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Childhood Leukemia


Summary of Key Points

  • Incidence

  • Leukemia is the most common childhood cancer, accounting for 30% of cancers occurring before age 15 years and 25% before age 20 years.

  • Acute lymphoblastic leukemia (ALL) accounts for 75% to 80% of all cases of childhood leukemia; acute myeloid leukemia (AML) comprises 15% to 20%. Approximately 85% of ALL cases are B-lineage (B-ALL), and 15% are T-lineage (T-ALL).

  • Myeloproliferative neoplasms, including chronic myelogenous leukemia (CML), as well as myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), and mixed phenotype acute leukemia (MPAL), are less frequent and collectively comprise 5% to 10% of cases.

  • Etiology

  • Although environmental agents, such as ionizing radiation and chemical mutagens, have been implicated in leukemogenesis, identifiable environmental risk factors are lacking in almost all primary childhood leukemias.

  • The incidence of leukemia is substantially higher in some genetic disorders, most notably Down syndrome (trisomy 21).

  • Germline coding region mutations in cancer susceptibility genes ( TP53 ), and genes involved in hematopoietic differentiation ( CEBPA , ETV6 , PAX5, RUNX1 ) and signaling ( SH2B3 ) occur in small subsets of leukemia and can cause familial leukemia or familial cancer syndromes.

  • Germline mutations in genes in the RAS pathway ( CBL , NF1 , PTPN11 and others) occur in one-quarter to one-third of JMML cases.

  • Germline genetic polymorphisms associated with a modest (several-fold) increased risk of developing ALL have been identified, including ARIDB5 , CDKN2A , GATA3 , and IKZF1 .

  • Acquired (somatic) genetic changes are central to the development of leukemia, including aneuploidy (gain or loss of whole chromosomes), structural rearrangements, and point mutations.

  • Chromosome translocations and interstitial rearrangements that create novel fusion proteins or overexpress intact proteins play a prominent role in leukemogenesis.

  • Epidemiology

  • Leukemia is slightly more common in males than females in all age groups except infants.

  • In high-income countries, the incidence of ALL is highest between ages 2 and 5 years.

  • The incidence of AML is relatively constant during childhood, with slight peaks in the first 2 years of life and in late adolescence. AML cases exceed ALL cases starting in the early 20s.

  • JMML almost always occurs before 5 years of age; MDS typically occurs after 5 years.

  • The incidence of CML is low in early childhood and begins to increase in the teenage years.

  • Clinical Findings

  • Physical signs and symptoms of thrombocytopenia and anemia are common.

  • Neutropenia may lead to severe infection.

  • Bone pain and arthralgia caused by leukemic infiltration is more common in ALL than AML and may be especially severe in young children.

  • Common sites of extramedullary involvement in ALL include liver, spleen, thymus, and lymph nodes.

  • Skin, gums, and the head and neck area are typical sites of extramedullary disease in AML.

  • Infiltration of the central nervous system (CNS) can be found in both ALL and AML and requires treatment modification. The testes can also be affected in ALL and very rarely AML and may require treatment modification.

  • Differential Diagnosis

  • The acute onset of petechiae, ecchymoses, and bleeding may suggest idiopathic thrombocytopenic purpura.

  • Acute leukemia, aplastic anemia, and inherited bone marrow failure syndromes such as Fanconi anemia may present with pancytopenia and complications associated with marrow aplasia.

  • Infectious mononucleosis, dengue fever, and other viral infections can be confused with ALL and AML.

  • Bone pain, arthralgia, and occasionally arthritis may mimic juvenile idiopathic arthritis, rheumatic fever, other collagen vascular diseases, or osteomyelitis.

  • Pediatric small round cell tumors that involve the bone marrow can mimic childhood ALL and AML.

  • Therapy

  • Patients with ALL undergo a 4-week remission-induction phase followed by intensification (consolidation) therapy and then prolonged continuation (maintenance) treatment.

  • AML treatment regimens include remission induction and 3 to 4 courses of consolidation therapy, each of which produces at least 3 to 4 weeks of profound myelosuppression and a high risk of infection.

  • All patients with acute leukemia require treatment for subclinical CNS involvement with early intrathecal chemotherapy. Overt CNS involvement is treated with intensified CNS therapy, with fewer and fewer children receiving irradiation over time.

