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C H A P T E R 64CLINICAL MANIFESTATIONS AND TREATMENT OF ACUTE

LYMPHOBLASTIC LEUKEMIA IN CHILDREN

Sima Jeha and Ching-Hon Pui

Serial risk-directed clinical trials have optimized the combination of chemotherapeutic agents and, along with advances in supportive care, have led to current cure rates of childhood acute lymphoblastic leuke-mia (ALL) exceeding 85% compared with long-term survival less than 10% in the 1960s.1 However, because ALL is the most common cancer in children, relapsed ALL remains the leading cause of death from a disease in this age group. Over the past decade, minimal residual disease (MRD) has become a major determinant in risk strati-fication, cranial irradiation has been successfully omitted from some frontline protocols, and the tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with BCR-ABL1 rear-rangement. Our understanding of the immunology and molecular pathways involved in ALL is improving at a rapid pace, and several targeted therapies are showing promise in early clinical trials. The challenge is to successfully incorporate targeted therapy into personal-ized ALL regimens aiming at improving cure rates and reducing toxicity.2

EPIDEMIOLOGY

Acute lymphoblastic leukemia accounts for approximately 75% of all cases of childhood leukemia and is the most common pediatric cancer in developed countries, representing 23% of cancer diagnoses among children younger than 15 years of age. About 2400 children and adolescents are diagnosed with ALL each year in the United States, an annual rate of 30 to 40 per million. The peak incidence of ALL occurs around 4 years of age. This young age peak historically has appeared at different times in different countries and has been associ-ated with major periods of industrialization, suggesting a causative role for environmental carcinogens. ALL occurs more frequently in boys than in girls at all ages.3

Acquired and inherited genetic factors play an essential role in ALL as supported by the demonstration of genetic abnormalities in leuke-mic cells of children with ALL as well as by clinical observations. Children with the constitutional chromosomal abnormality trisomy 21 (Down syndrome) are up to 15 times more likely to develop leu-kemia than children without Down syndrome. Genetic instability and DNA repair disorders (e.g., Bloom syndrome, ataxia telangiectasia, Fanconi anemia) are also associated with an increased risk of develop-ing ALL.4 Among identical twins, if one is diagnosed with ALL during the first year of life, the risk that the other twin will develop ALL is more than 70%, approaching 100% in twins with a single monocho-rionic placenta. Highest in infancy, this risk diminishes with increas-ing age at diagnosis in the first twin to about one in 10 in older children. If the first twin develops ALL by 5 to 7 years of age, the risk to the second twin is at least twice that in the general population, regardless of zygosity.5 After the age of 7 years, the risk to the unaf-fected twin is similar to that for persons in the general population. The extraordinarily high concordance rate in monozygotic infants twins compared with dizygotic infant twins or non twinned siblings results from the metastasis of leukemic cells from one twin to the other through shared placental circulation. The majority of infants with ALL have a chromosome translocation that results in the fusion of the

MLL gene at 11q23 with a variety of partner genes but principally AF4. Identical twin infant pairs with concordant ALL share the same acquired MLL gene rearrangements.

The most common chromosome translocation in childhood ALL, t(12;21), results in ETV6(TEL)-RUNX1(AML1) fusion. In contrast to MLL-rearranged ALL, ETV6-RUNX1 leukemias present after infancy and have a concordance rate of only 10% in identical twins. ETV6-RUNX1 fusion can be found in as many as 1% of cord blood samples of normal newborn babies, a frequency 100 times higher than the prevalence of this subtype of leukemia, suggesting that additional postnatal mutations are necessary for malignant transfor-mation. Analysis of Guthrie cards of 2- to 6-year old children with ALL showed that most did have detectable, clonotypic ETV6-RUNX1 sequences at birth. In addition, identical ETV6 and RUNX1 break-points were present in each of twin pairs with a very asynchronous diagnosis, supporting the requirement for one or more additional postnatal events after in utero initiation. This interpretation suggests that ETV6-RUNX1 initiates leukemogenesis but is insufficient for overt disease, and further genetic alterations are required. ETV6 dele-tions on chromosome 12p, the most frequent additional genetic abnormalities described in cases of ALL with ETV6-RUNX1, appear to be subclonal in fluorescence in situ hybridization (FISH) analysis of leukemic cells from nontwin patients. These findings indicate that ETV6 deletion is a secondary or later event in leukemogenesis and suggest that leukemia might be initiated in utero but requires an essential second postnatal event (two hits).6

Several genetic, dietary, and environmental factors have been pro-posed to modify the risk of leukemia initiation. Children with various congenital immunodeficiency diseases, including Wiskott-Aldrich syndrome, congenital hypogammaglobulinemia, and ataxia telangiec-tasia, have an increased risk of developing lymphoid malignancies, as do patients under chronic treatment with immunosuppressive drugs. The loss of cellular immune surveillance capability for tumor antigens and the inability to self-regulate lymphoproliferative processes may contribute to malignant transformation in these patients. Absence of exposure to common infections in the first year of life is associated with a higher risk of developing ETV6-RUNX1positive or hyperdip-loid ALL in older children. A possible explanation is that in the absence of infection-driven modulation of the naive immune network in infants, subsequent infectious exposures could result in a highly dysregulated response to infections in older children, contributing to leukemogenesis. Exposure to ionizing radiation and certain toxic chemicals could also facilitate the development of acute leukemia. The high incidence of leukemia among survivors of atomic bomb explo-sions in Japan during World War II is well documented. Among sur-vivors of the atomic bomb, there was no increase in the incidence of leukemia in children exposed to radiation in utero. This experience contrasts with other reports of an increased incidence of ALL in chil-dren exposed to medical diagnostic radiation both in utero and in childhood. Other evidence linking most environmental exposures to risk of childhood ALL has largely been inconsistent. Causation path-ways are likely to be multifactorial, and it is probable that the risk of ALL from environmental exposure is influenced by genetic variation through the coinheritance of multiple low-risk variants.

