Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of childhood acute myeloid leukemia, myelodysplastic syndromes, and other myeloproliferative disorders.

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, and treatment of childhood acute myeloid (myelogenous) leukemia (AML) and other childhood myeloid malignancies.

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.¹ At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site. The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Myeloid leukemias in children

The myeloid leukemias in childhood represent a spectrum of hematopoietic malignancies. Over 90% of myeloid leukemias are acute and the remainder include chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia (CML) and juvenile myelomonocytic leukemia (JMML). Myelodysplastic syndromes (MDS) are rare in children.

AML is defined as a clonal disorder caused by malignant transformation of a bone marrow-derived, self-renewing stem cell or progenitor, which demonstrates a decreased rate of self-destruction and also aberrant differentiation. These events lead to increased accumulation in the bone marrow and other organs by these malignant myeloid cells. To be called acute, the bone marrow usually must include greater than 20% leukemic blasts, with some exceptions as noted in subsequent sections.

CML represents the most common of the chronic myeloproliferative disorders in childhood but still only comprises about 5% of childhood myeloid leukemia. Although CML has been diagnosed in very young children, most patients are 6 years or older. CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the white blood cell count can be extremely elevated, the bone marrow does not show increased numbers of leukemic blasts during the chronic phase of this disease. CML is nearly always characterized by the presence of the Philadelphia chromosome, a translocation between chromosomes 9 and 22, i.e., t(9;22). Other chronic myeloproliferative syndromes such as polycythemia vera and essential thrombocytosis are extremely rare in children.

JMML is caused by malignant transformation of a primitive hematopoietic stem cell or progenitor and represents the most common myeloproliferative syndrome observed in young children. JMML is characterized clinically by occurring primarily in children aged 2 years or younger who commonly present with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated white blood cell count and increased circulating monocytes. In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte colony-stimulating factor, and monosomy 7.

The transient myeloproliferative disorder (TMD) (also termed transient leukemia) observed in infants with Down syndrome represents a clonal expansion of myeloblasts that can be difficult to distinguish from AML. Most importantly, TMD spontaneously regresses in most cases within the first 3 months of life. TMD blasts are most commonly megakaryoblastic and have distinctive mutations involving the GATA1 gene.^2,³ TMD may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TMD is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk for developing subsequent AML.⁴ Approximately 20% of infants with Down syndrome and TMD eventually develop AML, with most cases diagnosed within the first 3 years of life.^3,⁴ Early death from TMD-related complications occurs in 10% to 20% of affected children.^4,⁵ Infants with progressive organomegaly, visceral effusions, and laboratory evidence of progressive liver dysfunction are at a particularly high risk for early mortality.^4,

The myelodysplastic syndromes in children represent a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors, cytopenias, and dysplastic morphologic changes. Although the majority of patients have normocellular or hypercellular bone marrows without increased numbers of leukemic blasts, some patients may present with a very hypocellular bone marrow, making the distinction between severe aplastic anemia difficult.

There are genetic risks associated with the development of AML. There is a high concordance rate of AML in identical twins, which is believed to be in large part a result of shared circulation and the inability of one twin to reject leukemic cells from the other twin.^6,^7,⁸ There is an estimated 2-fold to 4-fold risk of fraternal twins both developing leukemia up to about the age of 6 years, after which the risk is not significantly greater than that of the general population.^9,¹⁰ The development of AML has also been associated with a variety of predisposition syndromes that result from chromosomal imbalances or instabilities, defects in DNA repair, altered cytokine receptor or signal transduction pathway activation, as well as altered protein synthesis. (Refer to the following list of inherited and acquired genetic syndromes associated with myeloid malignancies.)

Inherited and Acquired Genetic Syndromes Associated with Myeloid Malignancies
Inherited syndromes
Chromosomal imbalances:
Down syndrome

Familial monosomy 7 syndrome

Chromosomal instability syndromes:
Fanconi anemia

Dyskeratosis congenita

Bloom syndrome

Syndromes of growth and cell survival signaling pathway defects:
Neurofibromatosis type 1 (particularly JMML development)

Noonans syndrome (particularly JMML development)

Severe congenital neutropenia (Kostmann syndrome)

Diamond-Blackfan anemia

Familial platelet disorder with a propensity to develop AML (FPD/AML)

Congenital amegakaryocytic thrombocytopenia (CAMT)

Acquired syndromes
Severe aplastic anemia

Paroxysmal nocturnal hemoglobinuria

Amegakaryocytic thrombocytopenia (AAMT)

Acquired monosomy 7

¹ Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

² Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003.

³ Mundschau G, Gurbuxani S, Gamis AS, et al.: Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101 (11): 4298-300, 2003.

⁴ Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006.

⁵ Homans AC, Verissimo AM, Vlacha V: Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 15 (4): 392-9, 1993.

⁶ Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969.

⁷ Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967.

⁸ Inskip PD, Harvey EB, Boice JD Jr, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991.

⁹ Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974.

¹⁰ Greaves M: Pre-natal origins of childhood leukemia. Rev Clin Exp Hematol 7 (3): 233-45, 2003.

Classification of Pediatric Myeloid Malignancies

FAB classification for childhood acute myeloid leukemia

The first most comprehensive morphologic-histochemical classification system for acute myeloid leukemia (AML) was developed by the French-American-British (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).

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).

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 a 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 children with AML.

WHO classification system

The World Health Organization (WHO) Classification System incorporates clinical, morphologic (i.e., FAB Classification information), immunophenotypic, cytogenetic, and molecular data.^8,^9,^10,

WHO classification of acute myeloid leukemias
AML with recurrent genetic abnormalities:
AML with t(8;21)(q22;q22); (AML1 [CBFA]/ETO).

AML with abnormal marrow eosinophils.
inv(16)(p13q22).

t(16;16)(p13;q22) (CBFB/MYH11).

Acute promyelocytic leukemia (AML with t(15;17)(q22;q12) (PML/RARA) and variants (included as M3 in the FAB classification).

AML with 11q23 (MLL) abnormalities.

AML with multilineage dysplasia (de novo or following a myelodysplastic syndrome-most cases of refractory anemia with excess of blasts in transformation fall in the latter category).

AML, therapy-related:
Alkylating agent-related AML.

Topoisomerase II inhibitor-related AML.

Acute leukemia of ambiguous lineage:
Undifferentiated acute leukemia (leukemic blasts show no or minimal signs of morphologic and/or protein expression signs of maturation).

Bilineal acute leukemia (more than one cell lineage that demonstrates leukemic transformation).

Biphenotypic acute leukemia (a single population of leukemic blasts have simultaneous expression of protein expression markers of different hematopoetic cell lineages).

AML not otherwise categorized (including the FAB morphology-based M0 to M2, and M4 to M7 categories):
AML minimally differentiated (FAB M0).

AML without maturation (FAB M1).

AML with maturation (FAB M2).

AML (FAB M4).

Acute monoblastic and monocytic leukemia (FAB M5a and M5b, respectively).

Acute erythroid leukemia (FAB M6).
Erythroleukemia (FAB M6a).

Pure erythroid leukemia (FAB M6b).

Acute megakaryoblastic leukemia (FAB M7).

Acute basophilic leukemia.

Acute panmyelosis with myelofibrosis.

Myeloid (granulocytic) sarcoma.

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, 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 Patterns
M0AML, APL (M1-M3) AMML (M4)AMoL (M5)AEL (M6)AMKL (M7)ALL(a) These reactions are inhibited by fluoride.Myeloperoxidase-++----Nonspecific esterases Chloracetate -++±---Alpha-naphthol acetate--+ (a)+ (a)-± (a)-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 proteins, termed cluster designations (CD), 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.^11,^12,¹³ The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.^11,^12,

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.¹⁴ 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).^15,

Cytogenetic evaluation and molecular abnormalities

Chromosomal analyses of the leukemia should be performed on children with AML because they are important diagnostic and prognostic markers.^16,^17,¹⁸ 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 M4 Eo, 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.¹⁹ 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 chromosome in children with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML.

