Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Childhood Acute Myeloid Leukemia Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia (AML) and other childhood myeloid malignancies. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

  • Classification of childhood myeloid malignancies.
  • Stage information.
  • Treatment options for childhood AML and other childhood myeloid malignancies.
  • Survivorship and late treatment effects.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

General Information

The National Cancer Institute (NCI) 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.

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 and Palliative 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.

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. More than 90% of myeloid leukemias are acute and the remainder includes chronic and/or subacute myeloproliferative disorders such as chronic myelogenous leukemia (CML) and juvenile myelomonocytic leukemia (JMML). Myelodysplastic syndromes represent less than 5% of myeloid malignancies in children.

Acute myeloid leukemia (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 as well as 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 although it accounts for only 5% of childhood myeloid leukemia. Although CML has been diagnosed in very young children, most patients are aged 6 years or older. CML is a clonal panmyelopathy that involves all hematopoietic cell lineages. While the white blood cell (WBC) 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 represents the most common myeloproliferative syndrome observed in young children. JMML occurs at a median age of 1.8 years and characteristically presents with hepatosplenomegaly, lymphadenopathy, fever, and skin rash along with an elevated WBC count and increased circulating monocytes.[2] In addition, patients often have an elevated hemoglobin F, hypersensitivity of the leukemic cells to granulocyte colony-stimulating factor, and monosomy 7.[2]

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.[3,4] 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 predict an increased risk for developing subsequent AML.[5] Approximately 20% of infants with Down syndrome and TMD eventually develop AML, with most cases diagnosed within the first 3 years of life.[4,5] Early death from TMD-related complications occurs in 10% to 20% of affected children.[5,6] Infants with progressive organomegaly, visceral effusions, and laboratory evidence of progressive liver dysfunction are at a particularly high risk for early mortality.[5]

The myelodysplastic syndromes in children represent a heterogeneous group of disorders characterized by ineffective hematopoiesis, impaired maturation of myeloid progenitors with dysplastic morphologic features, and cytopenias. 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 during fetal development.[7,8,9] There is an estimated twofold to fourfold risk of fraternal twins both developing leukemia up to about age 6 years, after which the risk is not significantly greater than that of the general population.[10,11] 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).
      • Noonan syndrome (particularly JMML development).
      • Severe congenital neutropenia (Kostmann syndrome).
      • Diamond-Blackfan anemia.
      • Familial platelet disorder with a propensity to develop AML.
      • Congenital amegakaryocytic thrombocytopenia.
  • ACQUIRED SYNDROMES
    • Severe aplastic anemia.
    • Paroxysmal nocturnal hemoglobinuria.
    • Amegakaryocytic thrombocytopenia.
    • Acquired monosomy 7.

References:

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. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Zuelzer WW, Cox DE: Genetic aspects of leukemia. Semin Hematol 6 (3): 228-49, 1969.
8. Miller RW: Persons with exceptionally high risk of leukemia. Cancer Res 27 (12): 2420-3, 1967.
9. Inskip PD, Harvey EB, Boice JD Jr, et al.: Incidence of childhood cancer in twins. Cancer Causes Control 2 (5): 315-24, 1991.
10. Kurita S, Kamei Y, Ota K: Genetic studies on familial leukemia. Cancer 34 (4): 1098-101, 1974.
11. 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). M0 AML appears to be associated with an inferior prognosis in non-Down syndrome patients.[8]
  • M1: acute myeloblastic leukemia with minimal differentiation but with the expression of MPO that is detected by immunohistochemistry or flow cytometry.
  • M2: acute myeloblastic leukemia with differentiation.
  • M3: acute promyelocytic leukemia (APL) hypergranular type.Identifying this subtype is critical since the risk of fatal hemorrhagic complication prior to or during induction is high and the appropriate therapy is different than for other subtypes of AML. (Refer to the Acute Promyelocytic Leukemia section of this summary for more information on treatment options under clinical evaluation.)
  • M3v: APL, microgranular variant. Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. Same clinical, cytogenetic, and therapeutic implications as FAB M3.
  • M4: acute myelomonocytic leukemia (AMML).
  • M4Eo: AMML with eosinophilia (abnormal eosinophils with dysplastic basophilic granules).
  • M5: acute monocytic leukemia (AMoL).
    • M5a: AMoL without differentiation (monoblastic).
    • M5b: AMoL with differentiation.
  • M6: acute erythroid leukemia (AEL).
  • M7: acute megakaryocytic leukemia (AMKL). Diagnosis of M7 can be difficult without the use of flow cytometry as the blasts can be morphologically confused with lymphoblasts. Characteristically, the blasts display cytoplasmic blebs. Marrow aspiration can be difficult due to myelofibrosis, and marrow biopsy with reticulin stain can be helpful.

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

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

World Health Organization Classification System

In 2002, the World Health Organization (WHO) proposed a new classification system that incorporated diagnostic cytogenetic information and more reliably correlated with outcome. In this classification, patients with t(8;21), inv(16), t(15;17) and those with MLL translocations, which collectively constituted nearly half of the cases of childhood AML, were classified as "AML with recurrent cytogenetic abnormalities." This classification system also decreased the bone marrow percentage of leukemic blast requirement for the diagnosis of AML from 30% to 20%; an additional clarification was made that patients with recurrent cytogenetic abnormalities did not need to meet the minimum blast requirement to be considered AML.[9,10,11] In 2008, WHO expanded the number of cytogenetic abnormalities linked to AML classification, and for the first time included specific gene mutations (CEBPA and NPM mutations) in its classification system.[12] (Refer to the WHO classification of myeloid leukemias section of this summary for more information.) Such a genetically based classification system links AML class with outcome and provides significant biologic and prognostic information. With new emerging technologies aimed at genetic, epigenetic, proteomic and immunophenotypic classification, AML classification will likely evolve and provide informative prognostic and biologic guidelines to clinicians and researchers.

WHO classification of AML

  • AML with recurrent genetic abnormalities:
    • AML with t(8;21)(q22;q22), RUNX1-RUNX1T1(CBFA/ETO).
    • AML with inv(16)(p13q22) or t(16;16)(p13;q22), CBFB-MYH11.
    • Acute promyelocytic leukemia with t(15;17)(q22;q11-12), PML-RARA.
    • AML with t(9;11)(p22;q23), MLLT3-MLL.
    • AML with t(6;9)(p23;q34); DEK-NUP214.
    • AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2), RPN1-EVI1.
    • AML (megakaryoblastic) with t(1;22)(p13;q13), RBM15-MKL1.
    • AML with mutated NPM1.
    • AML with mutated CEBPA.
  • AML with myelodysplasia-related features.
  • Therapy-related myeloid neoplasms.
  • AML, not otherwise specified:
    • AML with minimal differentiation.
    • AML without maturation.
    • AML with maturation.
    • Acute myelomonocytic leukemia.
    • Acute monoblastic and monocytic leukemia.
    • Acute erythroid leukemia.
    • Acute megakaryoblastic leukemia.
    • Acute basophilic leukemia.
    • Acute panmyelosis with myelofibrosis.
  • Myeloid sarcoma.
  • Myeloid proliferations related to Down syndrome:
    • Transient abnormal myelopoiesis.
    • Myeloid leukemia associated with Down syndrome.
  • Blastic plasmacytoid dendritic cell neoplasm.

Histochemical Evaluation

The treatment for children with AML differs significantly from that for ALL. As a consequence, it is crucial to distinguish AML from ALL. Special histochemical stains performed on bone marrow specimens of children with acute leukemia can be helpful to confirm their diagnosis. The stains most commonly used include myeloperoxidase, periodic acid-Schiff (PAS), Sudan Black B, and esterase. In most cases the staining pattern with these histochemical stains will distinguish AML from AMML and ALL (see below). This approach is being replaced by immunophenotyping using flow cytometry.

Table 1. Histochemical Staining Patterns

a These reactions are inhibited by fluoride.
  M0 AML, APL (M1-M3) AMML (M4) AMoL (M5) AEL (M6) AMKL (M7) ALL
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 CD proteins that are relatively lineage-specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIb/IIIa), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AMLs, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-associated T-lymphocytic antigens are present in 20% to 40% of AMLs.[13,14,15] The aberrant expression of lymphoid-associated antigens by AML cells is relatively common but generally has no prognostic significance.[13,14]

Immunophenotyping can also be helpful in distinguishing some FAB subtypes of AML. Testing for the presence of HLA-DR can be helpful in identifying APL. Overall, HLA-DR is expressed on 75% to 80% of AMLs but rarely expressed on APL. In addition, APL cases with PML/RARA were noted to express CD34/CD15 and demonstrate a heterogenous pattern of CD13 expression.[16] Testing for the presence of glycoprotein Ib, glycoprotein IIb/IIIa, or Factor VIII antigen expression is helpful in making the diagnosis of M7 (megakaryocytic leukemia). Glycophorin expression is helpful in making the diagnosis of M6 (erythroid leukemia).[17]

Cytogenetic Evaluation and Molecular Abnormalities

Chromosomal analyses of leukemia should be performed on children with AML because chromosomal abnormalities are important diagnostic and prognostic markers.[18,19,20] 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.[21] This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia (Ph) chromosome in patients with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML. Molecular methods are also being used to identify recurring gene mutations in adults and children with AML, and as described below, some of these recurring mutations appear to have prognostic significance.