Part VII Hematologic Malignancies952

PATHOBIOLOGY

Acute leukemias comprise a group of clonal disorders of maturation at an early phase of hematopoietic differentiation. ALL subtypes are a heterogeneous group of malignancies with distinctive immunophe-notype and molecular pathogenesis that result in varying clinical characteristics and response to therapy. Accurate pathobiologic diag-nosis is not only important for prognostic stratification but can also help define patient-specific therapeutic approaches.7

Lymphoblastic leukemias can arise from either B- or T-cell mutant hematopoietic cells capable of indefinite self-renewal. T-cell ALL can be classified into several distinct genetic subgroups that corre-spond to specific T-cell development stages and is frequently associated with translocations of T-cell receptor genes on chromo-some 14q11 or 7q34 with other gene partners. Recent studies have identified a novel high-risk immature T-cell subtype termed early T-cell precursor (ETP) ALL with immunologic markers and gene expression reminiscent of double-negative 1 thymocyte that retains the ability to differentiate into both T-cell and myeloid, but not B-cell, lineages.8 The discovery of its mutational spectrum recapitu-lated that of acute myeloid leukemia (AML) by whole-genome sequencing and a global transcription profile similar to that of normal hematopoietic stem cells (HSCs) and granulocyte macrophage precursors suggests that this subtype of leukemia is a stem cell leuke-mia. The prevalence of mutations in genes regulating cytokine recep-tor and Ras signaling, and histone modification further suggests that the addition of myeloid-directed therapy might improve the outcome of this subtype.9 Most B-lineage leukemias are early precursor B cell, expressing CD19 and CD10 (or cALLa, the common acute leukemia antigen) but lacking surface or cytoplasmic immuno-globulin. The mature B-cell ALLs, or Burkitt-cell leukemia, are strati-fied separately and are not included in this chapter (see Chapters 81 and 83).

Recent advances in global genome analysis have enabled the identification of recurring alterations in genes and pathways with key roles in cell growth and tumorigenesis. Several observations suggest that multiple lesions are acquired subsequent to founding transloca-tions to induce leukemogenesis. Single nucleotide polymorphism (SNP) array analysis demonstrated substantial differences in the fre-quency of copy number abnormality (CNA) among various ALL subtypes. MLL-rearranged cases had less than one CNA per case, suggesting that MLL is a potent oncogene that requires very few cooperating lesions to induce leukemia transformation, but ETV6-RUNX1 and BCR-ABL1 leukemias have more than six lesions per case.

Deletion or sequence mutation of the IKZF1, a gene that encodes the early lymphoid transcription factor IKAROS, is present in more than 80% of BCR-ABL1positive ALL and in a novel high-risk sub-group of BCR-ABL1negative ALL that has a gene expression profile significantly similar to that of BCR-ABL1-positive ALL.10 The BCR-ABL1-like ALL occurs in as many as 7% to 9% of children with ALL. Approximately half of the BCR-ABL1like cases have rearrange-ments of the lymphoid cytokine receptor gene CRLF2, with con-comitant Janus kinases (JAKs) mutations in one-third of the CRLF2-rearranged cases.11 This genotype is associated with high risk of relapse, independent of age, leukocyte count at diagnosis, cytoge-netics, and levels of MRD after remission induction. A recent tran-scriptome sequencing study of 12 cases of BCR-ABL1like cases (with whole-genome sequencing in two of them) identified structural alterations and mutations activating kinase and cytokine receptor signaling in all cases, including EBF1-PDGFRB, NUP214-ABL1, RANBP2-ABL1, BCR-JAK2, STRN3-JAK2, and activating mutations of IL7R or FLT3. Importantly, preclinical studies showed that primary leukemic cells harboring PDGFRB or ABL1 fusion responded to ABL1 TKIs, and those harboring BCR-JAK2 or mutated IL7R responded to JAK2 inhibitor, suggesting that these patients would benefit from the targeted therapy.12 Another novel subtype of B-cell precursor ALL, characterized by CRLF2 alterations (PAR1 deletion and IGH-CRLF2), occurs in 5% to 7% of children with ALL and, remarkably, in approximately 50% of the cases with Down syndrome.

These patients probably would require more intensive therapy because this genotype was associated with poor outcome in the reported series, albeit not independently significant in one.13

Experimental models have established that cooperative mutations are necessary to induce leukemia and contribute to the development of drug resistance. Association studies of ALL based on the candidate gene approach have evaluated a restricted number of polymorphisms in genes implicated in the metabolism of carcinogens, folate metabo-lism, protection of DNA from carcinogen-induced damage, and cell cycle regulation. Such studies highlight difficulties in conducting statistically and methodologically rigorous investigations into ALL risk. Genome-wide association studies of childhood ALL have recently demonstrated that common variation at four genetic loci [7p12.2 (IKZF1), 9p12 (CDKN2A/CDKN2B), 10q21.2 (ARID5B) and 14q11.2 (CEBPE)] confers a modest increase in risk, establishing a role for genetic susceptibility in the development of ALL. In addi-tion to identifying common, low-penetrance susceptibility alleles, these data provide insights into disease causation by identifying risk variants and annotating genes involved in transcriptional regulation and differentiation of B-cell progenitors.

CLINICAL MANIFESTATIONS

Children with ALL present with nonspecific symptoms and signs reflecting the degree of disruption in bone marrow (BM) function and the extent of extramedullary infiltration. The most common presenting symptoms are fever, fatigue, pallor, petechiae, bruising, bleeding from mucosal surfaces, and pain (Table 64-1). Patients, especially young children, may present with bone pain, arthralgia, or refusal to walk because of leukemic infiltration of the bone or joint or because of expansion of the BM cavity by leukemic cells. The evolution of symptoms may proceed over a few days, weeks, or months. Less common presenting symptoms include headache, visual complaints, vomiting, respiratory distress, oliguria, and anuria. Occasionally, patients present with life-threatening infection or bleeding.