Specific recurring cytogenetic and molecular abnormalities include:
AML with t(8;21): In leukemias with t(8;21), the AML1 (RUNX1, CBFA2) gene on chromosome 21 is fused with the ETO gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas.^20,²¹ Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.^16,²² Most reports of recent studies describe a more favorable outcome for children with t(8;21) AML than the average outcome for all children with AML.^16,^23,^24,²⁵

AML with inv(16): In leukemias with inv(16), the CBFß 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.²⁶ Inv(16) confers a favorable prognosis for both adults and children with AML.^16,^23,^24,^25,

AML with 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.²⁷ 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).²⁸ Identification of cases with the t(11;17) is important because of their decreased sensitivity to all-trans retinoic acid.^27,^28,

AML with MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most AML secondary to epipodophyllotoxin,²⁹ are associated with monocytic differentiation (FAB M4 and M5) and generally have an unfavorable prognosis.^30,³¹ One exception to the poor prognostic significance of translocations at chromosome band 11q23 may be for children with t(9;11) in which the MLL gene is fused with the AF9 gene. In some reports, outcome has been relatively favorable for children whose leukemia cells have t(9;11),^25,^31,³² though favorable outcome has not been observed in other series.²⁴
The t(10;11) translocation has been reported to define a group at particularly high risk of relapse in bone marrow and the central nervous system (CNS).³³ Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10 (MLLT10) gene on chromosome 10, with most of these cases having the FAB M5 subtype.³⁴ AML with t(10;11) may also have fusion of the CALM gene on chromosome 11 with the AF10 gene.³⁵ Based on the limited number of cases reported, prognosis appears poor for cases with t(10;11) regardless of the type of gene fusion present.^36,

Other unfavorable chromosomal abnormalities: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 7 (monosomy 7 and del(7q)), chromosome 5 (monosomy 5 and del(5q)) and the long arm of chromosome 3 (inv(3)(q21q26) or t(3;3)(q21q26)).^16,²² These cytogenetic subgroups are also associated with poor prognosis in children with AML, though abnormalities of the long arm of chromosome 3q and 5q are extremely rare in children with AML.^22,^37,^38,

AML with t(1;22): The t(1;22)(p13;q13) translocation is restricted to acute megakaryoblastic leukemia (AMKL) and occurs in as many as one third of AMKL cases in children.^39,^40,⁴¹ Most AMKL cases with t(1;22) occur in infants, and the translocation is uncommon in children with Down syndrome who develop AMKL.^39,⁴¹ In leukemias with t(1;22), the OTT (RBM15) gene on chromosome 1 is fused to the MAL (MLK1) gene on chromosome 22.^42,⁴³ Cases with detectable OTT/MAL fusion transcripts in the absence of t(1;22) have been reported, as well.⁴¹ 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.^41,^44,

AML with FLT3 mutations: Presence of a FLT3 internal-tandem duplication (ITD) mutation appears to be associated with poor prognosis in adults with AML,⁴⁵ particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.^46,⁴⁷ FLT3-ITD mutations also occur in pediatric AML cases,^48,^49,^50,⁵¹ and as with adults, FLT3-ITD mutations appear to be associated with poor prognosis in children with AML.^48,^49,^50,⁵¹ The frequency of FLT3-ITD mutations in children appears to be lower than that observed for adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% for adults).^50,⁵¹ Activating point mutations of FLT3 have also been identified in both adults and children with AML,^46,^50,⁵² though the clinical significance of these mutations is not clearly defined. Gene expression profiling of pediatric AML has shown that within FLT3-mutant cases, relative expression of the genes RUNX3 and ATRX can define high, intermediate, and low risk prognostic groups.⁵³ FLT3-ITD and point mutations occur in 30% to 40% of children and adults with APL.^49,^54,^55,⁵⁶ Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.^49,⁵⁶ 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.^54,⁵⁵

ras and tyrosine kinase receptor mutations: Although mutations in ras have been identified in approximately 25% of patients with AML, the prognostic significance has not been clearly shown.^57,⁵⁸ Mutations in c-KIT occur in less than 5% of AML, but in up to 10% to 40% of AML with core-binding factor abnormalities.^50,^59,⁶⁰ The presence of the activating c-KIT mutations in this subgroup of AML appears to be associated with a poor prognosis.^60,⁶¹ When patients with ras, c-KIT or FLT3-ITD mutations are considered as a single group, they have a significantly worse outcome than patients without these mutations and may benefit, at least in terms of disease-free survival, from allogeneic hematopoietic stem cell transplantation.^50,^62,

GATA1 mutations: GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease (TMD) or AMKL.^63,^64,^65,⁶⁶ GATA1 mutations are not observed in non–Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.^65,⁶⁶ GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.⁶⁷ 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.⁶⁸

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. NPM1 has also been identified as a partner in several chromosomal translocations in leukemia and lymphoma. Mutations in the NPM1 protein that diminish its nuclear localization have been shown to be primarily associated with a subset of AML with a normal karyotype and an improved prognosis in the absence of FLT3-ITD mutations in adults and younger adults.^69,^70,^71,⁷² Preliminary studies of children with AML suggest a similar rate of occurrence of this mutation in patients with normal cytogenetics and who lack a known genetic marker.^73,

Classification of myelodysplastic syndromes in children

The FAB classification of myelodysplastic syndromes (MDS) is not completely applicable to children.^74,⁷⁵ 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.^75,^76,^77,⁷⁸

A modified classification schema for MDS and myeloproliferative disorders has been developed by the WHO. The primary WHO classification changes include:

Cases with 20% to 29% blasts should be called AML, thus eliminating refractory anemia with excess blasts in transformation (RAEB-T).

RAEB is now divided into RAEB-1 (5%-9% bone marrow [BM] blasts) and RAEB-2 (10%-19% BM blasts).

Multilineage dysplasia will be highlighted under refractory anemia with ringed sideroblasts (RARS) or refractory anemia (RA).

Juvenile myelomonocytic leukemia (JMML) and proliferative chronic myelomonocytic leukemia (CMML) will be under MDS/MPD (myeloproliferative disorder).

MDS unclassified will include severe myelofibrosis.

MDS associated with isolated del(5q) will be a separate category.

Monocytosis (under 13,000 monocytes) will be listed under the other subtypes rather than a separate category.

Table 2. WHO Classification of Myelodysplastic Syndromes
RA RARSRCMDRCMD-RSRAEB-1 RAEB-2MDS-U5qRA= refractory anemia (includes only erythroid dysplasia).RARS= refractory anemia with ringed sideroblasts (includes only erythroid dysplasia).RCMD= refractory cytopenia with multilineage dysplasia. RCMD-RS= refractory cytopenia with multilineage dysplasia and ringed sideroblasts. RAEB-1= refractory anemia with excess blasts-1: 5% to 9% marrow blasts. RAEB-2= refractory anemia with excess blasts-2: 10% to 19% marrow blasts. MDS-U= myelodysplastic syndrome-unclassified.5q= myelodysplastic syndrome associated with isolated del(5q). (Adapted from Brunning, et al. 2001.) ^79,Anemia++± ± ± ± ±+Granulocytopenia ± ± + + + Thrombocytopenia ± ± + + + Marrow dysplasiaerythroid + + ± ±myeloid ≥10% in 2 or more myeloid cell lines ≥10% in 2 or more myeloid cell lines ± ± + in 1 myeloid cell line megakaryocytic ± ±±Auer’s rods None None None ± None None Ringed sideroblasts<15% ≥15% <15% ≥15% Peripheral blasts Rare or none None Rare or none Rare or none<5% 5-19% Rare or none <5% Bone marrow blasts<5%<5% <5% <5% 5-9% 10-19% <5% <5% Peripheral monocytosis (>1 x 109/L) No No No No

RARS is rare in children. RA and RAEB are more common. The WHO classification schema has a new subgroup that includes JMML (formerly Juvenile Chronic Myeloid Leukemia), CMML, and Philadelphia (Ph) chromosome–negative CML. This group can show mixed myeloproliferative and sometimes myelodysplastic features. JMML shares some characteristics with adult CMML ^80,^81,⁸² but is a distinct syndrome (see below). A subgroup of children younger than 4 years at diagnosis with myelodysplasia 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.⁸³ 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.^84,⁸⁵ The risk group or grade of MDS is defined according to IPSS guidelines.⁸⁶ 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.¹⁰ 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 2 systems are better able to effectively classify childhood MDS than the more general WHO system.⁸⁷ A prospective study should be done to definitively determine the optimal classification scheme for childhood MDS/MPD.^10,

Diagnostic classification of juvenile myelomonocytic leukemia

JMML is a rare leukemia that accounts for less than 1% of childhood leukemia cases.⁸⁰ JMML typically presents in young children (a median age of approximately 1 year) 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%).⁸⁸ In children presenting with clinical features suggestive of JMML, a definitive diagnosis requires the following:^89,

Table 3. Diagnostic Criteria for JMML
CategoryItemMinimal laboratory criteria (all 3 have to be fulfilled)1. Ph chromosome negative, no BCR/ABL rearrangement2. Peripheral blood monocyte count >1 x 109/L3. Bone marrow blasts <20%Criteria for definite diagnosis (at least 2 must be fulfilled) 1. Hemoglobin F increased for age2. Myeloid precursors on peripheral blood smear3. White blood count >10 x 109/L4. Clonal abnormality (including monosomy 7) 5. Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro

Distinctive characteristics of JMML cells include in vitro hypersensitivity to GM-CSF and activated ras signaling secondary to mutations in various components of this pathway.^90,^91,⁹² While the majority of children with JMML have no detectable cytogenetic abnormalities, a minority show loss of chromosome 7 in bone marrow cells.^81,^88,^93,^94,

¹ Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33 (4): 451-8, 1976.