Specific recurring cytogenetic and molecular abnormalities include:

  • 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.[22,23] Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.[18,24] Several reports describe a more favorable outcome for children with t(8;21) AML compared with children with AML characterized by normal or complex karyotypes.[18,25,26,27]
  • INV(16): In leukemias with inv(16), the CBF beta gene at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype.[28] Inv(16) confers a favorable prognosis for both adults and children with AML.[18,25,26,27]
  • 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.[29] 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).[30] Identification of cases with the t(11;17) is important because of their decreased sensitivity to all-trans retinoic acid.[29,30]
  • MLL GENE REARRANGEMENTS: Translocations of chromosomal band 11q23 involving the MLL gene, including most AML secondary to epipodophyllotoxin,[31] are associated with monocytic differentiation (FAB M4 and M5). Outcome for patients with de novo AML and MLL gene rearrangement are generally reported as being similar to that for other patients with AML.[18,32] However, the MLL gene can participate in translocations with many different fusion partners, and the specific fusion partner may influence prognosis. For example, several reports have described more favorable prognosis for cases with t(9;11), in which the MLL gene is fused with the AF9 gene.[18,33,34,35]

    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).[18,36] Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10 (MLLT10) gene on chromosome 10; most of these cases have the FAB M5 subtype.[37] AML with t(10;11) may also have fusion of the CALM gene on chromosome 11 with the AF10 gene.[38] 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.[39]

  • Translocation T(6;9): t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214.[40] This subgroup of AML has been associated with a poor prognosis.[40,41,42]
  • ABNORMALITIES WITH CHROMOSOMES 3, 5, AND 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 7 (monosomy 7), chromosome 5 (monosomy 5 and del[5q]), and the long arm of chromosome 3 (inv[3][q21q26] or t[3;3][q21q26]).[18,24] These cytogenetic subgroups are also associated with poor prognosis in children with AML, though abnormalities of the long arm of chromosomes 3 and 5 are extremely rare in pediatric patients.[24,43,44] In the past, patients with del(7q) were also considered to be at high risk of treatment failure. However, subsequent reports indicate that outcome for both adults and children with del(7q), but not monosomy 7, are comparable to that of other patients with AML. The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv[16], t[8;21]).[18,45,46]
  • T(1;22): The t(1;22)(p13;q13) translocation is restricted to AMKL and occurs in as many as one-third of AMKL cases in children.[47,48,49] Most AMKL cases with t(1;22) occur in infants, and the translocation is uncommon in children with Down syndrome who develop AMKL.[47,49] In leukemias with t(1;22), the OTT (RBM15) gene on chromosome 1 is fused to the MAL (MLK1) gene on chromosome 22.[50,51] Cases with detectable OTT/MAL fusion transcripts in the absence of t(1;22) have been reported, as well.[49] 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.[49,52]
  • FLT3 MUTATIONS: Presence of a FLT3 internal-tandem duplication (ITD) mutation appears to be associated with poor prognosis in adults with AML,[53] particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[54,55]FLT3-ITD mutations also convey a poor prognosis in children with AML.[56,57,58,59,60] The frequency of FLT3-ITD mutations in children is lower than that observed in adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% for adults).[58,59] A longer length of the ITD segment of FLT3-ITD has been reported to be associated with a poorer outcome.[61][Level of evidence: 2Di]
  • Activating point mutations of FLT3 have also been identified in both adults and children with AML,[54,58,62] though the clinical significance of these mutations is not clearly defined. FLT3-ITD and point mutations occur in 30% to 40% of children and adults with APL.[57,63,64,65] Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[57,65] 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.[63,64]
  • RAS AND OTHER TYROSINE KINASE RECEPTOR MUTATIONS (E.G., C-KIT): Although mutations in RAS have been identified in approximately 25% of patients with AML, the prognostic significance has not been clearly shown.[66,67] A report in adults has suggested that AML characterized by RAS mutations has increased sensitivity to cytarabine and benefits more from higher cytarabine doses than does wild-type RAS.[68] Mutations in c-KIT occur in less than 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[69,70] The presence of activating c-KIT mutations in adults with this subgroup of AML appears to be associated with a poorer prognosis compared with core-binding factor AML without c-KIT mutation.[70,71,72] The prognostic significance of c-KIT mutations occurring in pediatric core-binding factor AML remains unclear.[69,73,74,75]
  • GATA1 MUTATIONS:GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease or AMKL.[76,77,78,79]GATA1 mutations are not observed in non–Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.[78,79]GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.[80]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.[81]
  • NUCLEOPHOSMIN (NPM1) MUTATIONS: NPM1 is a protein that has been linked to ribosomal protein assembly and transport as well as being a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 mutations by the demonstration of cytoplasmic localization of NPM.[82] Mutations in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression,[83] and an improved prognosis in the absence of FLT3-ITD mutations in adults and younger adults.[83,84,85,86,87,88] Preliminary studies of children with AML suggest a lower rate of occurrence of this mutation in children compared with adults with normal cytogenetics.[89,83,84,85,86,90,91]NPM1 mutations have been reported to occur in approximately 8% of pediatric patients with AML and are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[92] In this pediatric population, the presence of NPM1 mutations did not appear to completely abrogate the poor prognosis of having an FLT3-ITD mutation.[92]
  • CEBPA MUTATIONS: Mutations in the CCAAT/Enhancer Binding Protein Alpha gene (CEBPA) occur in a subset of children and adults with cytogenetically normal AML. In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[87,93] Outcome for adults with AML, with CEBPA mutations, appears to be relatively favorable and similar to that of patients with core binding factor leukemias.[87,93] The prognostic significance of CEBPA mutations in children with AML is under evaluation.
  • WT1 MUTATIONS:WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[94,95]WT1 mutation was an independent predictor of the worst disease-free survival and overall survival in adults with AML. The prognostic significance of WT1 mutations in children is under evaluation.[96]

Classification of Myelodysplastic Syndromes in Children

The FAB classification of myelodysplastic syndromes (MDS) is not completely applicable to children.[97,98] 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.[98,99,100,101]

A modified classification schema for MDS and myeloproliferative disorders (MPDs) was published by WHO in 2008.[12] The primary WHO classification includes:

WHO classification of MDS

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

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

WHO classification of myelodysplastic/myeloproliferative neoplasms

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

      RARS-T is notable in that 50% to 60% of cases have JAK2 V617F mutations.[12]

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

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

The peripheral blood and bone marrow findings for the myelodysplastic syndromes according to the 2008 WHO classification schema [12] are summarized in Table 2.

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

EP = erythroid precursors; MDS-U = myelodysplastic syndromes, unclassifiable; ML = multilineage; RA = refractory anemia; RAEB = refractory anemia with excess blasts; RARS = refractory anaemia with ring sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RCUD = refractory cytopenia with unilineage dysplasia; RN = refractory neutropenia; RT = refractory thrombocytopenia; UL = unilineage.
a Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U.
b When accompanied by cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS.
c Cases with Auer rods and <5% myeloblasts in the blood and <10% in the marrow should be classified as RAEB-2.
d If the marrow myeloblast percentage is <5% but there are 2%–4% myeloblasts in the blood, the diagnostic classification is RAEB-1. Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as MDS-U.
  RCUD (including RA, RN and RT) RARS RCMD RAEB-1 RAEB-2 MDS-U del(5q)
CYTOPENIA(S) Unicytopenia or bicytopeniaa   + + + +  
ANEMIA   +         +
PLATELETS             Normal to increased
MARROW DYSPLASIA       UL or ML UL or ML    
  ERYTHROID   +          
  MYELOID =10% in 1 myeloid lineage   =10% in =2 myeloid lineages     <10% in =1 myeloid lineageb  
  MEGAKARYOCYTIC             Normal to increased with hypolobulated nuclei
AUER'S RODS (BLOOD AND/OR BONE MARROW)     None None ±c   None
RINGED SIDEROBLASTS <15% of EP =15% of EP ± 15%        
PERIPHERAL BLASTS Rare or none (<1%)d None Rare or none (<1%)d <5%d 5%–19% (=1%)d Rare or none (<1%)
BONE MARROW BLASTS <5% <5% <5% 5%–9%d 10%–19% <5% <5%
PERIPHERAL MONOCYTES     <1 x 109 /L <1 x 109 /L <1 x 109 /L    
CYTOGENETIC ABNORMALITY             Isolated del(5q)

RARS is rare in children. RA and RAEB are more common. The WHO classification schema has a subgroup that includes JMML (formerly juvenile chronic myeloid leukemia), CMML, and Ph chromosome–negative CML. This group can show mixed myeloproliferative and sometimes myelodysplastic features. JMML shares some characteristics with adult CMML [102,103,104] 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.[105] 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.[106,107] The risk group or grade of MDS is defined according to IPSS guidelines.[108] A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases was published in 2003; however, the usefulness of this classification has yet to be evaluated prospectively in clinical practice.[11] A retrospective comparison of the WHO classification with the category, cytology, and cytogenetics system and a Pediatric WHO adaptation for MDS/MPD, has shown that the latter two systems are better able to effectively classify childhood MDS than the more general WHO system.[109] A prospective study should be done to definitively determine the optimal classification scheme for childhood MDS/MPD.[11]