On physical examination, fever, pallor, petechiae, and ecchymoses may be present. The lymphoproliferative nature of the disease may

Table 64-1 ClinicalPresentationofAcuteLymphoblasticLeukemia

Symptoms and Signs Etiology Management

Fever Disease or infection Always conduct fever workup and provide broad antimicrobial coverage until infectious etiology is ruled out

Fatigue, pallor Anemia (ALL infiltrating BM)

RBC transfusion (slow if anemia is severe; avoid in hyperleukocytosis)

Petechiae, bruising, bleeding

Thrombocytopenia (ALL infiltrating BM)

Transfuse with platelets

Pain Leukemia infiltrating bones or joints or expanding BM cavity

Establish diagnosis and start chemotherapy

Respiratory distress, superior vena cava syndrome

Mediastinal mass Avoid sedation in the presence of tracheal compression; establish diagnosis as soon as possible and start chemotherapy

ALL, Acute lymphoblastic leukemia; BM, bone marrow; RBC, red blood cell.

Chapter 64 Clinical Manifestations and Treatment of Acute Lymphoblastic Leukemia in Children 953

be manifested as lymphadenopathy, splenomegaly, or less commonly hepatomegaly. Central nervous system (CNS) involvement is uncom-mon at presentation and in most instances is detected by screening lumbar puncture in high-risk patients who are asymptomatic at the time of the puncture (Fig. 64-1, A and B). Papilledema, retinal hem-orrhages, and cranial nerve palsies should be ruled out on examina-tion. CNS involvement usually is restricted to leptomeninges, and parenchymal mass lesions are uncommon. Epidural spinal cord com-pression is a rare but serious presenting finding and requires immedi-ate chemotherapy and high-dose glucocorticoid therapy. Laminectomy or radiotherapy is generally not necessary because leukemias are very sensitive to chemotherapy at diagnosis. Overt testicular involvement occurs in only 2% of boys and usually presents as painless, asym-metric enlargement that can be distinguished from hydrocele by ultrasonography (Fig. 64-1, C and D). Less common presenting features include ocular involvement, subcutaneous nodules (leukemia cutis) (see Fig. 64-1, E and F) and enlarged salivary glands (Mikulicz syndrome). Approximately 55% of T-cell cases present with an ante-rior mediastinal mass. A bulky mediastinal mass can compresses the great vessels and trachea, resulting in superior vena cava syndrome and respiratory distress. Patients with a large mediastinal mass gener-ally present with cough, dyspnea, orthopnea, dysphagia, stridor, cya-nosis, facial edema, increased intracranial pressure, and sometimes syncope. When significant tracheal compression is present, general anesthesia should be avoided and procedures should be performed under local anesthesia. Immediate diagnosis and initiation of steroids and chemotherapy is essential to prevent respiratory failure.

Clinical laboratory data often reveal a broad spectrum of abnormal findings. Various degrees of anemia and thrombocytopenia are usually

Figure64-1 CENTRAL NERVOUS SYSTEM (CNS), TESTICULAR, AND SUBCUTANEOUS INVOLVEMENT IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL). CNS disease identified in the cerebrospinal fluid (CSF) by screening lumbar puncture at the time of diagnosis in a 12-year-old boy with high-risk precursor B-cell ALL. The total count of the CSF specimen was 6131/L with 6076 white blood cells/L and 98% blasts. A and B, The cytospin preparation shows mostly blasts, slightly altered morphologically by the preparation. In B, there is a small lymphocyte (middle) for comparison with the blasts. C and D, Testicular disease noted at relapse in a 13-year-old boy with precursor B-cell ALL. Note the infiltrate of blasts in the parenchyma of the testes, surrounding the seminiferous tubules. Immunostaining (not shown) demonstrated that the blasts were CD19+, CD10+, and TdT+. E and F, Cutane-ous disease at diagnosis. The patient was an 8-year-old boy with a scalp lesion for 2 months that was initially treated with antibiotics. On biopsy, there was much crush artifact, but deep in the specimen, there was an infiltrate of blasts separating fibers (F) shown to be B-cell lineage. Interestingly, the patient had a normal complete blood count, but bone marrow was packed with blasts that had a precursor B-cell phenotype and a hyperdiploid karyotype.

A

B

CC

DD

E

F

present at diagnosis. The presenting leukocyte counts range widely from 0.1 to 1500 109/L. Leukemic blasts may or may not be seen on peripheral smear. Approximately 45% of children have leukocyte counts less than 10 109/L, and 15% present with hyperleukocytosis (>100 109/L). Patients with hyperleukocytosis are at increased risk of CNS disease, tumor lysis syndrome, and leukostasis. Leukostasis may manifest as dyspnea, chest pain, alterations in mental status, cranial nerve palsies, or priapism. The majority of childhood ALL are B cell in derivation with approximately 12% to 15% of children with ALL having a T-cell immunophenotype. T-cell ALL usually occurs in patients older than 9 years of age with elevated leukocyte counts and is associated with CNS involvement. Coagulopathy, usually mild, can occur in T-cell ALL and is only rarely associated with severe bleeding. Elevated serum uric acid and lactate dehydrogenase levels are common in patients with a large leukemic cell burden. Patients with massive renal involvement can have increased levels of creatinine, urea nitro-gen, uric acid, and phosphorus. Approximately 0.5% of patients have hypercalcemia at diagnosis, attributable to the release of parathyroid hormone-like protein from lymphoblasts and leukemic infiltration of bone; these patients tend to be in the older age group and present with low blast cell counts. This complication generally resolves rapidly with hydration and chemotherapy. Liver dysfunction caused by leukemic infiltration occurs in 10% to 20% of patients, is usually mild, and has no prognostic consequences. Because vincristine and daunorubicin are metabolized primarily through biliary excretion, modifications of the dosage of these agents are recommended if the direct bilirubin level is elevated.