² Bennett JM, Catovsky D, Daniel MT, et al.: Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103 (4): 620-5, 1985.

³ Bennett JM, Catovsky D, Daniel MT, et al.: Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French-American-British Cooperative Group. Ann Intern Med 103 (3): 460-2, 1985.

⁴ Bennett JM, Catovsky D, Daniel MT, et al.: A variant form of hypergranular promyelocytic leukaemia (M3) Br J Haematol 44 (1): 169-70, 1980.

⁵ Cheson BD, Bennett JM, Kopecky KJ, et al.: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21 (24): 4642-9, 2003.

⁶ Bennett JM, Catovsky D, Daniel MT, et al.: Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-MO) Br J Haematol 78 (3): 325-9, 1991.

⁷ Kaleem Z, White G: Diagnostic criteria for minimally differentiated acute myeloid leukemia (AML-M0). Evaluation and a proposal. Am J Clin Pathol 115 (6): 876-84, 2001.

⁸ Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100 (7): 2292-302, 2002.

⁹ Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3.

¹⁰ Hasle H, Niemeyer CM, Chessells JM, et al.: A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17 (2): 277-82, 2003.

¹¹ Kuerbitz SJ, Civin CI, Krischer JP, et al.: Expression of myeloid-associated and lymphoid-associated cell-surface antigens in acute myeloid leukemia of childhood: a Pediatric Oncology Group study. J Clin Oncol 10 (9): 1419-29, 1992.

¹² Smith FO, Lampkin BC, Versteeg C, et al.: Expression of lymphoid-associated cell surface antigens by childhood acute myeloid leukemia cells lacks prognostic significance. Blood 79 (9): 2415-22, 1992.

¹³ Dinndorf PA, Andrews RG, Benjamin D, et al.: Expression of normal myeloid-associated antigens by acute leukemia cells. Blood 67 (4): 1048-53, 1986.

¹⁴ Orfao A, Chillón MC, Bortoluci AM, et al.: The flow cytometric pattern of CD34, CD15 and CD13 expression in acute myeloblastic leukemia is highly characteristic of the presence of PML-RARalpha gene rearrangements. Haematologica 84 (5): 405-12, 1999.

¹⁵ Creutzig U, Ritter J, Schellong G: Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. AML-BFM Study Group. Blood 75 (10): 1932-40, 1990.

¹⁶ Grimwade D, Walker H, Oliver F, et al.: The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92 (7): 2322-33, 1998.

¹⁷ Gilliland DG: Targeted therapies in myeloid leukemias. Ann Hematol 83 (Suppl 1): S75-6, 2004.

¹⁸ Avivi I, Rowe JM: Prognostic factors in acute myeloid leukemia. Curr Opin Hematol 12 (1): 62-7, 2005.

¹⁹ Rubnitz JE, Look AT: Molecular genetics of childhood leukemias. J Pediatr Hematol Oncol 20 (1): 1-11, 1998 Jan-Feb.

²⁰ Rubnitz JE, Raimondi SC, Halbert AR, et al.: Characteristics and outcome of t(8;21)-positive childhood acute myeloid leukemia: a single institution's experience. Leukemia 16 (10): 2072-7, 2002.

²¹ Tallman MS, Hakimian D, Shaw JM, et al.: Granulocytic sarcoma is associated with the 8;21 translocation in acute myeloid leukemia. J Clin Oncol 11 (4): 690-7, 1993.

²² Mrózek K, Heerema NA, Bloomfield CD: Cytogenetics in acute leukemia. Blood Rev 18 (2): 115-36, 2004.

²³ Creutzig U, Zimmermann M, Ritter J, et al.: Definition of a standard-risk group in children with AML. Br J Haematol 104 (3): 630-9, 1999.

²⁴ Raimondi SC, Chang MN, Ravindranath Y, et al.: Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood 94 (11): 3707-16, 1999.

²⁵ Lie SO, Abrahamsson J, Clausen N, et al.: Treatment stratification based on initial in vivo response in acute myeloid leukaemia in children without Down's syndrome: results of NOPHO-AML trials. Br J Haematol 122 (2): 217-25, 2003.

²⁶ Larson RA, Williams SF, Le Beau MM, et al.: Acute myelomonocytic leukemia with abnormal eosinophils and inv(16) or t(16;16) has a favorable prognosis. Blood 68 (6): 1242-9, 1986.

²⁷ Mistry AR, Pedersen EW, Solomon E, et al.: The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Rev 17 (2): 71-97, 2003.

²⁸ Licht JD, Chomienne C, Goy A, et al.: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85 (4): 1083-94, 1995.

²⁹ Pui CH, Relling MV, Rivera GK, et al.: Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia 9 (12): 1990-6, 1995.

³⁰ Schoch C, Schnittger S, Klaus M, et al.: AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 102 (7): 2395-402, 2003.

³¹ Rubnitz JE, Raimondi SC, Tong X, et al.: Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol 20 (9): 2302-9, 2002.

³² Swansbury GJ, Slater R, Bain BJ, et al.: Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants. Leukemia 12 (5): 792-800, 1998.

³³ Casillas JN, Woods WG, Hunger SP, et al.: Prognostic implications of t(10;11) translocations in childhood acute myelogenous leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 25 (8): 594-600, 2003.

³⁴ Van Limbergen H, Poppe B, Janssens A, et al.: Molecular cytogenetic analysis of 10;11 rearrangements in acute myeloid leukemia. Leukemia 16 (3): 344-51, 2002.

³⁵ Carlson KM, Vignon C, Bohlander S, et al.: Identification and molecular characterization of CALM/AF10fusion products in T cell acute lymphoblastic leukemia and acute myeloid leukemia. Leukemia 14 (1): 100-4, 2000.

³⁶ Dreyling MH, Schrader K, Fonatsch C, et al.: MLL and CALM are fused to AF10 in morphologically distinct subsets of acute leukemia with translocation t(10;11): both rearrangements are associated with a poor prognosis. Blood 91 (12): 4662-7, 1998.

³⁷ Stevens RF, Hann IM, Wheatley K, et al.: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 101 (1): 130-40, 1998.

³⁸ Wells RJ, Arthur DC, Srivastava A, et al.: Prognostic variables in newly diagnosed children and adolescents with acute myeloid leukemia: Children's Cancer Group Study 213. Leukemia 16 (4): 601-7, 2002.

³⁹ Carroll A, Civin C, Schneider N, et al.: The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study. Blood 78 (3): 748-52, 1991.

⁴⁰ Lion T, Haas OA: Acute megakaryocytic leukemia with the t(1;22)(p13;q13). Leuk Lymphoma 11 (1-2): 15-20, 1993.

⁴¹ Duchayne E, Fenneteau O, Pages MP, et al.: Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult and childhood cases by the Groupe Français d'Hématologie Cellulaire (GFHC). Leuk Lymphoma 44 (1): 49-58, 2003.

⁴² Ma Z, Morris SW, Valentine V, et al.: Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28 (3): 220-1, 2001.

⁴³ Mercher T, Coniat MB, Monni R, et al.: Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc Natl Acad Sci U S A 98 (10): 5776-9, 2001.

⁴⁴ Bernstein J, Dastugue N, Haas OA, et al.: Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group. Leukemia 14 (1): 216-8, 2000.

⁴⁵ Schnittger S, Schoch C, Dugas M, et al.: Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 100 (1): 59-66, 2002.

⁴⁶ Thiede C, Steudel C, Mohr B, et al.: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99 (12): 4326-35, 2002.

⁴⁷ Whitman SP, Archer KJ, Feng L, et al.: Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 61 (19): 7233-9, 2001.

⁴⁸ Iwai T, Yokota S, Nakao M, et al.: Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia 13 (1): 38-43, 1999.