Diagnostic Classification of Juvenile Myelomonocytic Leukemia

JMML is a rare leukemia that accounts for less than 1% of childhood leukemia cases.[102] JMML typically presents in young children (a median age of approximately 1.8 years) and occurs more commonly in boys (male to female ratio approximately 2.5:1). Common clinical features at diagnosis include hepatosplenomegaly (97%), lymphadenopathy (76%), pallor (64%), fever (54%), and skin rash (36%).[110] In children presenting with clinical features suggestive of JMML, a definitive diagnosis requires the following:[111]

Table 3. Diagnostic Criteria for JMML

GM-CSF = Granulocyte-macrophage colony-stimulating factor.
Category Item
Minimal laboratory criteria (all 3 have to be fulfilled) 1. Ph chromosome negative, no BCR/ABL rearrangement
2. Peripheral blood monocyte count >1 x 109 /L
3. Bone marrow blasts <20%
Criteria for definite diagnosis (at least 2 must be fulfilled) 1. Hemoglobin F increased for age
2. Myeloid precursors on peripheral blood smear
3. White blood count >10 x 109 /L
4. Clonal abnormality (including monosomy 7)
5. GM-CSF hypersensitivity of myeloid progenitors in vitro

Distinctive characteristics of JMML cells include in vitro hypersensitivity to granulocyte-macrophage colony-stimulating factor and activated RAS signaling secondary to mutations in various components of this pathway including NF1, KRAS,NRAS, and PTPN11.[112,113,114] While the majority of children with JMML have no detectable cytogenetic abnormalities, a minority show loss of chromosome 7 in bone marrow cells.[103,110,115,116]

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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 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.[2]

Remission

Remission is defined in the United States as 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]

References:

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 acute myeloid leukemia (AML) requires control of bone marrow and systemic disease. Treatment of the central nervous system (CNS), usually with intrathecal (IT) medication, is a component of most pediatric AML protocols but has not yet been shown to contribute directly to an improvement in survival. CNS irradiation is not necessary in patients either as prophylaxis or for those presenting with cerebrospinal fluid leukemia that clears with IT and systemic chemotherapy.

Treatment is ordinarily divided into two 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 two courses of induction chemotherapy followed by two MRC or three COG additional courses of intensification chemotherapy.[3]

Maintenance therapy is not part of most pediatric AML protocols except for acute promyelocytic leukemia; exceptions are the Berlin-Frankfurt-Munster (BFM) 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] The BFM 98 study confirmed a lack of benefit for the use of G-CSF in a randomized pediatric AML trial.[9]

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.[10]

Prognostic Factors in Childhood Acute Myeloid Leukemia

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

  • PATIENT CHARACTERISTICS
    • Age: Several reports published since 2000 have identified older age as being an adverse prognostic factor.[11,12,13,14] The age effect is not large, but there is consistency in the observation that adolescents have a somewhat poorer outcome than younger children.
    • Race/Ethnicity: In both the Children's Cancer Group (CCG) CCG-2891 and CCG-2961 (COG-2961) studies, Caucasian children had higher overall survival rates than African American and Hispanic children.[13,15] A trend for lower survival rates for African American children compared with Caucasian children was also observed in children treated on St. Jude Children's Research Hospital AML clinical trials.[16]
    • Down syndrome: For children with Down syndrome who develop AML, outcome is generally favorable.[17] The prognosis is particularly good (event-free survival exceeding 80%) in children aged 4 years or younger at diagnosis, the age group that accounts for the vast majority of Down syndrome patients with AML.[18,19]
    • Body mass index (BMI): In the CCG-2961 (COG-2961) study, obesity (BMI more than 95th percentile for age) was predictive of inferior survival.[13,20] Inferior survival was attributable to early treatment-related mortality that was primarily due to infectious complications.[20]
  • CLINICAL CHARACTERISTICS
    • White blood cell count at diagnosis has been consistently noted to be inversely related to survival.[21,22] Associations between FAB subtype and prognosis have been more variable. The M3 (APL) subtype has a favorable outcome in studies utilizing all-trans retinoic acid in combination with chemotherapy.[23,24,25] Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,[17,26] though reports suggest an intermediate prognosis for this group of patients when contemporary treatment approaches are used.[3,27] The M0, or minimally differentiated subtype, has been associated with a poor outcome.[28]
    • Response to therapy: Early response to therapy, generally measured after the first course of induction therapy, is predictive of outcome and can be assessed either by standard morphologic examination of bone marrow,[21,29] by cytogenetic analysis,[30] or by more sophisticated techniques to identify minimal residual disease.[31,32]
  • 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 subsection of this summary for detailed information.) Cytogenetic and molecular characteristics that are used in clinical trials for treatment assignment include the following:
    • Favorable: inv(16)/t(16;16) and t(8;21), t(15;17).
    • Unfavorable: monosomy 7, monosomy 5/del(5q), and FLT3-ITD with high-allelic ratio.

References:

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. Lehrnbecher T, Zimmermann M, Reinhardt D, et al.: Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. Blood 109 (3): 936-43, 2007.
10. 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.
11. Webb DK, Harrison G, Stevens RF, et al.: Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia. Blood 98 (6): 1714-20, 2001.
12. Razzouk BI, Estey E, Pounds S, et al.: Impact of age on outcome of pediatric acute myeloid leukemia: a report from 2 institutions. Cancer 106 (11): 2495-502, 2006.
13. Lange BJ, Smith FO, Feusner J, et al.: Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood 111 (3): 1044-53, 2008.
14. Creutzig U, Büchner T, Sauerland MC, et al.: Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A. Cancer 112 (3): 562-71, 2008.
15. 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.
16. Rubnitz JE, Lensing S, Razzouk BI, et al.: Effect of race on outcome of white and black children with acute myeloid leukemia: the St. Jude experience. Pediatr Blood Cancer 48 (1): 10-5, 2007.
17. 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.
18. 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.
19. 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.
20. Lange BJ, Gerbing RB, Feusner J, et al.: Mortality in overweight and underweight children with acute myeloid leukemia. JAMA 293 (2): 203-11, 2005.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. Barbaric D, Alonzo TA, Gerbing RB, et al.: Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961. Blood 109 (6): 2314-21, 2007.
29. Wheatley K, Burnett AK, Goldstone AH, et al.: A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties. Br J Haematol 107 (1): 69-79, 1999.
30. Marcucci G, Mrózek K, Ruppert AS, et al.: Abnormal cytogenetics at date of morphologic complete remission predicts short overall and disease-free survival, and higher relapse rate in adult acute myeloid leukemia: results from Cancer and Leukemia Group B study 8461. J Clin Oncol 22 (12): 2410-8, 2004.
31. 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.
32. 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) and Down syndrome.

Overall survival (OS) rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 65% range.[1,2,3,4] Overall remission induction rates are approximately 85% to 90%, and event-free survival (EFS) rates from the time of diagnosis are in the 45% to 55% range.[2,3,4] There is, however, a wide range in outcome for different biological subtypes of AML (refer to the Cytogenetic Evaluation and Molecular Abnormalities section of this summary for more information); after taking specific biological factors of their leukemia into account, the predicted outcome for any individual patient may be much better or much worse than the overall outcome for the general population of children with AML.

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 pediatric AML protocols result in 85% to 90% complete remission rates.[3,5,6] 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 two 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.[3,5,6] 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 two 4-day treatments separated by 6 days.[3,7] The German Berlin-Frankfurt-Munster Group studied cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE) administered over 8 days.[6,8,9] The United Kingdom Medical Research Council (MRC) 10 Trial compared induction with ADE versus cytarabine and daunorubicin administered with thioguanine (DAT); the results showed no difference between the thioguanine and etoposide arms in remission rate or disease-free survival.[10] The MRC also studied cytarabine, mitoxantrone, and etoposide (MAE).[2,5,10]

The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,5,6] though idarubicin and the anthracenedione mitoxantrone have also been used.[8] A randomized study in children with newly diagnosed AML comparing daunorubicin with idarubicin (each given with cytarabine and etoposide) observed a trend favoring idarubicin in terms of remission rate, but use of idarubicin did not produce significant improvements in either EFS or OS.[8] Similarly, studies comparing idarubicin and daunorubicin in adults with AML have not produced compelling evidence that idarubicin is more efficacious than daunorubicin.[6] Excessive toxicity from IDA-DCTER compared with historical data from DCTER was reported in a CCG pilot study.[7] Preliminary results of the randomized comparison of daunorubicin or mitoxantrone combined with cytarabine and etoposide showed comparable complete remission rates and OS rates for the two induction regimens.[2] 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 EFS than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer).[3] The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.[5] 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,[11,12] 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.[13]

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 adults with AML in attempts to reduce the toxicity associated with prolonged myelosuppression.[14,15] These studies have generally shown a reduction of several days in the duration of neutropenia with the use of either G-CSF or GM-CSF [14] but have not shown significant effects on treatment-related mortality or OS.[14] A randomized study in children with AML evaluating G-CSF administered following induction chemotherapy showed a reduction in duration of neutropenia, but no difference in infectious complications or mortality.[16] Thus, routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

  • St. Jude Children's Research Hospital is conducting a randomized trial (AML08) for children with newly diagnosed AML. This trial compares two induction regimens: cytarabine/daunorubicin/etoposide (ADE) versus clofarabine/cytarabine. Responses are assessed via morphology and flow cytometry (MRD) at the end of the induction phase.
  • The Children's Oncology Group is conducting a randomized study (AAML0531) of the MRC backbone [17] with or without the addition of gemtuzumab ozogamicin (GMTZ) in both induction and postremssion treatment blocks. GMTZ is a recombinant humanized anti-CD33 monoclonal antibody linked to NAC-gamma calicheamicin, a potent antitumor antibiotic. Patients are assigned to low-risk, intermediate-risk, and high-risk groups based on cytogenetics, FLT3 ITD status, and response to induction chemotherapy. All risk groups participate in the GMTZ randomization. Low-risk patients are treated with five cycles of chemotherapy and no stem cell transplant (SCT). Intermediate-risk patients receive matched family donor (MFD) SCT after three cycles of chemotherapy. If there is no MFD, these patients receive five cycles of chemotherapy. High-risk patients (defined by presence of monosomy 7, monosomy 5/del[5q], FLT3- ITD with high allelic ratio, or elevated levels of persistent disease after course one) receive MFD or alternative donor SCT if a suitable donor is available after three cycles of chemotherapy; if a suitable donor is not available, they complete the five cycles of chemotherapy. The study includes patients aged 4 years or older with Down syndrome and excludes patients with APL.