Abnormalities of the bone, such as metaphyseal banding, perios-teal reactions, osteolysis, osteosclerosis, or osteopenia, can be


fusion, have been abolished by recent improvements in risk-directed treatment. Aberrant expression of myeloid-associated antigens has been observed with certain genetic subtypes. CD15, CD33, and CD65 are expressed in ALL cases with a rearranged MLL gene, and CD13 and CD33 are expressed in cases with the ETV6-RUNX1 fusion. Once associated with a poor outcome in some studies, myeloid-associated antigen expression has no prognostic impact in contemporary risk-directed treatment programs. The recently identified ETP ALL subtype is characterized by immature genetic and immunophenotypic features (CD1a negative, CD8 negative, and CD5 weak and the expression of stem cell or myeloid markers) and a dismal prognosis with conventional therapy.9

Acute lymphoblastic leukemia can be classified according to modal chromosomal number (ploidy) and specific genetic abnormali-ties of the leukemia stem line. Hyperdiploidy (>50 chromosomes per cell) is associated with an age of 1 to 10 years, a lower median leu-kocyte count, increased sensitivity to antimetabolite agents, and a favorable prognosis. A hypodiploid karyotype (50 chromosomes), and is not associated with adverse prognosis.

DIFFERENTIAL DIAGNOSIS

Children with ALL present with a variety of nonspecific symptoms that may mimic other conditions. Pancytopenia and fever are also presenting symptoms for aplastic anemia. Failure of a single cell line, as in transient erythroblastic anemia, idiopathic thrombocytopenic purpura, and congenital or acquired neutropenia, sometime produces a clinical picture that is difficult to distinguish from ALL. Routine BM aspiration is not necessary for patients with severe thrombocy-topenia and no other hematologic or physical evidence of leukemia. However, BM aspiration should be performed to exclude leukemia in patients who require glucocorticoid treatment. Children with infectious mononucleosis or other acute viral illnesses may present with fever, adenopathy, splenomegaly, lymphocytosis, or pancytope-nia. Fever, arthralgias, or a limp may frequently be confused with juvenile rheumatoid arthritis, which can also be associated with anemia, leukocytosis, and mild splenomegaly. Children with promi-nent bone pain frequently have nearly normal blood counts, a finding that can contribute to a delay in diagnosis. Immunostains and molec-ular studies help differentiate ALL from AML and other small blue cell malignancies that invade the BM, including neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and retinoblastoma. Infants may present with subcutaneous nodules (leukemia cutis) that look clinically like Langerhans cell histiocytosis.

PROGNOSIS

Contemporary regimens have abolished the prognostic impact of many clinical and biologic features, demonstrating that the single most important prognostic factor in childhood ALL is appropriate risk-directed therapy (Table 64-2). Accurate assessment of relapse hazard is an integral part of ALL therapy, so that only high-risk patients are treated aggressively, with less toxic therapy reserved for cases at lower risk of failure.

To facilitate comparison of treatment results among different clinical trials, participants in a 1993 workshop sponsored by the United States National Cancer Institute adopted a uniform risk clas-sification based on age and leukocyte count. Two-thirds of the patients who were 1 to 9 years old with precursor B-cell ALL and a leukocyte count less than 50 109/L were considered to be at stan-dard risk of relapse; the other third was classified as high risk. This classification proved to be of limited prognostic value because up to one-third of patients designated as standard risk may relapse, and these criteria cannot be applied to T-cell ALL. Moreover, the prog-nostic impact of age and, to a lesser extent, leukocyte count is largely attributable to their association with specific genetic abnormalities. For example, the overall poor prognosis of infants younger than 12 months of age can be explained by the very high frequency of MLL rearrangements (70%80%) in this age group,14 and the overall favor-able outcome of patients ages 1 to 9 years is related to the preponder-ance of cases (70%) with hyperdiploidy (>50 chromosomes) or ETV6-RUNX1 (also known as TEL-AML1) fusion, which are both favorable genetic features. Thus a more reasonable strategy is to develop clinical prognostic risk categories based on their major immunophenotypic features and genetic characteristics.

Early pre-B ALL, lacking immunoglobulin synthesis, is the most common form of acute leukemia in children. The high-risk features previously ascribed to pre-B ALL (presence of cytoplasmic immuno-globulin M) are closely associated with the presence of the t(1;19) translocation and E2APBX1 fusion. Prognostic distinctions among ALL immunophenotypes, including the negative prognostic impact once associated with T-cell ALL and pre-B ALL with E2A-PBX1

Minimal Residual Disease

The rapidity of response to induction therapy is an important independent predictor of outcome. There is strong concordance between the assessment of MRD by flow cytometry and by PCR methods. We (the authors) monitor MRD using primarily flow cytometry methods, which are simple and rapid, and we reserve PCR methods for the few patients (


Table 64-2 PrognosticFactorsinAcuteLymphoblasticLeukemia

Factor Prognosis Clinical Application

Age

9 yr Higher risk ALL biology may change risk

White Blood Cell Count

50 (DI >1.16) Low risk Good response to antimetabolites

0.1% Dismal outcome HSCT in first CR

CNS, Central nervous system; CR, complete remission; DI, DNA index; EOI, end of induction; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; JAK, Janus kinase; TKI, tyrosine kinase inhibitor.