⁴⁹ Arrigoni P, Beretta C, Silvestri D, et al.: FLT3 internal tandem duplication in childhood acute myeloid leukaemia: association with hyperleucocytosis in acute promyelocytic leukaemia. Br J Haematol 120 (1): 89-92, 2003.

⁵⁰ Meshinchi S, Stirewalt DL, Alonzo TA, et al.: Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 102 (4): 1474-9, 2003.

⁵¹ Zwaan CM, Meshinchi S, Radich JP, et al.: FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood 102 (7): 2387-94, 2003.

⁵² Abu-Duhier FM, Goodeve AC, Wilson GA, et al.: Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 113 (4): 983-8, 2001.

⁵³ Lacayo NJ, Meshinchi S, Kinnunen P, et al.: Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes. Blood 104 (9): 2646-54, 2004.

⁵⁴ Shih LY, Kuo MC, Liang DC, et al.: Internal tandem duplication and Asp835 mutations of the FMS-like tyrosine kinase 3 (FLT3) gene in acute promyelocytic leukemia. Cancer 98 (6): 1206-16, 2003.

⁵⁵ Noguera NI, Breccia M, Divona M, et al.: Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 16 (11): 2185-9, 2002.

⁵⁶ Gale RE, Hills R, Pizzey AR, et al.: Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 106 (12): 3768-76, 2005.

⁵⁷ Radich JP, Kopecky KJ, Willman CL, et al.: N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 76 (4): 801-7, 1990.

⁵⁸ Farr C, Gill R, Katz F, et al.: Analysis of ras gene mutations in childhood myeloid leukaemia. Br J Haematol 77 (3): 323-7, 1991.

⁵⁹ Shimada A, Taki T, Tabuchi K, et al.: KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood 107 (5): 1806-9, 2006.

⁶⁰ Schnittger S, Kohl TM, Haferlach T, et al.: KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107 (5): 1791-9, 2006.

⁶¹ Cairoli R, Beghini A, Grillo G, et al.: Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 107 (9): 3463-8, 2006.

⁶² Nanri T, Matsuno N, Kawakita T, et al.: Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22). Leukemia 19 (8): 1361-6, 2005.

⁶³ Groet J, McElwaine S, Spinelli M, et al.: Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet 361 (9369): 1617-20, 2003.

⁶⁴ Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003.

⁶⁵ Rainis L, Bercovich D, Strehl S, et al.: Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102 (3): 981-6, 2003.

⁶⁶ Wechsler J, Greene M, McDevitt MA, et al.: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32 (1): 148-52, 2002.

⁶⁷ Gurbuxani S, Vyas P, Crispino JD: Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 103 (2): 399-406, 2004.

⁶⁸ Ge Y, Stout ML, Tatman DA, et al.: GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97 (3): 226-31, 2005.

⁶⁹ Döhner K, Schlenk RF, Habdank M, et al.: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106 (12): 3740-6, 2005.

⁷⁰ Verhaak RG, Goudswaard CS, van Putten W, et al.: Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 106 (12): 3747-54, 2005.

⁷¹ Schnittger S, Schoch C, Kern W, et al.: Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106 (12): 3733-9, 2005.

⁷² Falini B, Mecucci C, Tiacci E, et al.: Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352 (3): 254-66, 2005.

⁷³ Cazzaniga G, Dell'Oro MG, Mecucci C, et al.: Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood 106 (4): 1419-22, 2005.

⁷⁴ Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982.

⁷⁵ Mandel K, Dror Y, Poon A, et al.: A practical, comprehensive classification for pediatric myelodysplastic syndromes: the CCC system. J Pediatr Hematol Oncol 24 (7): 596-605, 2002.

⁷⁶ Bennett JM: World Health Organization classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 72 (2): 131-3, 2000.

⁷⁷ Head DR: Proposed changes in the definitions of acute myeloid leukemia and myelodysplastic syndrome: are they helpful? Curr Opin Oncol 14 (1): 19-23, 2002.

⁷⁸ Nösslinger T, Reisner R, Koller E, et al.: Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution. Blood 98 (10): 2935-41, 2001.

⁷⁹ Brunning RD, Bennett JM, Flandrin G: Myelodysplastic syndromes: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 63.

⁸⁰ Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997.

⁸¹ Passmore SJ, Hann IM, Stiller CA, et al.: Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 85 (7): 1742-50, 1995.

⁸² Luna-Fineman S, Shannon KM, Atwater SK, et al.: Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood 93 (2): 459-66, 1999.

⁸³ Hasle H, Baumann I, Bergsträsser E, et al.: The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML). Leukemia 18 (12): 2008-14, 2004.

⁸⁴ Kardos G, Baumann I, Passmore SJ, et al.: Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. Blood 102 (6): 1997-2003, 2003.

⁸⁵ Passmore SJ, Chessells JM, Kempski H, et al.: Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 121 (5): 758-67, 2003.

⁸⁶ Greenberg P, Cox C, LeBeau MM, et al.: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89 (6): 2079-88, 1997.

⁸⁷ Occhipinti E, Correa H, Yu L, et al.: Comparison of two new classifications for pediatric myelodysplastic and myeloproliferative disorders. Pediatr Blood Cancer 44 (3): 240-4, 2005.

⁸⁸ Niemeyer CM, Arico M, Basso G, et al.: Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood 89 (10): 3534-43, 1997.

⁸⁹ Pinkel D: Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood 91 (1): 365-7, 1998.

⁹⁰ Emanuel PD, Bates LJ, Castleberry RP, et al.: Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77 (5): 925-9, 1991.

⁹¹ Tartaglia M, Niemeyer CM, Fragale A, et al.: Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34 (2): 148-50, 2003.

⁹² Loh ML, Vattikuti S, Schubbert S, et al.: Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103 (6): 2325-31, 2004.

⁹³ Sieff CA, Chessells JM, Harvey BA, et al.: Monosomy 7 in childhood: a myeloproliferative disorder. Br J Haematol 49 (2): 235-49, 1981.

⁹⁴ Hasle H, Aricò M, Basso G, et al.: Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS). Leukemia 13 (3): 376-85, 1999.

Stage Information

There is presently no therapeutically or prognostically meaningful staging system for these disorders. Leukemia is always disseminated in the hematopoietic system at diagnosis, even in children with acute myeloid leukemia (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.¹

Newly diagnosed

Childhood AML is diagnosed when bone marrow has greater than 20% blasts. The blasts have the morphologic and histochemical characteristics of one of the French-American-British (FAB) subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, children with a t(8;21) and less than 20% marrow blasts should be considered to have AML rather than myelodysplastic syndrome (MDS).^2,

Remission

Remission is defined in the United States as follows: peripheral blood counts (white blood cell 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 central nervous system 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 prior to 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; correlation with blood cell counts, clinical status, and cytogenetic/molecular testing is imperative in passing final judgment on the results of early bone marrow findings in AML.³ If the findings are in doubt, the bone marrow aspirate should be repeated in about 1 week.¹

¹ Ebb DH, Weinstein HJ: Diagnosis and treatment of childhood acute myelogenous leukemia. Pediatr Clin North Am 44 (4): 847-62, 1997.

² Chan GC, Wang WC, Raimondi SC, et al.: Myelodysplastic syndrome in children: differentiation from acute myeloid leukemia with a low blast count. Leukemia 11 (2): 206-11, 1997.

³ Konopleva M, Cheng SC, Cortes JE, et al.: Independent prognostic significance of day 21 cytogenetic findings in newly-diagnosed acute myeloid leukemia or refractory anemia with excess blasts. Haematologica 88 (7): 733-6, 2003.

Treatment Overview for Acute Myeloid Leukemia

The mainstay of the therapeutic approach is systemically administered combination chemotherapy.¹ Future approaches involving risk-group stratification and biologically-targeted therapies are being tested to improve antileukemic treatment while sparing normal tissues.² Optimal treatment of AML requires control of bone marrow and systemic disease. Treatment of the central nervous system, usually with intrathecal medication, is a component of most pediatric AML protocols but has not yet been shown to contribute directly to an improvement in survival. Central nervous system irradiation is not necessary in patients either as prophylaxis or for those presenting with cerebrospinal fluid leukemia that clears with intrathecal and systemic chemotherapy.

