease or AMKL.[119,120,121,122]GATA1 mutations are not observed in non-Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.[121,122]GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.[123]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.[124]
  • EVI1: High expression of EVI1 on chromosome 3q26 has been observed in approximately 10% of adults with AML and, like inv(3)/t(3;3), is associated with poor prognosis.[125] Some adult AML cases with high EVI1 expression have inv(3)/t(3;3), but most cases with high EVI1 expression do not.[125,126] High expression is virtually absent in cases with favorable cytogenetics, but is common in cases with monosomy 7 and in cases with MLL gene rearrangement.[125,126]EVI1 overexpression has been identified in approximately 10% of children with AML, predominantly cases with MLL gene rearrangement, monosomy 7, or FAB M6/M7.[65] Similar to adults, EVI1 overexpression was mutually exclusive with core-binding factor AML and was associated with poor prognosis.[65]
  • WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[127,128,129,130] The WT1 mutation has been shown in some,[127,128,130] but not all,[129] 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.[131,132] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3-ITD, but are less common among children younger than 3 years.[131,132] 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.[131,132] 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%.[131]
  • 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.[133] Mutations in this gene are independently associated with poor outcome.[133,134,135]DNMT3A mutations appear to be very uncommon in children.[136]
  • IDH1 and IDH2 mutations: Mutations in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[137,138,139,140,141] and they are enriched in patients with NPM1 mutations.[138,139,142] The specific mutations that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[143,144] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in TET2.[142] Mutations in IDH1 and IDH2 are uncommon in pediatric AML, occurring in 0% to 4% of cases.[136,145,146,147,148,149] There is no indication of a negative prognostic effect for IDH1 and IDH2 mutations in children with AML.[145]

Classification of Myelodysplastic Syndromes in Children

The FAB classification of myelodysplastic syndromes (MDS) is not completely applicable to children.[150,151] In adults, MDS is divided into several distinct categories based on the presence of myelodysplasia, types of cytopenia, specific chromosomal abnormalities, and the percentage of myeloblasts.[151,152,153,154]

A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by WHO in 2008.[155] The primary WHO classification includes:

WHO classification of MDS

  • Refractory cytopenia with unilineage dysplasia:
    • Refractory anemia (RA).
    • Refractory neutropenia.
    • Refractory thrombocytopenia.
  • Refractory anemia with ring sideroblasts (RARS).
  • Refractory cytopenia with multilineage dysplasia.
  • Refractory anemia with excess blasts (RAEB).
  • MDS with isolated del (5q).
  • MDS, unclassifiable.
  • Childhood MDS:
    • Provisional entity: Refractory cytopenia of childhood (RCC).

      RCC is noted to be reserved for children with MDS who have less than 2% blasts in their peripheral blood and less than 5% blasts in their bone marrow along with persistent cytopenia(s) and dysplasia. It is also noted in the new WHO classification that RCC, unlike MDS in adults, is usually characterized by bone marrow hypocellularity, making the distinction with aplastic anemia and bone marrow failure syndromes often difficult.

WHO classification of myelodysplastic/myeloproliferative neoplasms

  • Chronic myelomonocytic leukemia (CMML).
  • Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML).
  • Juvenile myelomonocytic leukemia (JMML).
  • Myelodysplastic/myeloproliferative neoplasm, unclassifiable.
    • Provisional entity: RARS and thrombocytosis (RARS-T).

      RARS-T is notable in that 50% to 60% of cases have JAK2 V617F mutations.[156]

WHO classification of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1

  • Myeloid and lymphoid neoplasms with PDGFRA rearrangement.
  • Myeloid neoplasms with PDGFRB rearrangement.
  • Myeloid and lymphoid neoplasms with FGFR1 abnormalities.

The peripheral blood and bone marrow findings for the myelodysplastic syndromes according to the 2008 WHO classification schema [155] are summarized in Table 2.