completion of remission induction, have a much more favorable prognosis than do those who do not achieve this status. Patients who are in morphologic remission but have a postinduction MRD level of 1% or more fare as poorly as those who do not achieve clinical remission by conventional criteria (5% blasts). About half of all patients show a disease reduction to 104 or lower after only 2 weeks of remission induction, and they appear to have an exception-ally good treatment outcome. The persistence of MRD (0.01%) beyond 4 months from diagnosis was associated with an estimated 70% cumulative risk of relapse. Patients with 0.1% MRD or more at 4 months had an especially dismal outcome. Most contemporary

clinical trials have incorporated MRD detection into the risk classi-fication system. Although MRD positivity is strongly associated with known presenting risk features, it has independent prognostic strength and is increasingly used in risk stratification of ALL in contemporary regimens.18

Currently, pediatric ALL patients are typically classified into three risk groupslow-, intermediate-, and high-risk (also referred to as standard-, high-, and very high-risk)which are categories based on age, leukocyte count at diagnosis, blast cell immunophenotype, and genotype, as well as early treatment response. More recently, gene expression profiling of leukemic cells by the DNA microarray method


corticosteroids to this regimen, although the benefit of these pulses and their optimal duration and frequency of administration in the context of contemporary therapy has not been established.19 Adjust-ing chemotherapy doses to maintain a white cell count between 2 to 3 109/L and neutrophil counts between 0.5 and 1.5 109/L has been associated with a better clinical outcome. Overzealous use of mercaptopurine, to the extent that neutropenia necessitates chemo-therapy interruption, reduces overall dose intensity and is counter-productive. The optimal duration of therapy remains unknown. Attempts to shorten therapy duration from 24 months to 12 or 18 months have resulted in a significant increase in relapses. Several studies showed no advantage to prolonging treatment beyond 3 years. A small number of patients with particularly poor prognostic features may undergo BM transplantation during first remission.

Radiation therapy was the first modality that was successfully used to prevent CNS relapse. The effectiveness of cranial radiation as preventive therapy was offset by substantial late effects in long-term survivors, including learning disabilities, multiple endocrinopathies, and an increased risk of second malignancies. Subsequent trials dem-onstrated that in the context of optimal systemic and intrathecal therapy, cranial irradiation can be reduced or even omitted altogether. Patients with high-risk genetic features, large leukemic cell burden, T-lineage ALL, and leukemic cells in the cerebrospinal fluid, even from iatrogenic introduction from a traumatic lumbar puncture at diagnosis, are at increased risk of CNS relapse and require more intense CNS-directed therapy.20 Studies have successfully used triple intrathecal therapy with methotrexate, hydrocortisone, and cytara-bine or intrathecal methotrexate alone. Systematically administered agents, including high-dose methotrexate, dexamethasone, and aspar-aginase, also contribute to prevention of extramedullary relapse.

Based on reports of more potent in vitro antileukemic activity and better CNS penetration, dexamethasone has replaced prednisone in many continuation regimens. Prednisone remains the preferred gluco-corticoid during induction because of the relative increased toxicity associated with dexamethasone use.21 Polyethylene glycolconjugated asparaginase, a long-acting and less allergenic form, is progressively replacing the native Escherichia coli and is being increasingly adminis-tered intravenously instead of intramuscularly. Asparaginase derived from Erwinia chrysanthemi has a short half-life, and its use is currently limited to patients who are allergic to the E. coli formulations. The dose schedule for asparaginase should take into account the variability in the pharmacokinetic profile and potency among the different preparations.22 Intensifying asparaginase therapy during the early phase of treatment benefits high-risk patients, particularly those with T-cell disease. Significant improvement was also reported in the outcome of patients receiving early intensification consisting of inter-mediate- or high-dose antimetabolite therapy.23 The optimal dose of methotrexate depends on the leukemic cell genotype and phenotype, as well as host pharmacogenetic and pharmacokinetic parameters. Methotrexate at 2.5 g/m2 is adequate for most patients with standard-risk B-cell precursor ALL, but a higher dose (5 g/m2) may benefit those with T-cell or high-risk B-cell precursor ALL. This observation is consistent with the finding that T-lineage blast cells accumulate meth-otrexate polyglutamates less avidly than do B-lineage blast cells. The increased ability of hyperdiploid ALL blasts cells to accumulate meth-otrexate polyglutamate could partially explain the excellent outcome

has proved useful in identifying previously unrecognized genes whose expression may have prognostic significance. The predictive power of these newly identified expression signatures requires validation in prospective clinical trials.

THERAPY, INCLUDING STEM CELL TRANSPLANTATION

With the exception of patients with mature B-cell ALL, who are treated with short-term intensive chemotherapy, therapy for patients with ALL is administered over 2 to 3 years. Treatment starts with a 4- to 6-week remission-induction phase aimed at eradicating the initial leukemic cell burden and restoring normal hematopoiesis. The induction phase typically includes the administration of a glucocor-ticoid (prednisone or dexamethasone), vincristine, and at least a third drug (asparaginase, anthracycline, or both). A three-drug induction regimen appears sufficient for most standard-risk cases, provided they receive intensified postremission therapy. The benefit in long-term survival of using four or more drugs during induction is widely accepted in higher risk patients but less clear in lower risk patients. With this approach, 98% to 99% of patients can attain remission, as defined by fewer than 5% blasts in the BM and a return of neutrophil and platelet counts to near normal levels. Intrathecal chemotherapy is usually initiated at the start of treatment.