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 OS 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-directed 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.[18]

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 three AML studies conducted by the former CCG, fewer than 1% of patients had isolated GS, and 11% had GS along with marrow disease at the time of diagnosis.[19] 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 bone marrow 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, or for disease that reoccurs locally.[19]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with untreated childhood acute myeloid leukemia and other myeloid malignancies. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Ries LAG, Melbert D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2005. Bethesda, Md: National Cancer Institute, 2007 Also available online. Last accessed January 13, 2009.
2. Gibson BE, Wheatley K, Hann IM, et al.: Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 19 (12): 2130-8, 2005.
3. Lange BJ, Smith FO, Feusner J, et al.: Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood 111 (3): 1044-53, 2008.
4. Creutzig U, Büchner T, Sauerland MC, et al.: Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A. Cancer 112 (3): 562-71, 2008.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. Creutzig U, Zimmermann M, Lehrnbecher T, et al.: Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol 24 (27): 4499-506, 2006.
16. Lehrnbecher T, Zimmermann M, Reinhardt D, et al.: Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. Blood 109 (3): 936-43, 2007.
17. Hann IM, Webb DK, Gibson BE, et al.: MRC trials in childhood acute myeloid leukaemia. Ann Hematol 83 (Suppl 1): S108-12, 2004.
18. Pui CH, Dahl GV, Kalwinsky DK, et al.: Central nervous system leukemia in children with acute nonlymphoblastic leukemia. Blood 66 (5): 1062-7, 1985.
19. 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 (MFD). 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, but appears to require at least three courses of intensive therapy, including the induction course.[6] As noted above, the United Kingdom Medical Research Council (MRC) studies have randomized patients to four versus five courses of intensive therapy.

The use of HSCT in first remission has been under evaluation since the late 1970s, and an evidence-based appraisal concerning indications for autologous and allogeneic HSCT has been published.[7] Prospective trials of transplantation in children with AML suggest that 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions.[8,9] 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.[8,9,10,11,12,13] In the 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.[9] Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[8,9,10,12]

Because of the improved outcome in patients with favorable prognostic features receiving contemporary regimens, it is now recommended that this group of patients receive an MFD HSCT only after first relapse and the achievement of a second complete remission (CR).[14] The Berlin-Frankfurt-Munster 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.[15] The MRC has identified a group of good-risk patients with a 7-year survival from CR of 78% and a disease-free survival (DFS) of 59%. The patients in this group primarily include those with t(8;21), t(15;17), FAB M3, and inv(16).[9] A retrospective analysis of 1,464 children with AML treated on Children's Cancer Group trials suggests that allogeneic HSCT improves overall survival and DFS for patients with low or high white blood cell counts with all subtypes except those with inv(16);[16] however, the ability of patients with t(8;21) treated with chemotherapy to be successfully cured following achievement of a second CR and MFD HSCT has led the Children's Oncology Group (COG) to not recommend transplantation in first CR for patients with t(8;21) and inv(16).

While there is a clear movement away from CR1 transplantation using matched family donors in pediatric patients with AML that has favorable prognostic features, there is evidence suggesting an advantage for allogeneic HSCT in patients with intermediate-risk characteristics. A large intent-to-treat analysis of 472 young adults treated on Bordeaux Grenoble Marseille Toulouse (BGMT) studies showed a survival benefit from allogeneic HSCT in intermediate-risk patients (all patients not favorable or unfavorable), while patients with favorable risk disease [M3, t(8:21), or inv (16)] did not appear to benefit. Of note, there were insufficient numbers in the study to determine whether patients with unfavorable-risk disease [complex karyotype (=5 cytogenetic findings), del(5q), monosomy 5 or 7, 3q rearrangements, t(9;22), t(6;9), or 11q23 rearrangements, except t(9;11)] benefit from this approach.[17] A second study combining the results of the POG-8821, CCG-2891, CCG-2961, and MRC ten studies confirmed an advantage for allogeneic HSCT in intermediate-risk patients (not favorable-risk as defined above or poor-risk, defined below). However, again, there were insufficient numbers in this study to assess the role of matched family member transplantation in poor-risk patients (del(5q), monosomy 5 or 7 or >15% blasts after first induction for POG/CCG studies, additionally 3q abnormalities and complex cytogenetics for the MRC study).[18] Because definitions of high-, intermediate-, and low-risk patients are evolving due to the ongoing association of molecular characteristics of the tumor with outcome (i.e., FLT-3 internal tandem duplications, WT1 mutations, etc.), 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 5 and 7, del(5q), 11q23 abnormalities other than t(9;11), abnormal 3q, t(y;9), or complex karyotypes.[19]

Maintenance chemotherapy has been shown to be effective in the treatment of acute promyelocytic leukemia (APL).[20] In other subtypes, there are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration with two randomized studies failing to show benefit for maintenance therapy with interleukin-2.[3,6,21]

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 randomized study (AAML0531) of the MRC backbone [22] with or without the addition of gemtuzumab ozogamicin (GMTZ) in both induction and postremission treatment blocks. GMTZ is a recombinant humanized anti-CD33 monoclonal antibody linked to NAC-gamma calicheamicin, a potent antitumor antibiotic. Patients are assigned to low-risk, intermediate-risk, and high-risk groups based on cytogenetics, FLT3 ITD status, and response to induction chemotherapy. All risk groups participate in the GMTZ randomization. Low-risk patients are treated with five cycles of chemotherapy and no stem cell transplant (SCT). Intermediate risk patients receive MFD SCT after three cycles. If there is no MFD, these patients receive five cycles of chemotherapy. High-risk patients (defined by presence of monosomy 7, monosomy 5/del[5q], FLT3 ITD with high allelic ratio, or elevated levels of persistent disease after course one) receive MFD or alternative donor SCT if a suitable donor is available after three cycles of chemotherapy; if a suitable donor is not available, they complete the five cycles of chemotherapy. The study includes patients aged 4 years or older with Down syndrome and excludes patients with APL.
  • St. Jude Children's Research Hospital is currently conducting a randomized trial (AML08) for children with newly diagnosed AML in which the efficacy of postchemotherapy NK cell transplantation is being assessed after five cycles of chemotherapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood acute myeloid leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

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. Lange BJ, Smith FO, Feusner J, et al.: Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood 111 (3): 1044-53, 2008.
7. Oliansky DM, Rizzo JD, Aplan PD, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 13 (1): 1-25, 2007.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. Horan JT, Alonzo TA, Lyman GH, et al.: Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: the Children's Oncology Group. J Clin Oncol 26 (35): 5797-801, 2008.
19. 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.
20. 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.
21. Perel Y, Auvrignon A, Leblanc T, et al.: Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit--multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group. Leukemia 19 (12): 2082-9, 2005.
22. 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. Optimal treatment requires rapid initiation of treatment and supportive care measures.[1] 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 promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) fusion protein.[2]

Clinically, APL is commonly characterized by a severe coagulopathy often present at the time of diagnosis.[3] Mortality during induction (with cytotoxic agents) due to bleeding complications is more common in this subtype than in 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.[4,5,6]

The leukemia cells from patients with APL are especially sensitive to the differentiation-inducing effects of all-trans retinoic acid (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.[7] Most patients with APL achieve a complete remission (CR) when treated with ATRA, though single-agent ATRA is generally not curative.[8,9] A series of randomized clinical trials has defined the benefit of combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.[10,11,12] For children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of ATRA and appropriate supportive care measures.[1,13,14,15,16]

Molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA.[17] Recognition of these rare variants is important as they differ in their sensitivity to ATRA and to arsenic trioxide.[18] The PLZF-RARA variant, characterized by t(11;17)(q23q21), represents about 0.8% of APL, expresses surface CD56 and has very fine granules compared with t(15;17) APL.[19,20,21] APL with PLZF-RARA has been associated with a poor prognosis and does not usually respond to ATRA or to arsenic trioxide.[18,19,20,21] The rare APL variants with NPM-RARA (t[5;17][q35,q21]) or with NuMA-RARA (t[11;17][q13,q21]) translocations are responsive to ATRA.[18,22,23,24,25]

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 higher than 10 x 109 /L) and a higher incidence of the microgranular morphologic subtype.[13,14,15,26] 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.[14,15,27]FLT3 mutations (either internal tandem duplications or kinase domain mutations) are observed in 40% to 50% of APL cases, with presence of FLT3 mutations correlating with higher WBC counts and with the microgranular (M3v) subtype.[28,29,30,31] While some reports describe an association of FLT3 mutation with increased risk of treatment failure, this has not been a consistent finding.[28,29,30,31]

The standard North American approach to treating children with APL utilizes induction therapy with ATRA, in conjunction with standard-dose cytarabine and daunorubicin, followed by consolidation therapy with ATRA and daunorubicin.[32] Maintenance therapy, includes ATRA plus 6-mercaptopurine and methotrexate; this combination showed an advantage over ATRA alone in randomized trials in adults.[10,33] European clinical trials groups (Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto–Associazione Italiana Ematologia ed Ocologia Pediatrica [GIMEMA–AIEOP] and Programa de Estudio y Tratamiento de las Hemopatias Malignas [PETHEMA]) have utilized idarubicin and ATRA without cytarabine for remission induction in children with APL.[14,15] 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.[14,15] Because of the favorable outcomes observed with chemotherapy plus ATRA (event-free survival [EFS] rates of 70%–80%), hematopoietic stem cell transplantation (HSCT) is not recommended in first CR.

