Acute Leukemia in Children

Transcription

1 Acute Leukemia in Children Maureen M. O Brien, MD, and Normal J. Lacayo, MD Acute leukemias represent approximately 30% of all malignancies diagnosed in children younger than 15 years and 25% of malignancies in children and adolescents younger than 20 years. Approximately 3250 new cases of leukemia are diagnosed annually in the United States. Acute lymphoblastic leukemia (ALL) accounts for approximately 80% of cases (2500 cases per year). About 20% of cases ( cases per year) are acute myeloid leukemia (AML) and a small fraction (1%) is chronic myeloid leukemia (CML). There is a sharp peak in ALL incidence among 2 and 3 year olds ( 80 per million), which decreases by ages 8 to 10 years (20 per million). The incidence of ALL among 2 and 3 year olds is approximately 4-fold greater than that for infants and is nearly 10-fold greater than that for 19 year olds. In contrast, AML rates are highest in the first 2 years of life, decrease with a nadir at approximately 9 years of age, and slowly increase again during adolescence. Leukemias are believed to arise from hematopoietic progenitor cells that acquire genetic alterations leading to unchecked proliferation and self-renewal. Over the past 50 years, our understanding of the molecular pathogenesis of acute leukemias has markedly increased. This knowledge, coupled with clinical risk stratification and clinical investigation, has led to substantial improvements in survival for children with acute leukemias. Currently, approximately 75% to 80% of children with ALL and 50% to 60% of children with AML achieve long-term survival. Ongoing challenges in the care of children with acute leukemias include novel strategies for the treatment of relapsed disease, which has a dismal prognosis, and treatment reduction strategies in children with low-risk disease in whom long-term complications of treatment are becoming more evident. In addition, advances in the supportive care of children This article was published in: Rakel RE, Bope ET. Conn s Current Therapy Section 6. Acute Leukemia in Children, p Elsevier Inc. Dis Mon 2008;54: /2008 $ doi: /j.disamonth DM, April 2008

2 during treatment as well as stem cell transplantation have contributed to the improved survival of children with leukemia. Diagnosis Classically, children with acute leukemia present with symptoms of pancytopenia, including pallor and fatigue from anemia and epistaxis, ecchymoses, and petechiae due to thrombocytopenia (75% of children have platelet count 100,000/ L at diagnosis). White blood cell (WBC) count may be elevated ( 50,000/ L in 20% of children) or low ( 10,000/ L in 50% of children). If they are neutropenic, children can present with significant infection or overwhelming sepsis. Children have lymphadenopathy in 50% of cases. Approximately 25% of children present with bone pain due to bone marrow expansion by malignant blasts and stretching of periosteal nerves. Rarely, extremity pain is also due to malignant joint effusion. Children with mediastinal masses (usually associated with T-cell ALL) can present with cough or other respiratory symptoms, which can be mistaken for pneumonia or asthma. Leukemia within the central nervous system (CNS) can manifest with headache or cranial nerve abnormalities. Uncommonly, ALL manifests as an isolated testicular mass and AML as a soft-tissue mass (chloroma). However, the presenting signs and symptoms of acute leukemia can be subtle and develop over weeks to months, often beginning with fatigue and decreased energy. Children can develop persistent or intermittent fevers and can present to their pediatrician with these nonspecific complaints, which can be easily attributed to a viral illness. These children require a careful physical examination including evaluation for lymphadenopathy or hepatosplenomegaly. Physical examination abnormalities or persistent nonspecific symptoms that do not resolve within 2 to 3 weeks merit further evaluation with a complete blood count (CBC). Abnormalities of the CBC, such as cytopenias of more than one lineage or the presence of peripheral blasts in blood should result in urgent referral to a pediatric oncology center. These centers provide specialized diagnostic testing, including flow cytometry and cytogenetic analysis that is standard in the evaluation of children with leukemia, as well as multidisciplinary treatment and coordination of patient participation in multi-institutional clinical trials. Evaluation of any child presenting with concerning symptoms or an abnormal CBC should include a chemistry panel, to evaluate for hepatic or renal dysfunction, and elevated uric acid, potassium, and DM, April