After remission induction, consolidation (or intensification) is given to eradicate drug-resistant residual leukemic cells. Therapy is tailored to the leukemia subtype and risk group. All patients benefit from a delayed intensification (or delayed reinduction), consisting of using drugs similar to those used in remission induction therapy after a 3-month period of a less intensive, interim maintenance chemo-therapy. Double-delayed intensification with a second reinduction at week 32 of treatment improves outcome in patients with intermediate-risk leukemia but does not benefit patients with rapid early response. An augmented intensification regimen consisting of the administra-tion of additional doses of vincristine and asparaginase during the myelosuppression period after delayed intensification and sequential escalating-dose parental methotrexate followed by asparaginase improved the outcome of high-risk patients whose disease had responded slowly to initial multiagent induction therapy.

After completion of induction and consolidation, patients receive a 2- to 2.5-year continuation (or maintenance) phase consisting of low-intensity metronomic chemotherapy designed to eradicate any residual leukemic cell burden. Weekly low-dose methotrexate and daily oral mercaptopurine form the backbone of most continuation regimens. Many groups add regular pulses of vincristine and

Consolidation Therapy

The importance of a consolidation phase after remission induc-tion is undisputed, but the treatment regimen and duration vary in the different childhood ALL studies. Commonly used strategies include high-dose methotrexate plus mercaptopurine, frequent pulses of vincristine and corticosteroid plus high-dose asparagi-nase for 20 to 30 weeks, and reinduction treatment with the same agents given during initial remission induction. Reinduction treatment has become an integral component of contemporary protocols. In one randomized study, double reinduction further improved treatment outcome in patients with intermediate-risk ALL, but additional pulses of vincristine and prednisone after a single reinduction course were not beneficial, suggesting that the increased dose intensity of other drugs, such as asparaginase, was responsible for the observed improvement. An augmented regimen including Capizzi methotrexate (escalating-dose intrave-nous methotrexate with no rescue followed by asparaginase) and additional doses of vincristine and asparaginase during periods of myelosuppression improved the outcome of patients with a slow early response to therapy.

High-Risk Central Nervous System Relapse

Patients with the following characteristics are at increased risk of CNS relapse and require more intense CNS-directed therapy:1. Patients with high-risk genetic features2. Large leukemic cell burden3. T-lineage ALL4. CNS-3 status (>5 WBC/L CSF with presence of

lymphoblasts on Cytospin)5. CNS-2 status (


refractory leukemia (failure to enter morphologic remission after 46 weeks of induction therapy), high level of MRD (>1%) after remis-sion induction, persistent MRD after consolidation treatment, and early hematologic relapse are candidates for allogeneic transplanta-tion. It is crucial to reduce residual disease to, or close to, undetect-able levels as outcome is superior if MRD is undetectable before HSCT and worsens with increasing MRD levels at the time of HSCT. Treatment approaches for adolescents and young adults with ALL have evolved considerably with the widespread adoption of pediatric-based protocols, which appears to have significantly improved survival and decreased the need for HSCT in this age group. The benefit of allogeneic HSCT in infants with t(4;11) ALL remains controversial and should be evaluated in the context of emerging molecular therapies such as FLT3 inhibitors and DNA methyltransferase inhibitors. Patients with the recently identified ETP ALL have a dismal prognosis (event-free survival of 22%), even though half of the patients received transplantation because of high MRD levels after remission induction. The therapeutic role of HSCT in this group of patients remains to be determined by studying a larger number of patients. Matched unrelated-donor or cord blood transplantation has yielded outcomes comparable to those obtained with matched related-donor HSCT and should be considered reason-able alternatives if a matched donor is not available. Many advances have been made in stem cell transplantation, such as prevention of graft-versus-host disease (GVHD), expansion of the pool of suitable unrelated or related donors, donor selection and tissue typing, accel-eration of engraftment, enhancement of the graft-versus-leukemia effect, and supportive care. Because improvements in transplantation tend to parallel those in chemotherapy, the indications for transplan-tation in newly diagnosed and relapsed patients should be reevaluated periodically. For example, the presence of Philadelphia chromosome is no longer a clear indication for transplantation with the advent of TKIs.

ACUTE LYMPHOBLASTIC LEUKEMIA RELAPSE

Most relapses occur during treatment or within the first 2 years after its completion, although relapses have been reported as late as 10 years after initial ALL diagnosis. The most common site of relapse is the BM.27 Relapse in extramedullary sites, such as the CNS and testes, has decreased to less than 5% and 2% respectively. Leukemia relapse occasionally occurs at other sites, including the eye, ovary, uterus, bone, muscle, tonsil, kidney, mediastinum, pleura, and paranasal sinus. Extramedullary relapse in children with ALL frequently pres-ents as an isolated clinical finding. However, in studies that included MRD assays, many extramedullary recurrences were associated with MRD in the BM. A small fraction of patients experience a recurrence of acute leukemia with an immunophenotype different from that determined at diagnosis. Some of the cases represent relapse of origi-nal leukemic clones with a shift in immunophenotype, but others are secondary malignancies caused by the mutagenic effects of leukemia treatment, especially from epipodophyllotoxin. Patients with isolated BM relapse generally fare worse than those with isolated extramedul-lary relapse.28 Factors indicating an especially poor prognosis are a short initial remission and a T-cell immunophenotype. Other adverse factors include t(9;22). The presence of MRD at the end of second remission induction is also a strong adverse prognostic indicator. Although chemotherapy may secure a prolonged second remission in children with ALL who experience late relapse (defined as >6 months after cessation of therapy), allogeneic HSCT is the treatment of choice for patients who experience hematologic relapse during therapy or shortly thereafter and for those with T-cell ALL. Patients with late-onset isolated CNS relapse who had not received cranial irradiation as initial CNS-directed therapy have a very high remission retrieval rate, with a long-term prognosis approaching that of newly diagnosed patients in those who had a long initial remission before the CNS event.