Arsenic trioxide has also been identified as an active agent in patients with APL. Approximately 85% of patients in relapse achieve morphologic remission following treatment with this agent.[34,35,36,37,38] Arsenic trioxide is well tolerated in children with relapsed APL. The toxicity profile and response rates in children are similar to that observed in adults.[38] In adults with newly diagnosed APL, the addition of two consolidation courses of arsenic trioxide to a standard APL treatment regimen resulted in a significant improvement in EFS and overall survival, although the outcome of patients who did not receive arsenic trioxide was inferior to the results obtained in the GIMEMA or PETHEMA trials.[32] The combination of arsenic trioxide and ATRA compared with ATRA alone or arsenic alone during induction therapy followed by conventional consolidation and maintenance therapy has been tested in both adult and pediatric patients with APL. The study in adults showed that the CR rate was the same among all three induction regimens, although CR was achieved sooner with the combination regimen (median 25.5 days) compared with ATRA alone (median 40.5 days) or arsenic alone (median 31 days). Additionally, the combination of ATRA and arsenic resulted in an increased disease-free survival (DFS) compared with the patients treated with the combined results of ATRA alone or arsenic alone; data on overall survival was not presented.[32] In the pediatric study, the results (event-free survival, DFS, overall survival [OS]) from the combination of ATRA and arsenic were comparable to the groups treated with ATRA alone or arsenic alone. The OS for the entire group of 65 patients was approximately 91% with a median follow-up of 38 months.[39] These results indicate that ATRA, arsenic, or the combination of ATRA and arsenic are effective remission induction regimens in both adult and pediatric patients although the role of the combination in terms of overall survival is unclear and will require larger randomized studies. Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes),[40] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[41]

Induction and consolidation therapies result in molecular remission as measured by retrotranscriptase polymerase chain reaction (RT-PCR) for PML/RAR-alpha in the large majority of APL patients. While two negative RT-PCR assays after completion of therapy are associated with long-term remission,[5] conversion from negative to RT-PCR positivity is highly predictive of subsequent hematologic relapse.[42] Patients with persistent or relapsing disease based upon PML/RAR-alpha RT-PCR measurement may benefit from intervention with relapse therapies (see the APL section of Recurrent Childhood Acute Myeloid Leukemia).

Treatment Options Under Clinical Evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

  • The Children's Oncology Group will be conducting a study, AAML0631, evaluating the addition of two courses of arsenic trioxide plus ATRA to a backbone treatment regimen based on the Italian "AIDA" treatment regimen, [43] but with modifications to reduce the cumulative doses of anthracyclines. The primary objective is to decrease the total anthracycline dose from that used in regimens with the best current published results while still maintaining a comparable EFS. Promising results from pilot studies using arsenic trioxide and ATRA in newly diagnosed patients with APL also support evaluation of this combination.[39,44]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood acute promyelocytic leukemia (M3). The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Sanz MA, Grimwade D, Tallman MS, et al.: Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113 (9): 1875-91, 2009.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. Montesinos P, Bergua JM, Vellenga E, et al.: Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 113 (4): 775-83, 2009.
17. Zelent A, Guidez F, Melnick A, et al.: Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene 20 (49): 7186-203, 2001.
18. Rego EM, Ruggero D, Tribioli C, et al.: Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha. Oncogene 25 (13): 1974-9, 2006.
19. 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.
20. 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.
21. 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.
22. Sukhai MA, Wu X, Xuan Y, et al.: Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha. Oncogene 23 (3): 665-78, 2004.
23. Redner RL, Corey SJ, Rush EA: Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia 11 (7): 1014-6, 1997.
24. Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 17 (1): 109-13, 1997.
25. Wells RA, Hummel JL, De Koven A, et al.: A new variant translocation in acute promyelocytic leukaemia: molecular characterization and clinical correlation. Leukemia 10 (4): 735-40, 1996.
26. 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.
27. 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.
28. Callens C, Chevret S, Cayuela JM, et al.: Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 19 (7): 1153-60, 2005.
29. 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.
30. 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.
31. 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.
32. Powell BL, Moser B, Stock W, et al.: Effect of consolidation with arsenic trioxide (As2O3) on event-free survival (EFS) and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710. [Abstract] J Clin Oncol 25 (Suppl 18): A-2, 2007.
33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. Fox E, Razzouk BI, Widemann BC, et al.: Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 111 (2): 566-73, 2008.
39. Zhang L, Zhao H, Zhu X, et al.: Retrospective analysis of 65 Chinese children with acute promyelocytic leukemia: a single center experience. Pediatr Blood Cancer 51 (2): 210-5, 2008.
40. 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.
41. Barbey JT: Cardiac toxicity of arsenic trioxide. Blood 98 (5): 1632; discussion 1633-4, 2001.
42. Diverio D, Rossi V, Avvisati G, et al.: Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial. Blood 92 (3): 784-9, 1998.
43. Mandelli F, Diverio D, Avvisati G, et al.: Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90 (3): 1014-21, 1997.
44. Estey E, Garcia-Manero G, Ferrajoli A, et al.: Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 107 (9): 3469-73, 2006.

Children With Down Syndrome

Children with Down syndrome have an increased risk of leukemia with a ratio of acute lymphoblastic leukemia 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 can be associated with significant morbidity and may be fatal in 10% to 20% of affected infants.[9,10,11][Level of evidence: 3iiA] Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), and very high white blood cell count are at particularly high risk for early mortality.[10,12] 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.[13]

The mean time for the development of AML in the 10% to 30% of children who have a spontaneous remission of TMD but then develop AML, has been reported to be 16 months with a range of 1 to 30 months.[9,14] Thus, most infants with Down syndrome and TMD who later develop AML will do so within the first 3 years of life. Patients with Down syndrome who develop AML with an antecedent TMD have superior event-free survival (EFS) (91% ± 5%) compared with such children without TMD (70% ± 4%) at 5 years.[12] 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.[15] The prognosis is particularly good (EFS exceeding 80%) in children aged 4 years or younger at diagnosis, the age group that accounts for the vast majority of Down syndrome patients with AML.[16] Appropriate therapy for these children is less intensive than current AML therapy, and hematopoietic stem cell transplant is not indicated in first remission.[3,14,16,17,18,19]

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 (COG) is conducting a nonrandomized study (AAML0431) of the treatment of newly diagnosed AML or myelodysplastic syndromes in children aged 4 years or younger with Down syndrome. The main goal of the study is to increase survival while reducing toxicity. The treatment reduces the amount of intrathecal chemotherapy and the cumulative dose of anthracycline compared with the prior COG and Children's Cancer Group (CCG) Down syndrome AML study treatment plans and moves the Capizzi II intensification to earlier in the regimen. The planned study will not include the small number (5%–10%) of Down syndrome patients aged 4 years and older at diagnosis, since these patients had an inferior outcome (28% EFS at 6 years) on CCG-2891.[18] These children are eligible for the COG study (AAML0531) but will not receive stem cell transplant or be randomized to receive gemtuzumab ozogamicin.