Treatment is ordinarily divided into 2 phases: (1) induction (to attain remission), and (2) postremission consolidation/intensification. Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). For example, currently ongoing trials of the Children’s Oncology Group (COG) and the United Kingdom Medical Research Council (MRC) utilize similar chemotherapy regimens consisting of 2 courses of induction chemotherapy followed by 2 MRC or 3 COG additional courses of intensification chemotherapy.^3,

Maintenance therapy is not part of most pediatric AML protocols except for APL; exceptions are the Berlin-Frankfurt-Munster protocols. Treatment of AML is usually associated with severe and protracted myelosuppression along with other associated complications. Treatment with hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor [G-CSF]) has been used in an attempt to reduce the toxicity associated with severe myelosuppression but does not influence ultimate outcome.⁴ Virtually all adult randomized trials of hematopoietic growth factors (GM-CSF, G-CSF) have demonstrated significant reduction in the time to neutrophil recovery,^5,^6,^7,⁸ but varying degrees of reduction in morbidity and little if any effect on mortality.^4,

Because of the intensity of therapy utilized to treat AML, children with this disease must have their care coordinated by specialists in pediatric oncology, and they must be treated in cancer centers or hospitals with the necessary supportive care facilities (e.g., to administer specialized blood products; to manage infectious complications; to provide pediatric intensive care; and to provide emotional and developmental support). Approximately one half of the remission induction failures are due to resistant disease and the other half to toxic deaths. For example, in the MRC 10 and 12 AML trials, there was a 4% resistant disease rate in addition to a 4% induction death rate.³ With increasing rates of survival for children treated for AML comes an increased awareness of long-term sequelae of various treatments. For children who receive intensive chemotherapy, including anthracyclines, continued monitoring of cardiac function is critical. Periodic renal and auditory examinations are also suggested. In addition, total-body irradiation before HSCT increases the risk of growth failure, gonadal and thyroid dysfunction, and cataract formation.^9,

Prognostic factors in childhood acute myeloid leukemia

Several prognostic factors in childhood AML have been identified and can be categorized as:

Patient characteristics (age): Age has not been a consistent prognostic factor in pediatric patients who are treated with intensive, multiagent chemotherapeutic regimens.^10,

Patient characteristics (race): Caucasians have better outcomes than African-Americans.^11,^12,^13,

Leukemia cell characteristics: Includes diagnostic white blood cell (WBC) count, French-American-British (FAB) morphologic classification, cytogenetics and specific molecular abnormalities. WBC count at diagnosis has been consistently noted to be inversely related to survival.^14,¹⁵ Associations between FAB subtype and prognosis have been more variable. Recent studies have consistently demonstrated a relatively good outcome for M3 (APL).^16,^17,¹⁸ Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,^19,²⁰ though more recent reports suggest an intermediate prognosis for this group of patients.^3,^21,

Response to therapy: Response to therapy, defined either by standard morphologic examination of bone marrow or by more sophisticated techniques to identify minimal residual disease, has emerged as a powerful prognostic indicator.^13,^14,^22,^23,

Cytogenetic and molecular characteristics: Cytogenetic and molecular characteristics are also associated with prognosis. (Refer to the Cytogenetic evaluation and molecular abnormalities section in the Classification of Pediatric Myeloid Malignancies section of this summary for more information.)

¹ Loeb DM, Arceci RJ: What is the optimal therapy for childhood AML? Oncology (Huntingt) 16 (8): 1057-66; discussion 1066, 1068-70, 2002.

² Arceci RJ: Progress and controversies in the treatment of pediatric acute myelogenous leukemia. Curr Opin Hematol 9 (4): 353-60, 2002.

³ Hann IM, Webb DK, Gibson BE, et al.: MRC trials in childhood acute myeloid leukaemia. Ann Hematol 83 (Suppl 1): S108-12, 2004.

⁴ Ozer H, Armitage JO, Bennett CL, et al.: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18 (20): 3558-85, 2000.

⁵ Büchner T, Hiddemann W, Koenigsmann M, et al.: Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 78 (5): 1190-7, 1991.

⁶ Ohno R, Tomonaga M, Kobayashi T, et al.: Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia. N Engl J Med 323 (13): 871-7, 1990.

⁷ Heil G, Hoelzer D, Sanz MA, et al.: A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood 90 (12): 4710-8, 1997.

⁸ Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 91 (10): 3607-15, 1998.

⁹ Leung W, Hudson MM, Strickland DK, et al.: Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 18 (18): 3273-9, 2000.

¹⁰ Woods WG, Kobrinsky N, Buckley JD, et al.: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood 87 (12): 4979-89, 1996.

¹¹ Webb DK, Wheatley K, Harrison G, et al.: Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party. Leukemia 13 (1): 25-31, 1999.

¹² Aplenc R, Alonzo TA, Gerbing RB, et al.: Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children's Oncology Group. Blood 108 (1): 74-80, 2006.

¹³ Sievers EL, Lange BJ, Alonzo TA, et al.: Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia. Blood 101 (9): 3398-406, 2003.

¹⁴ Creutzig U, Zimmermann M, Ritter J, et al.: Definition of a standard-risk group in children with AML. Br J Haematol 104 (3): 630-9, 1999.

¹⁵ Chang M, Raimondi SC, Ravindranath Y, et al.: Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) Study 8821. Leukemia 14 (7): 1201-7, 2000.

¹⁶ de Botton S, Coiteux V, Chevret S, et al.: Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Oncol 22 (8): 1404-12, 2004.

¹⁷ Testi AM, Biondi A, Lo Coco F, et al.: GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 106 (2): 447-53, 2005.

¹⁸ Ortega JJ, Madero L, Martín G, et al.: Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol 23 (30): 7632-40, 2005.

¹⁹ Lange BJ, Kobrinsky N, Barnard DR, et al.: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood 91 (2): 608-15, 1998.

²⁰ Athale UH, Razzouk BI, Raimondi SC, et al.: Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience. Blood 97 (12): 3727-32, 2001.

²¹ Reinhardt D, Diekamp S, Langebrake C, et al.: Acute megakaryoblastic leukemia in children and adolescents, excluding Down's syndrome: improved outcome with intensified induction treatment. Leukemia 19 (8): 1495-6, 2005.

²² Stevens RF, Hann IM, Wheatley K, et al.: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 101 (1): 130-40, 1998.

²³ Weisser M, Kern W, Rauhut S, et al.: Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 19 (8): 1416-23, 2005.

Treatment of Newly Diagnosed Acute Myeloid Leukemia

The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with acute promyelocytic leukemia (APL), Down syndrome, myelodysplastic syndromes (MDS), and juvenile myelomonocytic leukemia (JMML).

Induction chemotherapy

Because of the intensity of therapy used to treat children with AML, patients should have their care coordinated by specialists in pediatric oncology, and should be treated in cancer centers or hospitals with the necessary supportive care facilities (e.g., to administer specialized blood products; to manage infectious complications; to provide pediatric intensive care; and to provide emotional and developmental support).

Contemporary effective pediatric AML protocols result in 75% to 90% complete remission rates.^1,^2,³ Of those patients who do not go into remission, about one half have resistant leukemia and one half die from the complications of the disease or its treatment. To achieve a complete remission, inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.

The 2 most effective drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.^1,^2,³ For example, the Children’s Cancer Group (CCG) intensively-timed dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin (DCTER) and idarubicin (IDA)-DCTER regimens utilized cytarabine, daunorubicin or idarubicin, dexamethasone, etoposide, and thioguanine given as 2, 4-day treatments separated by 6 days.^3,⁴ The German Berlin-Frankfurt-Munster (BFM) Group studied cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE) given over 8 days.^2,^5,⁶ The United Kingdom Medical Research Council (MRC) 10 Trial compared induction with ADE versus cytarabine and daunorubicin given with thioguanine (DAT); the results showed no difference between the thioguanine and etoposide arms in remission rate or disease-free survival.⁷ The MRC also studied cytarabine, mitoxantrone, and etoposide (MAE).^1,^7,⁸

The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,^1,^2,³ though idarubicin and the anthracenedione, mitoxantrone, have also been used.⁵ A randomized study in children with newly diagnosed AML comparing daunorubicin and idarubicin (each given with cytarabine and etoposide) observed a trend favoring idarubicin, but the small benefit for idarubicin in terms of remission rate and event-free survival (EFS) was not statistically significant.⁵ Similarly, studies comparing idarubicin and daunorubicin in adults with AML have not produced compelling evidence that idarubicin is more efficacious than daunorubicin.² Excessive toxicity from IDA-DCTER compared with historical data from DCTER was reported in a CCG pilot study.⁴ Preliminary results of the randomized comparison of daunorubicin or mitoxantrone combined with cytarabine and etoposide showed similar induction deaths and resistant disease percentages.⁸ In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome to daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.