Genome-wide studies using matched diagnosis and relapse samples from the same patients are exploring the genetic basis of relapse.

of children with hyperdiploid greater than 50 chromosomes per cell ALL treated on low-intensity antimetabolite-based regimens. Leu-covorin rescue is necessary after treatment with high-dose methotrex-ate; however, overzealous rescue might counteract the antileukemic activity of methotrexate. Although the intensive asparaginase and high-dose methotrexate treatment has significantly improved the outcome for patients with T-cell ALL, the emergence of specific therapy such as the purine nucleoside analog nelarabine will likely increase the tendency to assign patients with T-cell ALL to a specific treatment protocol or strata.

It is generally recommended to give mercaptopurine at bedtime to patients with an empty stomach and to avoid taking it together with milk or milk products that contain xanthine oxidase, an enzyme that can degrade the drug. About 10% of the population inherit one wild-type gene encoding thiopurine methyltransferase (TPMT) and one nonfunctional variant allele, resulting in intermediate enzyme activity, but one in 300 people inherits two nonfunctional variant alleles and are completely deficient of this enzyme that catalyses the S-methylation of mercaptopurine to its inactive metabolite. Patients with heterozy-gous and especially homozygous deficiency of TPMT are at high risk of severe myelosuppression. Identification of these patients allows physicians to selectively guide reductions in mercaptopurine dosage without modifying the dose of methotrexate. Substituting thiogua-nine for mercaptopurine during continuation therapy was associated with a high incidence of profound thrombocytopenia and hepatic venoocclusive disease. Thioguanine use has therefore been limited to short pulses administered during consolidation therapy in some trials; mercaptopurine is selected for prolonged administration.

Because optimizing the administration of existing therapies is reaching its limit, further improvements in outcome will require the development of therapeutic approaches directed against rational therapeutic targets. An example is the significant improvement in the outcome of Philadelphia chromosomepositive (Ph+) ALL with the advent of TKIs targeting the constitutively active BCR-ABL1 TKI in ALL subset. Ph+ ALL has historically had an extremely poor outcome, but recent studies have demonstrated dramatic improvements in treatment outcome with incorporation of BCR-ABL1 inhibitors into Ph+ ALL treatment.24 Recent identification of novel chimeric fusions involving kinases in ALL (e.g., NUP214ABL1 and STRN3JAK2) suggests that additional high-risk cases may benefit from targeted therapies directed at kinase signaling.

The expanded understanding of the biologic, immunologic, and genetic heterogeneity of ALL has enabled development of several novel therapeutic strategies.25 Various monoclonal antibodies are showing promise in early clinical trials and may be incorporated into ALL regimens in the future.

Autologous transplantation has failed to improve outcome in ALL. Comparisons between allogeneic HSC transplantation (HSCT) and intensive chemotherapy have yielded inconsistent results because of the small numbers of patients studied and differences in case selec-tion criteria. It is generally accepted that allogeneic HSCT is a treat-ment modality for patients with ALL who are predicted to respond poorly to intensive chemotherapy.26 At present, patients with

Dose Schedule

The biologically equivalent doses among the different formula-tions of corticosteroids, thiopurines, and asparaginase are not clear. Trials comparing such agents should be cautiously inter-preted, taking into account the dose schedule used and the effect of variability in the pharmacokinetic profile and potency among the agents involved. Simple modification of the dose or schedule may result in significant differences in efficacy and toxicity. Also, when comparing regimens containing high-dose intravenous methotrexate, the dose schedule of leucovorin rescue should not be ignored because it plays a crucial role in modulating the activ-ity and toxicity of methotrexate.


Although 90% of the patients exhibit differential gaining or losing genetic lesions from diagnosis to relapse, most relapse samples are clonally related to diagnosis samples. Relapse clones could be present as minor populations at diagnosis and selected during treatment to emerge as the predominant clone at relapse displaying alterations of genes that have been implicated in treatment resistance. Almost 20% of relapsed cases have sequence or deletion mutations of CREBBP, which impair histone acetylation and transcriptional regulation of CREBBP targets, suggesting that the mutations may confer drug resistance and raising the possibility of using drugs to reverse the aberrant epigenetic programs, such as histone deacetylase inhibitors.29 The next generation of deep sequencing technologies promises to unravel many more if not the full repertoire of genetic alterations in leukemia. Parallel gene expression studies, which have identified a proliferative gene signature that emerges at relapse and consistent upregulation of genes such as survivin, provide attractive targets for novel therapeutic intervention.

SUPPORTIVE CARE

Stringent supportive care significantly contributes to a favorable ALL outcome and should be initiated at diagnosis because remission induction is associated with an increased risk from cardiovascular, metabolic, and infectious complications. All febrile patients with or without documented infection should be given broad-spectrum intra-venous antibiotics until an infectious disease can be excluded. Rapid turnover of leukemia cells before and immediately after the initiation of chemotherapy leads to metabolic disturbances, including hyperka-lemia, hyperuricemia, hyperphosphatemia, and hypocalcemia. Patients with high levels of uric acid are at risk for the development of acute renal failure secondary to uric acid deposition in the kidneys. All patients require intravenous hydration to prevent or treat hyper-uricemia and hyperphosphatemia. Allopurinol, a xanthine oxidase inhibitor, can prevent uric acid formation. Rasburicase, a recombi-nant urate oxidase that breaks down uric acid to allantoin (a readily excretable metabolite with five- to 10-fold higher solubility than uric acid), is more effective than allopurinol but is associated with met-hemoglobinemia or hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency because hydrogen peroxide is a byproduct of the uric acid breakdown.30 Phosphate binders should also be used to prevent or treat hyperphosphatemia. Transfusions should be administered slowly in patients with severe anemia to prevent congestive heart failure. In patients with extreme hyperleu-kocytosis, packed red blood cell transfusion should be delayed until after leukocyte count is decreased to prevent complications of leukostasis. All blood products should be irradiated in patients who are receiving immunosuppressive therapy to prevent GVHD. Patients should avoid foods that may be contaminated with patho-gens and reduce salt intake, which could induce hypertension and resultant seizure in patients receiving glucocorticoids during induc-tion. Adolescents, obese individuals, and individuals with