3 phosphate suggesting tumor lysis syndrome. Determination of prothrombin time (PT), activated partial thromboplastin time (aptt), and fibrinogen is necessary to evaluate for coagulopathy, which can increase bleeding risk and is common in acute promyelocytic leukemia (APML). Patients should be examined for signs of infection, and appropriate cultures (blood, urine, stool) should be drawn in children with fever or concerning symptoms. Chest radiography should be performed to evaluate for the presence of a mediastinal mass, which can complicate management of the patient due to respiratory distress and the inability to sedate the child for invasive procedures (see the Current Diagnosis section at the end of this article). Ultimately, however, diagnosis depends on the results of bone marrow aspirate and biopsy, which typically reveal replacement of normal hematopoeitic precursors with leukemic blasts. Morphologically, these blasts have high nuclear-to-cytoplasmic ratios and can have prominent nucleoli, vacuoles (Burkitt s leukemia), and intracytoplasmic inclusions (Auer rod, M2 AML). The presence of more than 25% blasts in the bone marrow is diagnostic of acute leukemia, and samples are then submitted for morphologic evaluation, flow cytometry, cytogenetic analysis, and further investigational studies. When the diagnosis of acute leukemia is confirmed, further evaluation will also include lumbar puncture and morphologic examination of the cerebrospinal fluid (CSF) for leukemic blasts. In boys, examination for testicular swelling and masses is necessary to determine whether leukemic involvement is present; this should be documented by ultrasound evaluation and testicular biopsy if the diagnosis is in question because treatment varies depending on involvement of these sanctuary sites (CNS or testes). Classification Acute leukemia is separated into two major subgroups: ALL and AML. Historically, the FAB (French American British) classification has been used in which ALL consists of three subtypes, L1 through L3, and AML consists of eight subtypes, M0 through M7. However, the 1999 WHO classification conference has suggested that, for ALL, these FAB terms are not relevant because they do not predict immunophenotype, cytogenetics, or clinical outcome. The exception is L3 lymphoblasts, which are undifferentiated and contain large nucleoli and have deep blue vacuolated cytoplasm. This morphology is synonymous with Burkitt s (mature B-cell) leukemia. 204 DM, April 2008

4 In contrast, the FAB classification for AML remains standard and characterizes blasts by differentiation pathways. In general, M0 and M1 blasts are undifferentiated and lack granules. M2 blasts are more mature, contain cytoplasmic granules, and can have Auer rods (coalesced granules). M3 blasts are found in APML and have prominent granules. M4 blasts occur in acute myelomonocytic leukemia and are a mixture of myeloblasts and monoblasts. One specific subtype, M4eo, shows markedly increased marrow eosinophils and blasts with large, coarse granules. M4eo morphology is strongly associated with the cytogenetic abnormality inversion 16 [inv(16)]. M5 AML (acute monoblastic leukemia) blasts have indented nuclei consistent with monoblastic differentiation. M6 AML (acute erythroid leukemia) blasts show evidence of erythroid lineage, and M7 AML (acute megakaryocytic leukemia) blasts appear undifferentiated. M7 AML is often associated with extensive bone marrow fibrosis, and the diagnosis may be hampered by difficulty aspirating an adequate sample. The biopsy is critical to the correct diagnosis in this case. Children with trisomy 21 (Down syndrome) who develop AML almost exclusively have M7 AML. Immunophenotyping The accuracy of morphologic diagnosis is significantly increased with the incorporation of immunophenotyping of cell surface cluster of differentiation (CD) markers by flow cytometry and cytogenetic analysis for translocations associated with specific subtypes of leukemia. This testing is particularly important for risk stratification in pediatric ALL. In general, ALL is divided into three major subtypes based on immunophenotype: B-precursor (70% to 80% of patients), mature B cell (2% to 5% of patients), and T cell (15% of patients) blasts. B-precursor blasts express CD10, CD19, and CD20, whereas mature B-cell blasts express these markers in addition to CD22, CD25, and surface immunoglobulin (sig). In contrast, T cell lineage lymphoblasts express CD2, CD3, CD4, CD5, CD7, and CD8, whereas myeloid blasts express CD11, CD13, CD15, CD33, CD34, and CD65. Usually, lymphoblasts of different lineages can be readily distinguished from each other and from myeloid leukemias, although in some cases the leukemic blasts can aberrantly express a variety of cell surface proteins. Diagnosis in these cases is determined by the predominance of lymphoid versus myeloid markers, and the blasts may ultimately be described as biphenotypic. DM, April