The intensity of induction therapy influences the overall outcome of therapy. The CCG 2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better event-free survival (EFS) than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer).³ The MRC Group has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.¹ Another way of intensifying induction therapy is by the use of high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2-3 g/m2/dose) compared with standard-dose cytarabine,^9,¹⁰ a benefit for the use of high-dose cytarabine compared with standard-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m2 given twice daily for 7 days with daunorubicin and thioguanine.^11,

Randomized trials evaluating hematopoietic growth factors during induction therapy for patients with AML have not been reported in children, and so the potential benefit of these agents for children with AML must be extrapolated from the adult experience. Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in attempts to reduce the toxicity associated with prolonged myelosuppression.¹² Treatment with hematopoietic growth factor generally begins within a day or 2 following the completion of cytotoxic therapy and continues until granulocyte recovery. A reduction of several days in the duration of neutropenia with the use of either G-CSF or GM-CSF has been observed.¹² Most, but not all, randomized studies showed statistically significant reductions in the duration of hospitalization and antibiotic use in patients receiving hematopoietic growth factors.¹² Significant effects on treatment-related mortality or overall survival, however, were rarely observed.^12,

Central nervous system prophylaxis for acute myeloid leukemia

Although the presence of central nervous system (CNS) leukemia at diagnosis (i.e., clinical neurologic features and/or leukemic cells in cerebral spinal fluid on cytocentrifuge preparation) is more common in childhood AML than in childhood acute lymphoblastic leukemia (ALL), reduction in overall survival directly attributable to CNS involvement has not been convincingly demonstrated in childhood AML. This finding is perhaps related to both the higher doses of chemotherapy used in AML (with potential crossover to the CNS) and the fact that marrow disease has not yet been as effectively brought under long-term control in AML as in ALL. Children with M4 and M5 AML have the highest incidence of CNS leukemia (especially those with inv(16) or 11q23 chromosomal abnormalities). The use of some form of CNS treatment (intrathecal chemotherapy with or without cranial irradiation) is now incorporated into most protocols for the treatment of childhood AML and is considered a standard part of the treatment for AML.¹³

Granulocytic sarcoma/chloroma

Granulocytic sarcoma (GS) (chloroma), describes extramedullary collections of leukemia cells. These collections can occur, albeit rarely, as the sole evidence of leukemia. In a review of 3 AML studies conducted by the former Children's Cancer Group, <1% of patients had isolated GS, and 11% had GS along with marrow disease at the time of diagnosis.¹⁴ Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated GS have a good prognosis if treated with current AML therapy. For those patients who have GS in addition to marrow involvement, the patients with disease limited to the skin do worse than those without GS; those with AML that involves sites other than skin (e.g., orbit, head, and neck), have a similar prognosis to patients with medullary leukemia alone. Many of these patients have t(8;21) with orbital myeloblastomas. The use of radiation therapy does not improve survival in patients with GS who have a complete response to chemotherapy, but may be necessary if the site(s) of GS do not show complete response to chemotherapy.^14,

¹ Stevens RF, Hann IM, Wheatley K, et al.: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 101 (1): 130-40, 1998.

² Creutzig U, Ritter J, Zimmermann M, et al.: Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster 93. J Clin Oncol 19 (10): 2705-13, 2001.

³ Woods WG, Kobrinsky N, Buckley JD, et al.: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood 87 (12): 4979-89, 1996.

⁴ Lange BJ, Dinndorf P, Smith FO, et al.: Pilot study of idarubicin-based intensive-timing induction therapy for children with previously untreated acute myeloid leukemia: Children's Cancer Group Study 2941. J Clin Oncol 22 (1): 150-6, 2004.

⁵ Creutzig U, Ritter J, Zimmermann M, et al.: Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia 15 (3): 348-54, 2001.

⁶ Creutzig U, Zimmermann M, Reinhardt D, et al.: Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98. J Clin Oncol 22 (21): 4384-93, 2004.

⁷ Hann IM, Stevens RF, Goldstone AH, et al.: Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Blood 89 (7): 2311-8, 1997.

⁸ Hann IM, Webb DK, Gibson BE, et al.: MRC trials in childhood acute myeloid leukaemia. Ann Hematol 83 (Suppl 1): S108-12, 2004.

⁹ Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996.

¹⁰ Bishop JF, Matthews JP, Young GA, et al.: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87 (5): 1710-7, 1996.

¹¹ Becton D, Ravindranath Y, Dahl GV, et al.: A phase III study of intensive cytarabine (Ara-C) induction followed by cyclosporine (CSA) modulation of drug resistance in de novo pediatric AML; POG 9421. [Abstract] Blood 98 (11 Pt 1): A-1929, 461a, 2001.

¹² Ozer H, Armitage JO, Bennett CL, et al.: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18 (20): 3558-85, 2000.

¹³ Pui CH, Dahl GV, Kalwinsky DK, et al.: Central nervous system leukemia in children with acute nonlymphoblastic leukemia. Blood 66 (5): 1062-7, 1985.

¹⁴ Dusenbery KE, Howells WB, Arthur DC, et al.: Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 25 (10): 760-8, 2003.

Postremission Therapy for Acute Myeloid Leukemia

A major challenge in the treatment of children with acute myeloid leukemia (AML) is to prolong the duration of the initial remission with additional chemotherapy or hematopoietic stem cell transplantation (HSCT). In practice, most patients are treated with intensive chemotherapy after remission is achieved, as only a small subset have a matched-family donor. Such therapy includes the drugs used in induction and often includes high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.^1,² Randomized studies evaluating the contribution of high-dose cytarabine to postremission therapy have not been conducted in children, but studies employing historical controls suggest that consolidation with a high-dose cytarabine regimen improves outcome compared with less intensive consolidation therapies.^3,^4,⁵ The optimal number of postremission courses of therapy remains unclear.

The use of HSCT in first remission has been under evaluation since the late 1970s. Recent prospective trials of transplantation in children with AML suggest that 60% to 70% of children with matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions.^6,⁷ Prospective trials of allogeneic HSCT compared with chemotherapy and/or autologous HSCT have demonstrated a superior outcome for patients who were assigned to allogeneic transplantation based on availability of a family 6/6 or 5/6 HLA-matched donor.^6,^7,^8,^9,^10,¹¹ In the United Kingdom Medical Research Council (MRC) trials, the difference (70% vs. 60%) did not reach statistical significance but the numbers of patients enrolled did not give the study the power to demonstrate this difference.⁷ Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.^6,^7,^8,^10,

It is now recommended that patients with favorable prognostic features receive a matched family-donor HSCT only after first relapse and the achievement of a second complete remission (CR).¹² The Berlin-Frankfurt-Munster (BFM) Group uses a combination of day-15 marrow response (<5% blasts) and French-American-British (FAB) subtypes M1 and M2 with Auer Rods, M3, or M4Eo to define a good-risk group.¹³ Similarly, the MRC has identified a group of good-risk patients with a 7-year survival from CR of 78% and a disease-free survival of 59%. The patients in this group primarily include those with t(8;21), t(15;17), FAB M3 and inv(16).⁷ A retrospective analysis of 1,464 children with AML treated on Children's Cancer Group (CCG) trials suggests that allogeneic HSCT improves overall and disease-free survival for patients with low or high white blood cell counts with all subtypes except those with inv(16);¹⁴ however, the ability of patients with t(8;21) treated with chemotherapy to be successfully cured following achievement of a second CR and matched family donor HSCT has led the Children's Oncology Group to not recommend transplantation in first CR for patients with t(8;21) and inv(16). A large intent-to-treat analysis of 472 young adults treated on Bordeaux-Grenoble-Marseille-Toulouse (BGMT) studies did not show benefit from allogeneic HSCT in high- or low-risk patients but did show a benefit in intermediate-risk patients.¹⁵ Further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials. Based on a published retrospective study of 95 children who received unrelated cord blood (UCB) transplantation for AML, the Eurocord Group is recommending UCB transplantation for children who have very poor-prognosis AML and who lack an HLA-identical sibling. Poor-risk AML was defined as that having cytogenetics with any of the following abnormalities: monosomy 7 and 5, 5q-, 11q23 abnormalities other than t(9;11), abnormal 3q, t(y:9), or complex karyotypes) AML.^16,

Maintenance chemotherapy has been shown to be effective in the treatment of acute promyelocytic leukemia (APL).¹⁷ In other subtypes, there are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration.

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

COG is conducting a pilot study (AAML03P1) ¹⁸ that tests the feasibility and toxicity of an intensive regimen using MRC-based therapy plus gemtuzumab ozogamicin (GMTZ) as a strategy for both remission induction and consolidation for children with newly diagnosed AML excluding patients with APL and those with Down syndrome.

