Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute 2/11

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version

Classification of Pediatric Myeloid Malignancies

In This Section

• French-American-British (FAB) Classification System for Childhood AML
• World Health Organization (WHO) Classification System for Childhood AML
  • 2016 WHO classification of AML and related neoplasms
  • 2016 WHO classification of acute leukemias of ambiguous lineage
• WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes

French-American-British (FAB) Classification System for Childhood AML

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for acute myeloid leukemia (AML) was developed by the FAB Cooperative Group.[1-5] This classification system, which has been replaced by the World Health Organization (WHO) system described below, categorized AML into major subtypes primarily on the basis of morphology and immunohistochemical detection of lineage markers.

The major subtypes of AML include the following:

• 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.)
• M3v: APL, microgranular variant. Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. M3v has the 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.

The FAB classification was superseded by the WHO classification described below but remains relevant as it forms the basis of the WHO's subcategory of AML, not otherwise specified (AML, NOS).

World Health Organization (WHO) Classification System for Childhood AML

In 2001, the WHO proposed a new classification system that incorporated diagnostic cytogenetic information and that more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17), or KMT2A (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 an AML patient.[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) in its classification system.[11] In 2016, the WHO classification underwent revisions to incorporate the expanding knowledge of leukemia biomarkers that are significantly important to the diagnosis, prognosis, and treatment of leukemia.[12] With emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will certainly continue to evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.

2016 WHO classification of AML and related neoplasms

• AML with recurrent genetic abnormalities:
  • AML with t(8;21)(q22;q22), RUNX1-RUNX1T1.
  • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11.
  • APL with PML-RARA.
  • AML with t(9;11)(p21.3;q23.3), MLLT3-KMT2A.
  • AML with t(6;9)(p23;q34.1), DEK-NUP214.
  • AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2), GATA2, MECOM.
  • AML (megakaryoblastic) with t(1;22)(p13.3;q13.3), RBM15-MKL1.
  • AML with BCR-ABL1 (provisional entity).
  • AML with mutated NPM1.
  • AML with biallelic mutations of CEBPA.
  • AML with mutated RUNX1 (provisional entity).
• AML with myelodysplasia-related features.
• Therapy-related myeloid neoplasms.
• AML, NOS:
  • AML with minimal differentiation.
  • AML without maturation.
  • AML with maturation.
  • Acute myelomonocytic leukemia.
  • Acute monoblastic/monocytic leukemia.
  • Pure erythroid leukemia.
  • Acute megakaryoblastic leukemia.
  • Acute basophilic leukemia.
  • Acute panmyelosis with myelofibrosis.
• Myeloid sarcoma.
• Myeloid proliferations related to Down syndrome:
  • Transient abnormal myelopoiesis (TAM).
  • Myeloid leukemia associated with Down syndrome.

2016 WHO classification of acute leukemias of ambiguous lineage

For the group of acute leukemias that have characteristics of both AML and acute lymphoblastic leukemia (ALL), the acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[13,14] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.[12]

Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa

Condition	Definition
NOS = not otherwise specified.
aBéné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[13] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgExit Disclaimer.
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); KMT2A (MLL) rearranged	Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving the KMT2A 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 KMT2A
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 KMT2A
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

Table 2. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa

Lineage	Criteria
aAdapted from Arber et al.[12]
bStrong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid Lineage	Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); ormonocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T Lineage	Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3
B Lineage	Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10

Leukemias of mixed phenotype may be seen in various presentations, including the following:

1. Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
2. Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage.

Biphenotypic cases represent the majority of mixed phenotype leukemias.[15] 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 precursor B-cell ALL.[15] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[16-19] A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplantation (HSCT) in first CR was not beneficial, with the possible exception of cases with morphologic evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[19]

WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes

The FAB classification of myelodysplastic syndromes (MDS) was not completely applicable to children.[20,21] Traditionally, MDS classification systems have been divided into several distinct categories based on the presence of the following:[21-24]

• Myelodysplasia.
• 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.[25] This pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was initially proposed in 2003.[10] The 2016 revision to the WHO classification has removed focus on the specific lineage (anemia, thrombocytopenia, or neutropenia) and now distinguishes cases with dysplasia in single versus multiple lineages. The category of MDS with excess blasts (MDS-EB) now encompasses the pediatric cases previously classified as refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEB-T).[26] The category of refractory cytopenia of childhood is retained as a provisional entity. The bone marrow and peripheral blood findings for MDS according to the 2008 WHO classification schema are summarized in Tables 3 and 4.[12,25] When MDS-EB is associated with the recurrent cytogenetic abnormalities that are usually associated with AML, a diagnosis of AML is made and patients are treated accordingly.