5 TABLE 1. Prognostic features in childhood ALL Favorable Age years WBC at presentation 50,000/ L Immunophenotype (B-precursor) Genetic abnormalities Hyperdiploidy t(12;21) translocation with TEL-AML1 fusion gene Triple trisomies of chromosomes 4, 10, 17 Clinical response: MRD negative ( 0.01%) at day 8 and end of induction Unfavorable Age 1year or 10 years WBC at presentation 50,000/ L Immunophenotype (T-cell) Genetic abnormalities Hypodiploidy t(4;11) translocation with MLL-AF4 fusion gene t(9;22) translocation with BCR-ABL fusion gene Clinical response Induction failure (M3 marrow, 25% blasts) MRD positive at end of induction Abbreviations: MRD, minimal residual disease; MLL, mixed lineage leukemia; WBC, white blood cell. ALL Cytogenetics and Risk Stratification Leukemic blasts are further classified based on their chromosomal number and cytogenetic profile using standard karyotype analysis as well as molecular techniques to detect specific translocations that have both diagnostic and prognostic significance (Table 1). In B-precursor ALL, modal chromosome number is important in prognosis. Hyperdiploidy (50-60 chromosomes) occurs in 30% of cases and is associated with good prognosis, particularly if combined with trisomies of chromosomes 4, 10, and 17, but hypodiploidy (fewer than 45 chromosomes) is associated with poor outcome. Specific translocations in ALL lymphoblasts include t(9;22) bcr/abl translocation (Philadelphia chromosome [Ph], typically the 185-kDa fusion protein), which occurs in about 5% of ALL patients, mainly adolescents, and is associated with poor outcome. The t(4;11) translocation fuses the MLL (mixed lineage leukemia) gene on chromosome 11 band q23 to the AF4 gene on chromosome 4 band q21, forming an MLL/AF4 fusion gene. This translocation is prevalent in infant ALL (60% of infants) and is associated with poor outcome, as are other MLL fusion partner leukemias. 206 DM, April 2008

6 In contrast to these translocations associated with poor outcome, t(12;21)(p12;q22) (TEL/AML-1) is the most common genetic lesion in childhood ALL, occurring in 15% to 25% of children with B-precursor ALL and is associated with a good prognosis. The translocation is cryptic and requires specific molecular techniques (reverse-transcriptase polymerase chain reaction [RT-PCR] or fluorescence in situ hybridization [FISH] analysis) for detection. This translocation is generally considered to have good prognosis, with high blast sensitivity to intensive asparaginase therapy, although an association with late relapse has been reported. Other translocations include t(1;19) E2A/PBX1 translocation in 5% of B-precursor ALL patients, which is not currently used for risk stratification. Mature B-cell ALL is characterized by the t(8;14) translocation, which places the MYC gene under the control of the immunoglobulin heavy chain promoter. In T-cell ALL, approximately 60% of patients have an abnormal karyotype, often involving chromosomes 14 or 7 at the locations of the T-cell receptor (TCR) genes, which become fused to a transcription factor (LMO2, LYL, TAL1). In addition, T-cell ALL lymphoblasts have a high frequency ( 50% of cases) of gain-offunction Notch-1 mutations, which may be associated with improved prognosis. Treatment of the child with ALL is based on risk-adapted therapy. As cure rates for childhood ALL have improved overall, great interest has developed in risk stratification of patients based on clinical characteristics, immunophenotype, and cytogenetics in order to identify groups of low-risk patients for whom toxic therapy can be minimized and high-risk patients for whom aggressive treatment, including consideration of bone marrow transplant (BMT), is indicated. For example, T-cell ALL patients tend to be male and to have elevated WBC count and extramedullary disease (mediastinal mass, CNS involvement). These patients had historically poor outcome compared with B-precursor ALL patients. However, with current intensive treatment protocols, long-term survival for these patients now approaches 70% to 80%, similar to survival of children with B-precursor ALL. Important clinical characteristics for risk stratification include WBC count and age at the time of diagnosis, which are independent predictors of prognosis and have been established by the National Cancer Institute (NCI) as the standard criteria for risk assignment at diagnosis in precursor B-cell ALL. Other prognostic factors used for risk assignment during induction therapy include presence of CNS DM, April