The MRC is currently studying ADE (daunorubicin, cytarabine, etoposide) compared to FLAG-IDA (fludarabine, cytarabine, G-CSF and idarubicin).¹⁹

Another phase III trial being conducted by a consortium of US institutions led by St. Jude Children’s Research Hospital is also testing GMTZ for patients postremission with persistence of minimal residual disease.

¹ Mayer RJ, Davis RB, Schiffer CA, et al.: Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 331 (14): 896-903, 1994.

² Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992.

³ Wells RJ, Woods WG, Buckley JD, et al.: Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study. J Clin Oncol 12 (11): 2367-77, 1994.

⁴ Wells RJ, Woods WG, Lampkin BC, et al.: Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid leukemia: a report from the Childrens Cancer Group. J Clin Oncol 11 (3): 538-45, 1993.

⁵ Creutzig U, Ritter J, Zimmermann M, et al.: Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster 93. J Clin Oncol 19 (10): 2705-13, 2001.

⁶ Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001.

⁷ Stevens RF, Hann IM, Wheatley K, et al.: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 101 (1): 130-40, 1998.

⁸ Ravindranath Y, Yeager AM, Chang MN, et al.: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med 334 (22): 1428-34, 1996.

⁹ Feig SA, Lampkin B, Nesbit ME, et al.: Outcome of BMT during first complete remission of AML: a comparison of two sequential studies by the Children's Cancer Group. Bone Marrow Transplant 12 (1): 65-71, 1993.

¹⁰ Amadori S, Testi AM, Aricò M, et al.: Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica Cooperative Group. J Clin Oncol 11 (6): 1046-54, 1993.

¹¹ Bleakley M, Lau L, Shaw PJ, et al.: Bone marrow transplantation for paediatric AML in first remission: a systematic review and meta-analysis. Bone Marrow Transplant 29 (10): 843-52, 2002.

¹² Creutzig U, Reinhardt D: Current controversies: which patients with acute myeloid leukaemia should receive a bone marrow transplantation?--a European view. Br J Haematol 118 (2): 365-77, 2002.

¹³ Creutzig U, Ritter J, Zimmermann M, et al.: Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia 15 (3): 348-54, 2001.

¹⁴ Alonzo TA, Wells RJ, Woods WG, et al.: Postremission therapy for children with acute myeloid leukemia: the children's cancer group experience in the transplant era. Leukemia 19 (6): 965-70, 2005.

¹⁵ Jourdan E, Boiron JM, Dastugue N, et al.: Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: an intent-to-treat long-term analysis of the BGMT experience. J Clin Oncol 23 (30): 7676-84, 2005.

¹⁶ Michel G, Rocha V, Chevret S, et al.: Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis. Blood 102 (13): 4290-7, 2003.

¹⁷ Fenaux P, Chastang C, Chevret S, et al.: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 (4): 1192-200, 1999.

¹⁸ Franklin J, Children's Oncology Group: Phase II Pilot Study of Gemtuzumab Ozogamicin in Children With Newly Diagnosed Acute Myeloid Leukemia Undergoing Intensive Remission Induction and Intensification Therapy, COG-AAML03P1, Clinical trial, Completed.

¹⁹ Hann IM, Webb DK, Gibson BE, et al.: MRC trials in childhood acute myeloid leukaemia. Ann Hematol 83 (Suppl 1): S108-12, 2004.

Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) and is treated differently than other types of AML. The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoid acid receptor and that leads to production of the PML/RARA fusion protein.¹

Clinically, APL is commonly characterized by a severe coagulopathy often present at the time of diagnosis.² Mortality during induction due to bleeding complications is more common in this subtype than other French-American-British classifications. Because of the extremely low incidence of central nervous system disease in patients with APL, a lumbar puncture is not required at the time of diagnosis and prophylactic intrathecal chemotherapy is not administered. Studies have demonstrated that the absence of PML/RARA RNA chimeric transcript expression at the end of therapy, as detected by reverse-transcription–polymerase chain reaction monitoring, predicts a low risk of relapse.^3,^4,^5,

Some molecular variants are generally believed to be resistant to treatment with all-trans retinoic acid (ATRA). One such variant, characterized by t(11;17), represents about 0.8% of APL, expresses surface CD56 and has very fine granules compared to t(15;17) APL.^6,^7,⁸ The t(11;17) variant has been associated with a poor prognosis. Although intensive multiagent chemotherapy regimens are usually used, novel approaches to therapy are needed for this rare but poor prognosis subgroup of patients. Of interest, though believed to be refractory to ATRA, remissions have been achieved in these patients using ATRA plus granulocyte-macrophage colony-stimulating factor or ATRA plus chemotherapy.^9,

The leukemia cells from patients with APL are especially sensitive to the differentiation-inducing effects of ATRA. The basis for the dramatic efficacy of ATRA against APL is the ability of pharmacologic doses of ATRA to overcome the repression of signaling caused by the PML/RARA fusion protein at physiologic ATRA concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis.¹⁰ Most patients with APL achieve a complete remission (CR) when treated with ATRA, though single-agent ATRA is generally not curative.^11,¹² A series of randomized clinical trials have defined the benefit for combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.^13,^14,¹⁵ For children with APL, survival rates exceeding 80% are now achievable.^16,^17,¹⁸

APL in children is generally similar to APL in adults, though children have a higher incidence of hyperleukocytosis (defined as white blood cell [WBC] count greater than 10 x 109/L) and a higher incidence of the microgranular morphologic subtype.^16,^17,^18,¹⁹ Similar to adults, children with WBC count less than 10 x 109/L at diagnosis have significantly better outcome than patients with higher WBC count.^17,^18,²⁰ The North American approach to treating children with APL utilizes induction therapy with ATRA, and standard-dose cytarabine and daunorubicin, followed by consolidation therapy with ATRA and daunorubicin.²¹ Maintenance therapy, especially for high-risk patients, includes ATRA plus 6-mercaptopurine and methotrexate; this combination showed an advantage over ATRA alone in randomized trials in adults.^13,²² European clinical trials groups (GIMEMA–AIEOP [Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto–Associazione Italiana Ematologia ed Ocologia Pediatrica] and PETHEMA [Programa de Estudio y Tratamiento de las Hemopatias Malignas]) have utilized idarubicin and ATRA without cytarabine for remission induction for children with APL.^17,¹⁸ Subsequent therapies for these groups include treatment courses with an anthracycline (idarubicin and mitoxantrone) plus ATRA (PETHEMA) or treatment courses with an anthracycline, ATRA, and other agents (GIMEMA-AIEOP), with both groups utilizing maintenance therapy as described above.^17,¹⁸ Because of the positive results of the use of chemotherapy plus ATRA, HSCT is not recommended in first CR but only following relapse and achievement of a second CR.

Arsenic trioxide has also been identified as an active agent in patients with APL with approximately 85% of patients achieving remission following treatment with this agent in relapse.^23,^24,^25,²⁶ Data are limited on the use of arsenic trioxide in children, though published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults.^23,^25,^27,²⁸ A recent study in China randomized adults and older children (14 years or older) with newly diagnosed APL to induction with ATRA alone, arsenic trioxide alone, or a combination of the 2, followed by consolidation and maintenance. While the CR rate was high (>90%) in all 3 groups, the combination group demonstrated greater reduction of PML/RARA transcripts at CR and better disease-free survival (100% of 20 patients) with a median follow-up of 18 months.²⁶ Although based on relatively small numbers of patients, these preliminary results are intriguing and may serve as the basis for future investigation with arsenic and ATRA combinations in trials for patients with newly diagnosed APL.²⁹ Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes),³⁰ it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.^31,

¹ Melnick A, Licht JD: Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93 (10): 3167-215, 1999.

² Tallman MS, Hakimian D, Kwaan HC, et al.: New insights into the pathogenesis of coagulation dysfunction in acute promyelocytic leukemia. Leuk Lymphoma 11 (1-2): 27-36, 1993.

³ Gameiro P, Vieira S, Carrara P, et al.: The PML-RAR alpha transcript in long-term follow-up of acute promyelocytic leukemia patients. Haematologica 86 (6): 577-85, 2001.

⁴ Jurcic JG, Nimer SD, Scheinberg DA, et al.: Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood 98 (9): 2651-6, 2001.

⁵ Hu J, Yu T, Zhao W, et al.: Impact of RT-PCR monitoring on the long-term survival in acute promyelocytic leukemia. Chin Med J (Engl) 113 (10): 899-902, 2000.