References:

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. Muramatsu H, Kato K, Watanabe N, et al.: Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol 142 (4): 610-5, 2008.
12. Klusmann JH, Creutzig U, Zimmermann M, et al.: Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 111 (6): 2991-8, 2008.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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), RA with excess blasts (RAEB), and RA with excess blasts in transformation (RAEB-T). Juvenile myelomonocytic leukemia and monosomy 7 will be discussed below. The optimal therapy for childhood MDS is controversial. The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[3] There were 77 patients with RA (2), RAEB (33), RAEB-T (26), or acute myeloid leukemia (AML) with antecedent MDS (16) who were enrolled and randomized to standard or intensively timed induction. Subsequently patients were allocated to allogeneic hematopoietic stem cell transplantation (HSCT) if there was a suitable family donor, or randomized to autologous HSCT or chemotherapy. Patients with RA/RAEB had a poor remission rate (45%), and those with RAEB-T (69%) or AML with history of MDS (81%) had similar remission rates compared with de novo AML (77%). Six-year survival was poor for those with RA/RAEB (28%) and RAEB-T (30%). Patients with AML and antecedent MDS had a similar outcome to those with de novo AML (50% survival compared with 45%). Allogeneic HSCT appeared to improve survival at a marginal level of significance (P = .08). Based on analysis of these data and the literature, the authors conclude that children with a history of MDS who present with AML (excluding those with monosomy 7) and many of those with RAEB-T do as well with AML therapy at diagnosis as AML patients. For patients who achieve remission and for whom there is no matched-family donor (MFD), it is unclear whether aggressive continuation of chemotherapy or alternative donor stem cell transplant is optimum therapy.[3] Children with RA/RAEB as well as patients with AML have a low response rate to AML induction therapy. Because failure rates after HSCT are lower in this group when treated at diagnosis, strong consideration should be given for such treatment, especially when a 5/6 or 6/6 HLA-MFD is available. The optimum therapy for patients with RA/RAEB without MFDs is unknown. Some of these patients require no therapy for years and have indolent diseases. However, alternative forms of HSCT, utilizing matched unrelated donors, or perhaps cord blood, should be considered in an exploratory fashion when treatment is required, usually for severe cytopenia. An analysis of 37 children with MDS treated on Berlin-Frankfurt-Munster AML protocols 83, 87, and 93 confirmed the induction response of 74% for patients with RAEB-T, and suggested that transplantation was beneficial.[4]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted.

  • The use of a variety of inhibitors of DNA methylation and histone deacetylase inhibitors, as well as other therapies designed to induce differentiation, are currently being studied in both young and older adults with MDS.[5,6,7]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood myelodysplastic syndromes. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. 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.
2. 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.
3. Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002.
4. Creutzig U, Bender-Götze C, Ritter J, et al.: The role of intensive AML-specific therapy in treatment of children with RAEB and RAEB-t. Leukemia 12 (5): 652-9, 1998.
5. Mufti G, List AF, Gore SD, et al.: Myelodysplastic syndrome. Hematology (Am Soc Hematol Educ Program) : 176-99, 2003.
6. Esteller M: DNA methylation and cancer therapy: new developments and expectations. Curr Opin Oncol 17 (1): 55-60, 2005.
7. Bhalla K, List A: Histone deacetylase inhibitors in myelodysplastic syndrome. Best Pract Res Clin Haematol 17 (4): 595-611, 2004.

Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML), formerly termed juvenile chronic myeloid leukemia, is a rare hematopoietic malignancy of childhood accounting for less than 1% of all childhood leukemias.[1] A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia. Children with neurofibromatosis 1 (NF1) and Noonan syndrome are at increased risk for developing JMML [2,3] and up to 14% of cases of JMML occur in children with NF1.[4] Approximately 75% of JMML cases harbor one of three mutually exclusive mutations leading to activated RAS signaling, including direct oncogenic RAS mutations (approximately 20%),[5,6] NF1 inactivating mutations (approximately 15% to 25%),[7] or protein tyrosine phosphatase, non-receptor type 11 (PTPN11) (SHP-2) mutations (approximately 35%).[8,9]

Historically, more than 90% of patients with JMML died despite the use of chemotherapy,[10] but with the application of hematopoietic stem cell transplant (HSCT), survival rates of approximately 50% are now reported.[11] Patients appeared to follow three distinct clinical courses: (1) rapidly progressive disease and early demise; (2) transiently stable disease followed by progression and death; and (3) clinical improvement that lasted up to 9 years before progression or, rarely, long-term survival. Children aged 2 years or older and high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[4,12]

The role of conventional antileukemia in the treatment of JMML is not defined. The absence of consensus response criteria for JMML complicates determination of the role of specific agents in the treatment of JMML.[13] Among the agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and 6-mercaptopurine), and isotretinoin.[13,14] Acute myeloid leukemia (AML) induction chemotherapy can induce remissions in children with JMML, but resistant disease is much more common for JMML than for de novo AML and the role of AML-type therapy in the treatment of JMML is not clear.[15]

HSCT offers the best chance of cure for JMML.[11,16,17] A report from the European Working Group on Childhood myelodysplastic syndrome notes a 55% and 49% 5-year event-free survival for a large group of children with JMML transplanted with HLA-identical matched family donors or unrelated donors, respectively.[11] The trial included 100 recipients at multiple centers using a common preparative regimen of busulfan, cyclophosphamide, and melphalan, with or without antithymocyte globulin. Recipients had been treated with varying degrees of pretransplant chemotherapy or differentiating agents and some patients had splenectomy performed. Multivariate analysis showed no effect on survival of prior AML-like chemotherapy versus none or low-dose chemotherapy, the presence or absence of a spleen or difference in spleen size, or related versus unrelated donors. Only gender and age older than 4 years were shown to be poor prognostic factors for outcome (relative risk [RR] 2.24 [1.07–4.69], P = 0.032, RR 2.22 [1.09–4.50], P = 0.028 for older age and female gender, respectively). Disease recurrence is the primary cause of treatment failure for children with JMML following HSCT and occurs in 30% to 40% of cases.[11,16,17]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with juvenile myelomonocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997.
2. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994.
3. Choong K, Freedman MH, Chitayat D, et al.: Juvenile myelomonocytic leukemia and Noonan syndrome. J Pediatr Hematol Oncol 21 (6): 523-7, 1999 Nov-Dec.
4. 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.
5. Flotho C, Valcamonica S, Mach-Pascual S, et al.: RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13 (1): 32-7, 1999.
6. Miyauchi J, Asada M, Sasaki M, et al.: Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood 83 (8): 2248-54, 1994.
7. Side LE, Emanuel PD, Taylor B, et al.: Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 92 (1): 267-72, 1998.
8. 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.
9. Loh ML, Vattikuti S, Schubbert S, et al.: Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103 (6): 2325-31, 2004.
10. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall.
11. Locatelli F, Nöllke P, Zecca M, et al.: Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 105 (1): 410-9, 2005.
12. 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.
13. Bergstraesser E, Hasle H, Rogge T, et al.: Non-hematopoietic stem cell transplantation treatment of juvenile myelomonocytic leukemia: a retrospective analysis and definition of response criteria. Pediatr Blood Cancer 49 (5): 629-33, 2007.
14. Castleberry RP, Emanuel PD, Zuckerman KS, et al.: A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med 331 (25): 1680-4, 1994.
15. Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002.
16. Smith FO, King R, Nelson G, et al.: Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Haematol 116 (3): 716-24, 2002.
17. Yusuf U, Frangoul HA, Gooley TA, et al.: Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone Marrow Transplant 33 (8): 805-14, 2004.

Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.[1] The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t[9;22]) resulting in a bcr-abl fusion protein.[2] CML is characterized by a marked leukocytosis and is often associated with thrombocytosis, sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals hypercellularity with relatively normal granulocytic maturation and no significant increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase activity is seen in CML, this is not a specific finding.

CML has three clinical phases: chronic, accelerated, and blast crisis. Chronic phase, which lasts for approximately 3 years, usually presents with side effects secondary to hyperleukocytosis such as weakness, fever, night sweats, bone pain, respiratory distress, priapism, left upper quadrant pain (splenomegaly), and, rarely, hearing loss and visual disturbances. The accelerated phase is characterized by progressive splenomegaly, thrombocytopenia, and increased percentage of peripheral and bone marrow blasts, along with accumulation of karyotypic abnormalities in addition to the Ph chromosome. Blast crisis is notable for the bone marrow, showing greater than 30% blasts and a clinical picture that is indistinguishable from acute leukemia. Approximately two-thirds of blast crisis is myeloid and the remainder lymphoid, usually of B lineage. Patients in blast crisis will die within a few months.[3]

The only currently known curative treatment for CML is allogeneic hematopoietic stem cell transplantation (HSCT). Published reports describe survival rates of 70% to 80% when an HLA-matched family donor (MFD) is used in the treatment of children in early chronic phase, with lower survival rates when HLA-matched unrelated donors are used.[4,5,6] Relapse rates are low (less than 20%) when transplant is performed in chronic phase.[4,5] The primary cause of death is treatment-related mortality, which is increased with HLA-matched unrelated donors compared with HLA-MFDs in most reports.[4,5] High-resolution DNA matching for HLA alleles may reduce rates of treatment-related mortality leading to improved outcome for HSCT using unrelated donors.[7] As compared with transplant in chronic phase, transplantation in accelerated or blast crisis as well as a second chronic phase results in significantly reduced survival.[4,5,6] The use of T-lymphocyte depletion to avoid graft-versus-host disease results in a higher relapse rate and overall decreased survival,[8] supporting the contribution of a graft-versus-leukemia effect to favorable outcome following allogeneic HSCT.