Table 2. World Health Organization (WHO) Peripheral Blood and Bone Marrow Findings for Myelodysplastic Syndromes (MDS)

EP = erythroid precursors; MDS-U = myelodysplastic syndromes, unclassifiable; ML = multilineage; RA = refractory anemia; RAEB = refractory anemia with excess blasts; RARS = refractory anaemia with ring sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RCUD = refractory cytopenia with unilineage dysplasia; RN = refractory neutropenia; RT = refractory thrombocytopenia; UL = unilineage.
a Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U.
b When accompanied by cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS.
c Cases with Auer rods and <5% myeloblasts in the blood and <10% in the marrow should be classified as RAEB-2.
d If the marrow myeloblast percentage is <5% but there are 2%–4% myeloblasts in the blood, the diagnostic classification is RAEB-1. Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as MDS-U.
RCUD (including RA, RN and RT)RARSRCMDRAEB-1RAEB-2MDS-Udel(5q)
Cytopenia(s)Unicytopenia or bicytopeniaa++++
Anemia++
PlateletsNormal to increased
Marrow dysplasiaUL or MLUL or ML
erythroid+
myeloid=10% in 1 myeloid lineage=10% in =2 myeloid lineages<10% in =1 myeloid lineageb
megakaryocyticNormal to increased with hypolobulated nuclei
Auer's rods (blood and/or bone marrow)NoneNone±cNone
Ringed sideroblasts<15% of EP=15% of EP± 15%
Peripheral blastsRare or none (<1%)dNoneRare or none (<1%)d<5%d5%–19%(=1%)dRare or none (<1%)
Bone marrow blasts<5%<5%<5%5%–9%d10%–19%<5% <5%
Peripheral monocytes<1 x 109 /L <1 x 109 /L <1 x 109 /L
Cytogenetic abnormalityIsolated del(5q)

RARS is rare in children. RA and RAEB are more common. 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 [157,158,159] but is a distinct syndrome (see below). A subgroup of children younger than 4 years at diagnosis with myelodysplasia will have monosomy 7. For this subset of children, their disease is best classified as a subtype of JMML. The International Prognostic Scoring System (IPSS) 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.[160] These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS. Older children with monosomy 7 and high-grade MDS, however, behave more like adults with MDS and are best classified that way and treated with allogeneic hematopoietic stem cell transplantation.[161,162] The risk group or grade of MDS is defined according to IPSS guidelines.[163] A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was published in 2003; however, the usefulness of this classification has yet to be evaluated prospectively in clinical practice.[11] A retrospective comparison of the WHO classification with the category, cytology, and cytogenetics system and a Pediatric WHO adaptation for MDS/MPD, has shown that the latter two systems are better able to effectively classify childhood MDS than the more general WHO system.[164] A prospective study should be done to definitively determine the optimal classification scheme for childhood MDS/MPD.[11]

Diagnostic Classification of Juvenile Myelomonocytic Leukemia

JMML is a rare leukemia that occurs approximately ten times less frequently than AML in children.[162] 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%).[165] In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are as follows:[166]

Table 3. Diagnostic Criteria for Juvenile Myelomonocytic Leukemia (JMML)

GM-CSF = granulocyte-macrophage colony-stimulating factor.
a Current World Health Organization (WHO) criteria.
b Proposed additions to the WHO criteria that were discussed by participants attending the JMML Symposium in Atlanta, Georgia in 2008.[167]CBL mutations were discovered subsequent to the symposium and should be screened for in the workup of a patient with suspected JMML.[168]
c Patients 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.
d Patients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria.
e Note 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.
Category 1 (all of the following)aCategory 2 (at least one of the following)b,cCategory 3 (two of the following if no category 2 criteria are met)a,d
Absence of the BCR/ABL1 fusion gene Somatic mutation in RAS or PTPN11White blood cell count >10 × 109 /L
>1 × 109 /L circulating monocytesClinical diagnosis of NF1 or NF1 gene mutationCirculating myeloid precursors
<20% blasts in the bone marrowMonosomy 7 Increased hemoglobin F for age
Splenomegalyb,eClonal cytogenetic abnormality excluding monosomy 7b
GM-CSF hypersensitivity

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.[169,170,171] Mutations of the E3 ubiquitin ligase CBL are observed in 10% to 15% of JMML cases,[172,173] with many of these cases occurring in children with germline CBL mutations.[174,175]CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML.[174] Some individuals with CBL germline mutations experience spontaneous regression of their JMML, but develop vasculitis later in life.[174]CBL mutations are mutually exclusive with RAS/PTPN11 mutations.[172] While the majority of children with JMML have no detectable cytogenetic abnormalities, a minority (20%–25%) show loss of chromosome 7 in bone marrow cells.[158,165,174,176,177]

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