7 disease and specific cytogenetic abnormalities. European investigators have traditionally used clinical response to a 1-week treatment prophase with prednisone and intrathecal methotrexate to stratify those with poor prednisone response to intensive therapy, because this is an independent predictor of poor clinical outcome. Response to induction therapy based on bone marrow evaluation is another cornerstone of risk stratification. Rapid responders with an M1 remission marrow ( 5% blasts by morphology) by day 8 of induction have excellent outcomes, and slower responders fare worse. In extreme cases, patients who fail induction or have continued presence of overt morphologic leukemia after 4 to 6 weeks of intensive chemotherapy (which occurs in 1% of patients) have extremely poor outcomes and should proceed to BMT if remission is eventually achieved. New molecular techniques continue to refine risk stratification for children with ALL. Minimal residual disease (MRD) monitoring by multiparameter flow cytometry can detect leukemic blasts at a level of 0.1% to 0.01% even in a morphologically M1 bone marrow aspirate sample. Studies have demonstrated that children with negative blood MRD by day 8 of induction have an excellent prognosis, and those with positive bone marrow MRD by day 29 (end of induction) have high rates of relapse. Current clinical trials for children with leukemia now incorporate MRD monitoring at the end of induction into risk stratification for additional therapy and are evaluating the sensitivity and specificity of MRD in predicting later relapse. Based on these considerations, at the time of diagnosis, children with ALL are stratified as standard risk (age years and WBC 50,000/ L) or high risk (age 1 year or 10 years, WBC 50,000/ L, overt CNS leukemia). Once cytogenetic and inductionresponse data are available, patients are further stratified into lower risk (trisomies of chromosomes 4, 10, and 17 or TEL/AML1 and translocation), standard risk (unremarkable cytogenetics), high risk (adolescents, infants), or very high risk [induction failure, t(9;22), t(4;11)], and subsequent treatment intensity is based on this classification. AML Cytogenetics and Risk Stratification Factors with favorable prognostic significance in AML include Down syndrome, the karyotypic abnormalities inv(16) and t(8;21) seen in the core binding factor leukemias, and (15;17) (Table 2). Poor 208 DM, April 2008

8 TABLE 2. Prognostic features in childhood AML Low Risk inv(16) or t(16;16) t(8;21) t(15;17) Down syndrome Standard Risk Absence of low-risk features Absence of high-risk features High Risk FLT3-internal tandem duplication M6 and M7 t(6;9) Monosomy 7 del5q Treatment-related AML MDS/AML RAEB-T Primary induction failures Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; RAEB-T, refractory anemia with excess blasts in transformation. prognostic factors include failure to achieve remission, FLT3 (a member of the receptor tyrosine kinase family) internal tandem duplication (FLT3-ITD), therapy-related AML, AML arising from myelodysplastic syndrome (MDS), FAB subtypes M6 and M7, monosomy 7, del5q (less common), and refractory anemia with excess blasts in transformation (RAEB-T). Patients without favorable or poor prognostic factors are considered to have an intermediate risk status. Remission induction and long-term survival vary substantially between these subgroups; therefore, accurate risk stratification is critical to identify patients who will benefit from aggressive therapies such as hematopoietic stem-cell transplantation or novel therapies, as well as patients who have good outcome with current regimens. The use of MRD in pilot studies shows that it can identify a subset of patients at higher risk of relapse. This group of patients can benefit from new therapeutic approaches. As the MRD technology improves, its sensitivity and specificity and positive predictive value for relapse will also improve. DM, April