The introduction of imatinib mesylate (Gleevec) as a therapeutic drug targeted at inhibiting the bcr-abl fusion kinase has revolutionized the treatment of patients with CML.[9] Imatinib mesylate treatment can achieve clinical, cytogenetic, and molecular remissions (as defined by the absence of bcr-abl fusion transcripts) in a high proportion of patients when treated in chronic phase.[10] Imatinib mesylate has replaced the use of alpha-interferon in the initial treatment of CML based on the results of a large phase III trial comparing imatinib mesylate with interferon plus cytarabine.[11,12] Patients receiving imatinib mesylate had higher complete cytogenetic response rates (76% vs. 14%) and had a complete cytogenetic rate of 87% at 5 years. The rate of treatment failure diminished over time, from 3.3% and 7.5% in the first and second years of imatinib mesylate treatment, respectively, to less than 1% by the fifth year of treatment.[12] After censoring for patients who died from causes unrelated to CML or transplantation, the overall estimated survival rate for patients randomly assigned to imatinib mesylate was 95% at 60 months.[12] Guidelines for imatinib mesylate treatment have been developed for adults with CML based on patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR-ABL/control gene ratio).[13,14,15] Development of BCR-ABL kinase domain mutations during imatinib mesylate treatment also appears to identify a group of patients at high risk of disease progression.[16] Identification of these kinase domain mutations has clinical implications, as there are alternative bcr-abl kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib mesylate.[17,18]

An important question is the impact of imatinib mesylate treatment on outcome for patients who subsequently proceed to allogeneic HSCT. A retrospective comparison of 145 patients who received imatinib mesylate prior to transplant compared with a historical cohort of 231 patients who did not, showed no difference in early hepatotoxicity or engraftment delay.[19] In addition, overall survival, disease-free survival, relapse, and nonrelapse mortality were similar between the two cohorts. The only factor associated with poor outcome in the cohort that received imatinib mesylate was a poor initial response to imatinib mesylate. Further evidence for a lack of effect of pretransplant imatinib mesylate on posttransplant outcomes was supplied by a report from the Center for International Blood and Marrow Transplant Research. This report compared outcome for 181 pediatric and adult subjects with CML in first chronic phase treated with imatinib mesylate before HSCT with that for 657 subjects who did not receive the agent before HSCT.[20] Among the patients in first chronic phase, imatinib mesylate therapy before HSCT was associated with better overall survival. Better HLA-matched donors, use of bone marrow, and transplantation within 1 year of diagnosis were also associated with better survival.

Imatinib has shown a high level of activity in children with CML that is comparable to that observed in adults.[21,22] The pharmacokinetics of imatinib in children appears consistent with prior results in adults.[23] The target oral dose in children, determined from the POG 9973 and ADVL0122 trials, is 440 mg/m2/day.[21]Gleevec prescribing information[23]

Although imatinib mesylate is an active treatment for children and adults with CML, there is little evidence that it is curative. Most adults with CML treated with imatinib mesylate continue to have bcr-abl transcripts detectable by highly sensitive molecular methods, although the rate of molecular complete remission does increase with duration of therapy.[24,25] Six of 12 adults with molecularly undetectable disease who stopped imatinib mesylate lost their molecular remission within 18 months of treatment cessation.[26] At this time, therefore, imatinib mesylate can not be viewed as a replacement for allogeneic HSCT in children for whom there is a suitable HLA-matched donor.[27,28]

In patients who develop a hematologic or cytogenetic relapse on imatinib, alternative kinase inhibitors, such as dasatinib or nilotonib, should be considered.[29,30,31] Patients on kinase inhibitor therapy should be monitored approximately every six months by quantitative retrotranscriptase polymerase chain reaction on peripheral blood. A persistently rising bcr/abl to abl transcript level indicates the likely need to change therapy, usually increasing the dose of imatinib or changing to a different kinase inhibitor. Patients who show resistance to imatinib should be tested for the presence of the T315I mutation, and, if positive, strong consideration should be given to performing an allogeneic transplant.

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted.

  • In an attempt to reduce the adverse side effects of myeloablative HSCT, investigators are testing reduced intensity conditioning HSCT.[32]
  • Second generation BCR-ABL inhibitors (dasatinib and nilotinib) have been approved by FDA for treatment of imatinib-refractory CML in adults.[17,18] These agents are active against many bcr-abl mutants that confer resistance to imatinib, although the agents are ineffective in patients with the T315I bcr-abl mutation.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007.
2. Quintás-Cardama A, Cortes J: Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113 (8): 1619-30, 2009.
3. O'Dwyer ME, Mauro MJ, Kurilik G, et al.: The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100 (5): 1628-33, 2002.
4. Millot F, Esperou H, Bordigoni P, et al.: Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Bone Marrow Transplant 32 (10): 993-9, 2003.
5. Cwynarski K, Roberts IA, Iacobelli S, et al.: Stem cell transplantation for chronic myeloid leukemia in children. Blood 102 (4): 1224-31, 2003.
6. Weisdorf DJ, Anasetti C, Antin JH, et al.: Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood 99 (6): 1971-7, 2002.
7. Lee SJ, Klein J, Haagenson M, et al.: High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 110 (13): 4576-83, 2007.
8. Horowitz MM, Gale RP, Sondel PM, et al.: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75 (3): 555-62, 1990.
9. Deininger M, Buchdunger E, Druker BJ: The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105 (7): 2640-53, 2005.
10. Kantarjian H, Sawyers C, Hochhaus A, et al.: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346 (9): 645-52, 2002.
11. O'Brien SG, Guilhot F, Larson RA, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348 (11): 994-1004, 2003.
12. Druker BJ, Guilhot F, O'Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355 (23): 2408-17, 2006.
13. Hehlmann R, Hochhaus A, Baccarani M, et al.: Chronic myeloid leukaemia. Lancet 370 (9584): 342-50, 2007.
14. Hughes T, Deininger M, Hochhaus A, et al.: Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108 (1): 28-37, 2006.
15. Mauro MJ, Deininger MW: Chronic myeloid leukemia in 2006: a perspective. Haematologica 91 (2): 152, 2006.
16. Khorashad JS, de Lavallade H, Apperley JF, et al.: Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol 26 (29): 4806-13, 2008.
17. Hazarika M, Jiang X, Liu Q, et al.: Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res 14 (17): 5325-31, 2008.
18. Brave M, Goodman V, Kaminskas E, et al.: Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res 14 (2): 352-9, 2008.
19. Oehler VG, Gooley T, Snyder DS, et al.: The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood 109 (4): 1782-9, 2007.
20. Lee SJ, Kukreja M, Wang T, et al.: Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood 112 (8): 3500-7, 2008.
21. Champagne MA, Capdeville R, Krailo M, et al.: Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. Blood 104 (9): 2655-60, 2004.
22. Millot F, Guilhot J, Nelken B, et al.: Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia 20 (2): 187-92, 2006.
23. Menon-Andersen D, Mondick JT, Jayaraman B, et al.: Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults. Cancer Chemother Pharmacol 63 (2): 229-38, 2009.
24. de Lavallade H, Apperley JF, Khorashad JS, et al.: Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 26 (20): 3358-63, 2008.
25. Branford S, Seymour JF, Grigg A, et al.: BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res 13 (23): 7080-5, 2007.
26. Rousselot P, Huguet F, Rea D, et al.: Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109 (1): 58-60, 2007.
27. Pulsipher MA: Treatment of CML in pediatric patients: should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy? Pediatr Blood Cancer 43 (5): 523-33, 2004.
28. Handgretinger R, Kurtzberg J, Egeler RM: Indications and donor selections for allogeneic stem cell transplantation in children with hematologic malignancies. Pediatr Clin North Am 55 (1): 71-96, x, 2008.
29. Hochhaus A, Baccarani M, Deininger M, et al.: Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22 (6): 1200-6, 2008.
30. le Coutre P, Ottmann OG, Giles F, et al.: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111 (4): 1834-9, 2008.
31. Kantarjian H, O'Brien S, Talpaz M, et al.: Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer 109 (8): 1556-60, 2007.
32. Burroughs L, Storb R: Low-intensity allogeneic hematopoietic stem cell transplantation for myeloid malignancies: separating graft-versus-leukemia effects from graft-versus-host disease. Curr Opin Hematol 12 (1): 45-54, 2005.

Recurrent Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Despite second remission induction in over one-half of children with acute myeloid leukemia (AML) treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is generally poor.[1,2] Approximately 50% to 60% of relapses occur within the first year following diagnosis with most relapses occurring by 4 years from diagnosis.[1] The vast majority of relapses occur in the bone marrow, with central nervous system (CNS) relapse being very uncommon.[1] Length of first remission is an important factor affecting the ability to attain a second remission; children with a first remission of less than 1 year have substantially lower rates of remission than children whose first remission is greater than 1 year (50%–60% vs. 70%–90%, respectively).[2,3,4] Survival for children with shorter first remissions is also substantially lower (approximately 10%) than that for children with first remissions exceeding 1 year (approximately 40%).[2,3,4]

Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with other agents, such as mitoxantrone,[2] fludarabine plus idarubicin,[5,6,7] and L-asparaginase.[8] The standard-dose cytarabine regimens used in the United Kingdom Medical Research Council AML 10 study for newly diagnosed children with AML (cytarabine plus daunorubicin plus either etoposide or thioguanine) have, when used in the setting of relapse, produced remission rates similar to those achieved with high-dose cytarabine regimens.[4] The combination of the anti-CD33 monoclonal antibody, gemtuzumab ozogamicin, with mitoxantrone plus cytarabine or with high dose cytarabine plus L-asparaginase (Capizzi II regimen), has been shown to be feasible in patients with highly refractory AML and able to induce remissions in slightly less than half of these patients.[9][Level of evidence: 2Di ]

The selection of further treatment following the achievement of a second remission depends on prior treatment as well as individual considerations. Consolidation chemotherapy followed by HSCT is the treatment of choice, though there are no controlled prospective data as to its contribution to the long-term cure of children with recurrent AML.[1] Unrelated donor HSCT has been reported to result in 5-year probabilities of leukemia-free survival of 45%, 20%, and 12% for patients with AML transplanted in second complete remission, overt relapse, and primary induction failure, respectively.[10][Level of evidence: 3iiA] There is evidence that long-term survival can be achieved in a portion of pediatric patients who undergo a second transplant subsequent to relapse after a first myeloablative transplant. Survival was associated with late relapse (>6 months from first transplant), achievement of complete response prior to the second procedure, and use of a total body irradiation (TBI)-based regimen (after receiving a non-TBI regimen for the first procedure).[11] Clinical trials, including new chemotherapy and/or biologic agents and/or novel bone marrow transplant (autologous, matched or mismatched unrelated donor, cord blood) programs, should be considered.[12,13] Information about ongoing clinical trials is available from the NCI Web site.