Drug Interactions

We have not yet reached a full understanding of the contribution of genetic polymorphisms to interindividual differences in drug effects to allow us to translate this new knowledge into clinical practice. However, by simply avoiding drug interactions, one can prevent increased toxicity or reduced efficacy of chemotherapy. Phenytoin and phenobarbital induce the activity of cytochrome P450 enzymes, significantly increasing the systemic clearance of several antileukemic agents that may adversely affect treatment outcome. We substitute these anticonvulsants with gabapentin or Keppra in patients receiving antileukemic therapy. On the other hand, azole compounds (e.g., fluconazole, itraconazole, ketocon-azole) can inhibit cytochrome P450 enzymes and increase the toxicities of various antileukemic agents, especially vincristine.

Down syndrome are at increased risk of hyperglycemia and other complications. Prophylactic use of trimethoprimsulfamethoxazole (or pentamidine or atovaquone in patients with poor tolerance to trimethoprimsulfamethoxazole) successfully prevents Pneumocystis jiroveci (formerly carinii) pneumonia. Dental evaluation at diagnosis and meticulous oral hygiene during chemotherapy minimize the oral complications of leukemia and its treatment. It is important to dis-tinguish between herpes simplex viral infection and chemotherapy-induced oral mucositis. Occasionally, patients have nausea and substantial pain on swallowing caused by esophageal herpes simplex viral infection, candidiasis, or both. Oral candidiasis occurs fre-quently, especially in young children. Azole compounds (e.g., fluco-nazole, itraconazole, ketoconazole) are frequently used to treat fungal infections. It should be recognized that they can inhibit cytochrome P450 enzymes and increase the toxicities of various antileukemic agents, especially vincristine. On the other hand, concomitant administration of anticonvulsants that induce cytochrome P450 enzymes (e.g., phenytoin, phenobarbital, carbamazepine) increases the systemic clearance of several antileukemic agents and may adversely affect treatment outcome. Anticonvulsants that are less likely to induce the activity of cytochrome P450 enzymes (e.g., Keppra) are recommended in patients receiving chemotherapy. Pho-tosensitive skin rash can occur during antimetabolite therapy. The rashes are erythematous, maculopapular, similar to atopic eczema, and most prominent on the face. Topical administration of simple emollients or a weak steroid preparation and avoidance of external exposure to sunlight should improve the skin condition. Patients with Down syndrome tolerate methotrexate poorly; appropriate dose adjustment is indicated. During each clinic visit, a thorough review of all drugs should be undertaken because of potential adverse inter-actions among them. In fact, chemotherapy can also interact with various food (e.g., grapefruit) and supplements (e.g., St. Johns wort, folic acid).31

LATE EFFECTS OF TREATMENT

The most problematic late effects of contemporary ALL therapy include neuropsychological impairments, bone morbidity, and obesity. Although neuropsychologic deficits are well-recognized side effects of cranial irradiation, intrathecal and systemic chemotherapy (especially methotrexate) can also cause brain atrophy and spinal cord dysfunction and contribute to the development of neurocognitive toxicities. Severe CNS toxicity has been attributed to cranial irradia-tion at doses of 2400 cGy or higher, but lower doses have also been associated with long-term neuropsychological impairments, espe-cially in younger children. Obesity, which is most prevalent among female survivors of childhood ALL, may be related to cranial radia-tion and corticosteroids. Osteopenia, fractures, and osteonecrosis have been observed in up to 30% of survivors of childhood ALL. Osteonecrosis, which can lead to significant pain, loss of function, and total joint replacement, has been reported in approximately 8% of children with ALL, with the highest frequency observed in those diagnosed in adolescence. Ovarian and testicular function are rela-tively unaffected by most antileukemic therapy. Offspring of patients successfully treated for childhood ALL are expected to be as normal as the general population. Second malignant neoplasms, including malignant gliomas, meningiomas, and AML, occur with increased frequency in patients treated on regimens that include irradiation, epipodophyllotoxins, or alkylating agents.

FUTURE DIRECTIONS

As the cure rate approaches 90%, treatment response assessed by MRD measurements of submicroscopic leukemia has emerged as a powerful and independent prognostic indicator for gauging the intensity of ALL therapy. Children at high risk of relapse may now benefit from early intensification of therapy. The next goal is to reduce the intensity of therapy in children at very low risk of relapse,


hence avoiding undue toxicity. The successful elimination of preven-tive cranial irradiation indicates that treatment reduction is feasible if done with caution and appropriate substitution with less toxic alternatives. Global genome analysis, in addition to refining leukemia classification, is helping identify potential molecular targets for therapy. Expanding the application of pharmacogenomics, a science that aims to define the genetic determinants of drug effects, will allow further personalized therapy in the future.

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Chapter 64 Clinical Manifestations and Treatment of Acute Lymphoblastic Leukemia in Children 959.e1

Key Words

Acute lymphoblastic leukemiaAcute lymphoblastic leukemia (ALL) epidemiologyAcute lymphoblastic leukemia (ALL) pathobiologyChemotherapyCentral nervous system (CNS)Concordant acute lymphoblastic leukemia (ALL)Molecular targetsMinimal residual disease (MRD)Risk classification

64 Clinical Manifestations and Treatment of Acute Lymphoblastic Leukemia in ChildrenEpidemiologyPathobiologyClinical ManifestationsDifferential DiagnosisPrognosisTherapy, Including Stem Cell TransplantationAcute Lymphoblastic Leukemia RelapseSupportive CareLate Effects of TreatmentFuture DirectionsKey WordsReferences

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