  • At present, the indications for allogeneic hematopoietic stem cell transplantation (HSCT) in ALL include remission failure, certain rare genetic subsets, persistence of detectable levels of minimal residual disease after 3 to 4 months of therapy, early hematologic relapse, and second or greater relapse.

  • For patients with AML, allogeneic HSCT is used for remission failure, high-risk patients in first remission, and all patients in second or greater remission.

  • Autologous HSCT is rarely used today for either ALL or AML.

  • Small-molecule tyrosine kinase inhibitors have revolutionized treatment of CML and Philadelphia chromosome–positive ALL and are being studied in other leukemias with genetic alterations affecting cytokine receptor and kinase signaling.

  • New immunotherapies show great promise in treating refractory and relapsed ALL and are being investigated in earlier stages of disease.

  • Prognosis

  • Five-year event-free survival (EFS) estimates for children with newly diagnosed ALL are now over 85%, and the overall survival rate exceeds 90%.

  • Strong adverse genetic prognostic factors for ALL include hypodiploidy with less than 44 chromosomes and the rare t(17;19)(q22;p13) and TCF3 - HLF fusion. The ETV6-RUNX1 fusion gene and hyperdiploidy with more than 50 to 53 chromosomes or favorable chromosome trisomies are strong favorable prognostic factors in B-ALL that are often used to stratify treatment intensity. At this time, there are no genetic risk factors used to stratify treatment in T-ALL.

  • The EFS for infant ALL with 11q23/ KMT2A (MLL ) rearrangement is only 30% to 35% and has not been improved significantly with chemotherapy intensification, allogeneic HSCT, or both.

  • Acute promyelocytic leukemia with PML - RARA fusion has an excellent prognosis with therapy based primarily on all-trans retinoic acid and arsenic trioxide, and many patients can be cured without cytotoxic chemotherapy.

  • In AML, patients with Down syndrome, inv(16), t(8;21), NPM and CEBPA mutations have favorable prognosis with chemotherapy alone. Patients with monosomy 7, del(5q), or high allelic ratio FLT3 internal tandem duplication have poor outcomes and typically receive HSCT in first remission.

  • Patients with acute megakaryoblastic leukemia without the t(1;22)/ RBM15-MKL1 fusion, certain KMT2A translocations, or ETV6 deletions have significantly worse outcomes than others.

  • Early bone marrow relapse and treatment-related AML typically carry a dismal prognosis.

  • Patients with MDS and AML arising from MDS require allogeneic HSCT for cure.

  • Slow response to remission induction therapy and persistent minimal residual disease are associated with a higher risk of relapse in both ALL and AML.

Introduction

Leukemia is the most common childhood cancer. The vast majority of childhood leukemias are acute, meaning that the leukemic cells are the counterpart of primitive blast cells rather than mature cells (chronic leukemia). The most common subtype, acute lymphoblastic leukemia (ALL), accounts for 75% to 80% of all cases of childhood leukemia, and acute myeloid leukemia (AML) comprises approximately 15% to 20%. AML becomes more common with age and comprises one-third of leukemias in older teenagers.

Acute leukemia is a malignant clonal proliferation and accumulation of immature blast or progenitor cells. Detailed sequencing studies demonstrate a bulk population of leukemia cells present at initial diagnosis, along with smaller subclones, each derived from ancestral cells that do not contain all the mutations required to display the malignant phenotype. Acute leukemias typically have mutations in several classes of genes that result in dysregulated proliferation, blocked differentiation, and alterations in programmed cell death (apoptosis). These mutations can make leukemic cells resistant to many chemotherapy drugs. By the time of diagnosis, leukemia cells have usually replaced normal bone marrow cells and disseminated to extramedullary sites; the presenting features of leukemia typically reflect the degree of bone marrow replacement and the extent of extramedullary spread.

Both ALL and AML are heterogeneous diseases that comprise different biological subtypes that may look similar under the microscope but are driven by different constellations of mutations. The major morphologic and immunophenotypic divisions based on lineage association and degree of maturation are subclassified by the identification of distinct, recurrent chromosomal and molecular abnormalities, and gene expression patterns.

Myeloproliferative neoplasms (MPNs) and myelodysplastic syndrome (MDS) are uncommon in children. In some cases, they are biologically and clinically quite similar to the same diseases that arise in adults, such as chronic myelogenous leukemia (CML). However, there are substantial differences between the spectrum of genetic alterations and the clinical behavior of pediatric versus adult MDS and MPN. Juvenile myelomonocytic leukemia (JMML), which is characterized by a heterogeneous pattern of myeloproliferation, dysplasia, and hepatosplenomegaly in association with abnormal peripheral blood counts and often has a highly aggressive clinical course, is unique to young children and rarely occurs after age 5 years.