Distinguishing MDS from similar-appearing, reactive causes of dysplasia and/or cytopenias is noted to be difficult. In general, the finding of more than 10% dysplasia in a cell lineage is a diagnostic criteria for MDS, however, the WHO 2016 guidelines caution that reactive etiologies, rather than clonal, may have more than 10% dysplasia and should be excluded especially when dysplasia is subtle and/or restricted to a single lineage.[12]

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 juvenile myelomonocytic leukemia (JMML), only a blast count of less than 5% and a platelet count of more than 100 × 109/L were associated with a better survival in MDS, and a platelet count of more than 40 × 109/L predicted a better outcome in JMML.[27] These results suggest that MDS and JMML in children may be significantly different disorders than adult-type MDS.

Pediatric MDS can be grouped into several general categories, each with distinctive clinical and biological characteristics, as follows:[26]

• MDS arising from an inherited bone marrow failure syndrome, such as Fanconi anemia, severe congenital neutropenia, and Shwachman-Diamond syndrome.
• MDS arising from severe aplastic anemia.
• Secondary MDS arising from cytotoxic insults, such as high-dose alkylating chemotherapy.
• Primary MDS includes cases of MDS beyond those listed above, acknowledging that some of the cases characterized as primary MDS are also associated with predisposition syndromes.

Genomic characterization of pediatric primary MDS has identified specific subsets defined by alterations in selected genes (refer to the Molecular Abnormalities subsection of this summary for more information about MDS). For example, germline mutations in either GATA2 [28] or SAMD9/SAMD9L [29-31] are especially common in children with deletions of all or part of chromosome 7. Genomic characterization has also shown that primary MDS in children differs from adult MDS at the molecular level.[30,32]

Table 3. World Health Organization (WHO) Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes (MDS)a

Type of MDS		Bone Marrow	Peripheral Blood
aAdapted from Arber et al.[12]
bNote that cases with pancytopenia would be classified as MDS-U.
cWhen the marrow has <5% myeloblasts, but the peripheral blood has 2%–4% myeloblasts, the diagnosis is MDS-EB-1.
dThe diagnosis of MDS-EB-2 should be made if any one of the following criteria are met: marrow with 10%–19% blasts, peripheral blood with 5%–19% blasts, or presence of Auer rods.
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), del(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.
fThe diagnostic criteria for childhood MDS (refractory cytopenia of childhood [RCC]-provisional entry) include: 1) persistent cytopenia of 1–3 cell lines with <5% bone marrow blasts, <2% peripheral blood blasts, and no ringed sideroblasts and 2) dysplastic changes in 1–3 lineages should be present.
MDS with single lineage dysplasia		Unilineage dysplasia: ≥10% in one myeloid lineage	1–2 cytopeniasb
		<5% blasts	Blasts <1%c
		<15% ring sideroblasts
MDS with ring sideroblasts (MDS-RS)		Erythroid dysplasia only
		<5% blasts	No blasts
		≥15% ring sideroblasts
MDS with multilineage dysplasia		Dysplasia in ≥10% of cells in ≥2 myeloid lineages	1–3 cytopenias
		<5% blasts	Blasts (none or <1%)c
		±15% ring sideroblasts
		No Auer rods	No Auer rods
			<1×109 monocytes/L
MDS with excess blasts-1 (MDS-EB-1)		Single lineage or multilineage dysplasia	Cytopenia(s)
		5%–9% blastsc	<5% blastsc
		No Auer rods	No Auer rods
			<1×109 monocytes/L
MDS with excess blasts-2 (MDS-EB-2)		Single lineage or multilineage dysplasia	Cytopenia(s)
		10%–19% blastsd	5%–19% blastsd
		Auer rods ±d	Auer rods ±d
			<1×109 monocytes/L
MDS with isolated del(5q)		Normal to increased megakaryocytes (hypolobulated nuclei)	Anemia
		<5% blasts	Blasts (none or <1%)
		No Auer rods	Normal to increased platelet count
		Isolated del(5q)
MDS-unclassifiable (MDS-U)		Dysplasia in <10% of cells in ≥1 myeloid cell lineage	Cytopenias
		Cytogenetic abnormality associated with diagnosis of MDSe	≤1% blastsc
		<5% blasts
Provisional entity: Refractory cytopenia of childhood (RCC)f		Refer to Table 4 for more information.

Table 4. Definitions for Minimal Diagnostic Criteria for Childhood Myelodysplastic Syndrome (MDS) (Provisional Entity: Refractory Cytopenia of Childhood [RCC])a

	Erythroid Lineage	Myeloid Lineage	Megakaryocyte Lineage
aAdapted from Baumann et al.[33]
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
		<5% blastsd
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
		<2% blasts

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