Isolated Central Nervous System Relapse

In a study of newly diagnosed AML, 4.8% of patients entering remission had an isolated CNS relapse. Age younger than 2 years, M5 leukemia, chromosome 11 abnormalities, and organomegaly were significant risk factors for CNS relapse. Treatment after relapse was variable, and no treatment proved to be significantly more effective in this setting. The 8-year overall survival for the entire cohort was 26% (±16%). The outcome of isolated CNS relapse is similar to bone marrow relapse and better treatment is required to improve survival.[14]

Recurrent Acute Promyelocytic Leukemia

For children with recurrent acute promyelocytic leukemia (APL), the use of arsenic trioxide or regimens including all-trans retinoic acid should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in patients with recurrent APL, with approximately 85% of patients achieving remission following treatment with this agent.[15,16,17,18] 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.[15,17,19] Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias,[20] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[21] Retrospective pediatric studies have reported 5-year event-free survival (EFS) after either autologous or allogeneic approaches to be similar at just above 70%.[22,23] When considering autologous transplantation, an adult study demonstrated improved 7-years EFS (77% vs. 50%) when both the patient and the stem cell product had negative promyelocytic leukemia/retinoic acid receptor alpha retrotranscriptase polymerase chain reaction (molecular remission) prior to transplant.[13] Patients considering transplant who achieve molecular remission or patients with poorly matched allogeneic donors may achieve long-term survival with autologous transplantation. While long-term remission after relapse of APL has been documented with arsenic trioxide-based salvage regimens and autologous and allogeneic transplantation, optimal approaches and sequence of these therapies that maximize efficacy while avoiding unnecessary toxicity have yet to be defined.

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted.

  • AAML07P1 is a Children's Oncology Group (COG) study that is evaluating the addition of the proteasome inhibitor bortezomib to AML relapse regimens (idarubicin/cytarabine or etoposide/cytarabine). Patients with prior treatment of below a threshold cumulative anthracycline dose (400 mg/m2) receive bortezomib with idarubicin and cytarabine, while patients who have received higher cumulative anthracycline doses receive bortezomib with etoposide and cytarabine.
  • AAML06P1 is a pilot study to determine whether the FLT3 inhibitor lestaurtinib (CEP-701) can be safely combined with intensive reinduction chemotherapy for children with relapsed or refractory AML whose leukemia cells have an activating FLT3 mutation (either FLT3-ITD or FLT3 point mutation). Once a safe dose of lestaurtinib is identified, then the effectiveness of the regimen in inducing remission in children with relapsed or refractory FLT3-mutant AML will be determined.
  • AAML0531 is a COG phase II study evaluating the combination of the nucleoside and ribonucleotide reductase inhibitor clofarabine with high-dose cytarabine for children with relapsed or refractory AML or acute lymphoblastic leukemia.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Webb DK: Management of relapsed acute myeloid leukaemia. Br J Haematol 106 (4): 851-9, 1999.
2. Wells RJ, Adams MT, Alonzo TA, et al.: Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. J Clin Oncol 21 (15): 2940-7, 2003.
3. Stahnke K, Boos J, Bender-Götze C, et al.: Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia. Leukemia 12 (10): 1534-8, 1998.
4. 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.
5. Dinndorf PA, Avramis VI, Wiersma S, et al.: Phase I/II study of idarubicin given with continuous infusion fludarabine followed by continuous infusion cytarabine in children with acute leukemia: a report from the Children's Cancer Group. J Clin Oncol 15 (8): 2780-5, 1997.
6. Fleischhack G, Hasan C, Graf N, et al.: IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial. Br J Haematol 102 (3): 647-55, 1998.
7. Brethon B, Yakouben K, Oudot C, et al.: Efficacy of fractionated gemtuzumab ozogamicin combined with cytarabine in advanced childhood myeloid leukaemia. Br J Haematol 143 (4): 541-7, 2008.
8. Capizzi RL, Davis R, Powell B, et al.: Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study. J Clin Oncol 6 (3): 499-508, 1988.
9. Aplenc R, Alonzo TA, Gerbing RB, et al.: Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group. J Clin Oncol 26 (14): 2390-3295, 2008.
10. Bunin NJ, Davies SM, Aplenc R, et al.: Unrelated donor bone marrow transplantation for children with acute myeloid leukemia beyond first remission or refractory to chemotherapy. J Clin Oncol 26 (26): 4326-32, 2008.
11. Meshinchi S, Leisenring WM, Carpenter PA, et al.: Survival after second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia. Biol Blood Marrow Transplant 9 (11): 706-13, 2003.
12. Meloni G, Diverio D, Vignetti M, et al.: Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 90 (3): 1321-5, 1997.
13. de Botton S, Fawaz A, Chevret S, et al.: Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 23 (1): 120-6, 2005.
14. Johnston DL, Alonzo TA, Gerbing RB, et al.: Risk factors and therapy for isolated central nervous system relapse of pediatric acute myeloid leukemia. J Clin Oncol 23 (36): 9172-8, 2005.
15. Fox E, Razzouk BI, Widemann BC, et al.: Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 111 (2): 566-73, 2008.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. Barbey JT: Cardiac toxicity of arsenic trioxide. Blood 98 (5): 1632; discussion 1633-4, 2001.
22. Dvorak CC, Agarwal R, Dahl GV, et al.: Hematopoietic stem cell transplant for pediatric acute promyelocytic leukemia. Biol Blood Marrow Transplant 14 (7): 824-30, 2008.
23. Bourquin JP, Thornley I, Neuberg D, et al.: Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood. Bone Marrow Transplant 34 (9): 795-8, 2004.

Survivorship and Adverse Late Sequelae

While the issues of long term complications of cancer and its treatment cross many disease categories, there are several important issues that relate to the treatment of myeloid malignancies that are worth stressing. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

In a review from one institution, the highest frequency of adverse long-term sequelae for children treated for acute myeloid leukemia (AML) included the following incidence rates: growth abnormalities (51%), neurocognitive abnormalities (30%), transfusion acquired hepatitis (28%), infertility (25%), endocrinopathies (16%), restrictive lung disease (20%), chronic graft-versus-host disease (20%), secondary malignancies (14%), and cataract (12%).[1] Of note is that most of these adverse sequelae are the consequence of myeloablative, allogeneic, hematopoietic stem cell transplantation. Although cardiac abnormalities were reported in only 8% of patients, this is an issue that may be particularly relevant with the current use of increased anthracyclines in clinical trials for children with newly diagnosed AML. For children who were treated with hematopoietic stem cell transplantation for acute leukemias when they were younger than 3 years, growth disturbances and dyslipidemias were the most frequently observed late sequelae (about 60%), while quality of life and intelligence scores were in the normal range.[2] Cardiomyopathy has been reported in 4.3% of survivors of AML based on Berlin-Frankfurt-Munster studies. Of these, 2.5% showed clinical symptoms.[3] Retrospective analysis of a single study suggests cardiac risk may be increased in children with Down syndrome, but prospective studies are required to confirm this finding.[4] New therapeutic approaches to reduce long-term adverse sequelae are needed, but without reducing the antileukemic efficacy of treatment as relapsed leukemia is still the primary cause of death in patients with AML.

References:

1. 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.
2. Perkins JL, Kunin-Batson AS, Youngren NM, et al.: Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer 49 (7): 958-63, 2007.
3. Creutzig U, Diekamp S, Zimmermann M, et al.: Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML. Pediatr Blood Cancer 48 (7): 651-62, 2007.
4. O'Brien MM, Taub JW, Chang MN, et al.: Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children's Oncology Group Study POG 9421. J Clin Oncol 26 (3): 414-20, 2008.

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Changes to This Summary (08 / 12 / 2009)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

POSTREMISSION THERAPY FOR ACUTE MYELOID LEUKEMIA

Added text stating there is evidence suggesting an advantage for allogeneic HSCT in patients with intermediate risk characteristics (cited Jourdan et al. as reference 17, Horan et al. as reference 18, and Michel et al. as reference 19).

ACUTE PROMYELOCYTIC LEUKEMIA

Added Montesinos et al. as reference 16.

Added text to state that the combination of arsenic trioxide and ATRA resulted in a more rapid achievement of complete response and a longer disease-free survival compared to ATRA alone or arsenic alone during induction therapy.

RECURRENT CHILDHOOD ACUTE MYELOID LEUKEMIA AND OTHER MYELOID MALIGNANCIES

Added Brethon et al. as reference 7.

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  • PDQ® Cancer Information Summaries: Adult Treatment
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    Treatment options for childhood cancers.
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    Tests or procedures that detect specific types of cancer.
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Date Last Modified: 2009-08-12

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