Epidemiology

Before age 15 years, ALL is approximately four times more common than AML. Males are generally affected by leukemia slightly more often than females in all age groups, with two exceptions: males comprise about three-quarters of T-ALL cases, and infant leukemia is more common in females. In developed countries, the incidence of ALL is highest between ages 2 and 5 years. This age peak is accounted for largely by ALL with hyperdiploidy (>50 chromosomes) or ETV6-RUNX1 fusion caused by a cryptic t(12;21). There are important racial and ethnic differences in ALL incidence, with higher rates in Hispanics than whites and in whites than blacks. The spectrum of ALL subtypes also varies by race and ethnicity. Black children have a higher incidence of B-ALL with TCF3-PBX1 fusion and T-ALL and are less likely to have hyperdiploid ALL than are whites. Hispanics have an increased incidence of higher-risk genetic subtypes than whites, including Philadelphia chromosome–like (Ph-like) ALL with IGH - CRLF2 fusion.

Pediatric AML incidence peaks at 2 years, decreases to a nadir at 9 years, and then begins a steady increase until it supplants ALL as the most common acute leukemia in the early 20s. There are also racial and ethnic differences in AML subtypes, with Asians having the highest risk for AML. Intriguingly, acute promyelocytic leukemia (APML) accounts for 10% or less of AML in most populations of children, but it accounts for 25% of AML cases in Latin American children and is also more common in Italian children.

Collectively, inherited genetic syndromes that increase the risk of developing leukemia are present in about 5% of children with acute leukemia ( Table 93.1 ), with the most prominent of these being Down syndrome (DS). Overall, children with DS have a 10- to 20-fold increased incidence of acute leukemia. Notable differences exist in ALL subsets, including almost no cases in T-ALL and lower incidence of B-ALL with ETV6 - RUNX1 fusion or hyperdiploidy. Children with DS have an increased incidence of Ph-like ALL, and more than half of cases have CRLF2 fusions (usually with P2RY8 ) with or without concomitant JAK1 / JAK2 point mutations. The incidence of AML is also greatly increased in children with DS, particularly acute megakaryocytic leukemia (AMKL), which is increased 500-fold! The AMKL that occurs in DS (DS-AMKL) is clinically distinct from that arising in non-DS children, being much more curable and almost always associated with somatic GATA1 mutations. The GATA1 mutations frequently occur in utero, and 10% to 20% of newborns with DS are diagnosed with transient myeloproliferative disorder (TMD) with circulating clonal blasts that appear indistinguishable from AMKL cells and have GATA1 mutations. Most cases of TMD resolve spontaneously or with minimal cytotoxic chemotherapy, although severe complications (hepatomegaly, pericardial effusions, fetal hydrops, and others) and death occur in a minority of cases. However, about 20% to 30% of DS children with TMD later develop AMKL, with the identical GATA1 point mutations but now accompanied by other somatic mutations.

Table 93.1
Congenital Disorders Associated With an Increased Risk of Leukemia
Congenital Disorder Associated Leukemia(s)
Down syndrome ALL, AML
Ataxia-telangiectasia ALL
Wiskott-Aldrich syndrome AML
Bloom syndrome ALL, AML
Fanconi anemia AML
Kostmann disease AML
Neurofibromatosis AML, JMML
Noonan syndrome JMML
ALL, Acute lymphocytic leukemia; AML, acute myeloid leukemia; JMML, juvenile myelomonocytic leukemia.

Familial cases of acute leukemia outside the case of monozygotic twins are rare. The concordance rate of acute leukemia in identical twins is inversely related to age at diagnosis of the first leukemia. If ALL or AML is diagnosed before 1 year of age, it almost invariably develops in the other twin, typically within a few months. Molecular studies show that leukemia cells of identical twins concordant for leukemia share some somatic alterations, most commonly KMT2A ( MLL ) translocations, inferring that the initiating leukemogenic events occurred in one twin in utero with fetal transfer of partially or fully leukemic cells to the second twin. The incidence of concordant leukemia in fraternal twins may be increased modestly (two- to fourfold) over baseline, and some cases likely have similar in utero exchange of cells. If the index case of leukemia occurs after 5 years, then the rate of concordance for identical twins is substantially lower.

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