⁶ Licht JD, Chomienne C, Goy A, et al.: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85 (4): 1083-94, 1995.

⁷ Guidez F, Ivins S, Zhu J, et al.: Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91 (8): 2634-42, 1998.

⁸ Grimwade D, Biondi A, Mozziconacci MJ, et al.: Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Blood 96 (4): 1297-308, 2000.

⁹ Sirulnik A, Melnick A, Zelent A, et al.: Molecular pathogenesis of acute promyelocytic leukaemia and APL variants. Best Pract Res Clin Haematol 16 (3): 387-408, 2003.

¹⁰ Altucci L, Rossin A, Raffelsberger W, et al.: Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 7 (6): 680-6, 2001.

¹¹ Huang ME, Ye YC, Chen SR, et al.: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72 (2): 567-72, 1988.

¹² Castaigne S, Chomienne C, Daniel MT, et al.: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 76 (9): 1704-9, 1990.

¹³ Fenaux P, Chastang C, Chevret S, et al.: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 (4): 1192-200, 1999.

¹⁴ Fenaux P, Chevret S, Guerci A, et al.: Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia 14 (8): 1371-7, 2000.

¹⁵ Tallman MS, Andersen JW, Schiffer CA, et al.: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337 (15): 1021-8, 1997.

¹⁶ de Botton S, Coiteux V, Chevret S, et al.: Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Oncol 22 (8): 1404-12, 2004.

¹⁷ Testi AM, Biondi A, Lo Coco F, et al.: GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 106 (2): 447-53, 2005.

¹⁸ Ortega JJ, Madero L, Martín G, et al.: Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. J Clin Oncol 23 (30): 7632-40, 2005.

¹⁹ Guglielmi C, Martelli MP, Diverio D, et al.: Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases. Br J Haematol 102 (4): 1035-41, 1998.

²⁰ Sanz MA, Lo Coco F, Martín G, et al.: Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96 (4): 1247-53, 2000.

²¹ Powell BL, Cancer and Leukemia Group B: Phase III Randomized Study of Tretinoin, Cytarabine, and Daunorubicin With or Without Arsenic Trioxide as Induction/Consolidation Therapy Followed by Intermittent Tretinoin With or Without Mercaptopurine and Methotrexate as Maintenance Therapy in Patients With Previously Untreated Acute Promyelocytic Leukemia, CALGB-C9710, Clinical trial, Closed.

²² Sanz M, Martínez JA, Barragán E, et al.: All-trans retinoic acid and low-dose chemotherapy for acute promyelocytic leukaemia. Br J Haematol 109 (4): 896-7, 2000.

²³ Soignet SL, Maslak P, Wang ZG, et al.: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339 (19): 1341-8, 1998.

²⁴ Niu C, Yan H, Yu T, et al.: Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94 (10): 3315-24, 1999.

²⁵ Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89 (9): 3354-60, 1997.

²⁶ Shen ZX, Shi ZZ, Fang J, et al.: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101 (15): 5328-35, 2004.

²⁷ Zhang P: The use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia. J Biol Regul Homeost Agents 13 (4): 195-200, 1999 Oct-Dec.

²⁸ Shigeno K, Naito K, Sahara N, et al.: Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol 82 (3): 224-9, 2005.

²⁹ Wang G, Li W, Cui J, et al.: An efficient therapeutic approach to patients with acute promyelocytic leukemia using a combination of arsenic trioxide with low-dose all-trans retinoic acid. Hematol Oncol 22 (2): 63-71, 2004.

³⁰ Unnikrishnan D, Dutcher JP, Varshneya N, et al.: Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 97 (5): 1514-6, 2001.

³¹ Barbey JT: Cardiac toxicity of arsenic trioxide. Blood 98 (5): 1632; discussion 1633-4, 2001.

Children With Down Syndrome

Children with Down syndrome have an increased risk of leukemia with a ratio of acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML predominates and exhibits a distinctive biology.^1,^2,^3,^4,^5,^6,^7,⁸

In addition to increased risk for AML during the first 3 years of life, neonates with Down syndrome may also develop a transient myeloproliferative disorder (TMD) (also termed transient leukemia). This disorder mimics congenital AML, but typically improves spontaneously within the first 3 months of life, though TMD can remit as late as 20 months.⁹ Although TMD is usually a self-resolving condition, it may be sometimes associated with significant morbidity and may be fatal in 10% to 20% of affected infants.^9,¹⁰ Infants with progressive organomegaly, visceral effusions, and laboratory evidence of progressive liver dysfunction are at particularly high risk for early mortality.¹⁰ Therapeutic intervention is warranted in patients in whom severe hydrops or organ failure is apparent. Several treatment approaches have been used, including exchange transfusion, leukopheresis, and low-dose cytarabine.^11,

The mean time for the development of AML in the 10% to 30% of children who have a spontaneous remission of the TMD but then develop AML, has been reported to be 16 months with a range of 1 to 30 months.^9,¹² Thus, most of the infants with Down syndrome and TMD who later develop AML will do so within the first 3 years of life. While TMD is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk for developing subsequent AML.^10,

For children with Down syndrome who develop AML, outcome is generally favorable.¹³ The prognosis is particularly good (event-free survival [EFS] exceeding 80%) in children 4 years or younger at diagnosis, the age group that accounts for the vast majority of Down syndrome patients with AML.¹⁴ Appropriate therapy for these children is less intensive than current AML therapy, and hematopoietic stem cell transplant is not indicated in first remission.^3,^12,^14,^15,^16,^17,

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

The Children’s Oncology Group has completed a study of the treatment of children with Down syndrome (A2971) and is in the planning stage for another trial (AAML0431). These studies are evaluating the efficacy of reduced-dose chemotherapy for Down syndrome patients diagnosed with AML or MDS. The primary goal is to maintain or improve the current excellent outcome with fewer late effects. The secondary goal is to increase the understanding of the natural history of TMD and facilitate epidemiologic investigations of leukemia in Down syndrome. The planned study will not include the small number (5% to 10%) of Down syndrome patients 4 years or older at diagnosis, since these patients had an inferior outcome (6-year EFS = 28%) on CCG-2891.¹⁶ The recommendation is to include these older children on upfront AML trials.

¹ Ravindranath Y: Down syndrome and leukemia: new insights into the epidemiology, pathogenesis, and treatment. Pediatr Blood Cancer 44 (1): 1-7, 2005.

² Ross JA, Spector LG, Robison LL, et al.: Epidemiology of leukemia in children with Down syndrome. Pediatr Blood Cancer 44 (1): 8-12, 2005.

³ Gamis AS: Acute myeloid leukemia and Down syndrome evolution of modern therapy--state of the art review. Pediatr Blood Cancer 44 (1): 13-20, 2005.

⁴ Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005.

⁵ Massey GV: Transient leukemia in newborns with Down syndrome. Pediatr Blood Cancer 44 (1): 29-32, 2005.

⁶ Taub JW, Ge Y: Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 44 (1): 33-9, 2005.

⁷ Crispino JD: GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr Blood Cancer 44 (1): 40-4, 2005.

⁸ Jubinsky PT: Megakaryopoiesis and thrombocytosis. Pediatr Blood Cancer 44 (1): 45-6, 2005.

⁹ Homans AC, Verissimo AM, Vlacha V: Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 15 (4): 392-9, 1993.

¹⁰ Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006.

¹¹ Al-Kasim F, Doyle JJ, Massey GV, et al.: Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study. J Pediatr Hematol Oncol 24 (1): 9-13, 2002.

¹² Ravindranath Y, Abella E, Krischer JP, et al.: Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 80 (9): 2210-4, 1992.

¹³ Lange BJ, Kobrinsky N, Barnard DR, et al.: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood 91 (2): 608-15, 1998.

¹⁴ Creutzig U, Reinhardt D, Diekamp S, et al.: AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 19 (8): 1355-60, 2005.

¹⁵ Craze JL, Harrison G, Wheatley K, et al.: Improved outcome of acute myeloid leukaemia in Down's syndrome. Arch Dis Child 81 (1): 32-7, 1999.

¹⁶ Gamis AS, Woods WG, Alonzo TA, et al.: Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J Clin Oncol 21 (18): 3415-22, 2003.

¹⁷ Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005.

Myelodysplastic Syndromes

Studies have attempted to retrospectively classify and analyze the outcome of children with myelodysplastic syndromes (MDS).^1,² This continues to be problematic. The French-American-British (FAB) classification of adult MDS is only partially helpful in the categorization of children with MDS. Children with MDS present with FAB subtypes of refractory anemia (RA), refractory anemia with excess b