9 Treatment Acute Lymphoblastic Leukemia The vast majority of children with ALL are treated in a clinical trial. In the United States and Canada, although a small number of centers treat children on institutional protocols, most pediatric oncology centers are members of the Children s Oncology Group (COG) and enroll children in multicenter national trials. These clinical trials allow adequate patient numbers to determine efficacy of regimens, coordination of biological and molecular studies, and access of any child to the current state-of-the-art standard of care. Informed consent must be obtained for treatment according to the trial protocol as well as the submission of bone marrow or peripheral blood samples for biological studies. At the time of diagnosis, typically in conjunction with another diagnostic procedure (bone marrow aspirate/biopsy or lumbar puncture), the child should have placement of a central venous catheter (CVC) that can be used for delivering medications and for blood sampling. The type of CVC will depend on the individual institutional practices. In general, implanted catheters (portacaths) are associated with lower infection rates, but external multilumen catheters (Broviac or Hickman) should be placed in small infants and in patients likely to need BMT. In a child with a large mediastinal mass in whom sedation for procedures is not possible, bone marrow aspirate and lumbar puncture might need to be performed with local anesthesia only, and a peripherally inserted central catheter (PICC) may be placed in lieu of a CVC until the mediastinal mass has responded to chemotherapy. Treatment Phases. The treatment of ALL is divided into three general phases: remission induction (4-6 weeks), consolidation and delayed intensification (6 months), and maintenance. The total treatment lasts between 24 and 36 months. Induction. The induction regimen for standard-risk patients (age 1-10 years, WBC 50,000/ L) includes three chemotherapeutic agents, daily oral corticosteroid (prednisone or dexamethasone) for 28 days, four doses of weekly intravenous vincristine (Vincasar), and one dose of intramuscular pegylated asparaginase (Elspar). This is combined with CNS prophylaxis and treatment with intrathecal methotrexate. For high-risk patients, an anthracycline (daunorubicin [Cerubidine] or doxorubicin [Adriamycin]) is added to improve the rate of remission induction in this group. Overall, 98% of patients achieve first morphologic remission (M1 marrow defined as 5% bone marrow blasts with recovery of trilineage hematopoeisis and periph- 210 DM, April 2008

10 eral blood counts) at day 29 of induction with this regimen. Patients with M2 marrow (5% to 25% blasts) after 29 days of induction receive 2 additional weeks of therapy, and those who remain M3 ( 25% bone marrow blasts) have failed induction. Children who fail to achieve first remission after 6 weeks of induction have a very poor prognosis and should be considered for myeloablative allogeneic BMT if they achieve remission with an alternative regimen. A number of complications can develop during induction. The majority of these are secondary to chemotherapeutic agents and can be managed with aggressive supportive care. Prolonged use of high-dose steroids can result in hypertension, hyperglycemia, weight gain, mood changes, and gastritis. Perturbation of clotting factors by asparaginase therapy, which interferes with hepatic protein production, can lead to bleeding or thrombosis depending on the balance of procoagulant and anticoagulant factors. Asparaginase therapy can also result in acute anaphylaxis as well as severe pancreatitis, both of which are indications for omission of future asparaginase therapy (except in the case of allergy, when Erwinia asparaginase can be substituted). Use of anthracyclines requires monitoring of cardiac function, and vincristine can cause peripheral neuropathy, constipation, and ileus. Finally, the risks of infection and tumor lysis syndrome are highest during induction. Management of these problems is detailed in the section on supportive care. Consolidation, Interim Maintenance, and Delayed Intensification. Following achievement of first remission, the intensity of the consolidation, interim maintenance, and delayed intensification phases depends on risk stratification including clinical features, cytogenetics, and response to therapy or MRD. In general, consolidation is characterized by intensive therapy including cyclophosphamide (Cytoxan), cytarabine (Cytosar), 6-thioguanine (Tabloid) 1 or 6-mercaptopurine (Purinethol), asparaginase (Elspar), and vincristine (Vincasar). For lower-risk patients, consolidation may include only vincristine and antimetabolite therapy. Depending on risk stratification, consolidation lasts between 4 and 8 weeks. Consolidation is followed by interim maintenance, which lasts 8 weeks and includes antimetabolite therapy with daily oral 6-mercaptopurine, weekly oral methotrexate (Trexall), intermittent vincristine, and glucocorticoid pulses as well as continued CNS prophylaxis with intrathecal methotrexate. For higher-risk patients, interim maintenance is augmented 1 Not FDA approved for this indication. DM, April

11 with escalating-dose IV methotrexate and asparaginase. This less-intensive phase is then followed by delayed intensification, which includes reinduction and reconsolidation. High- risk patients may then receive second interim maintenance and delayed intensification courses before proceeding to maintenance therapy. For all patients, an additional goal of this phase of treatment is to target involved sanctuary sites (see the later discussion of CNS prophylaxis). In male patients, the testis is a sanctuary site and requires close monitoring at the time of each physical examination. For patients with testicular mass or swelling at the time of diagnosis, enlargement should be confirmed by ultrasound and then leukemic involvement proved by testicular biopsy. For patients with biopsy-proved testicular disease, treatment includes bilateral testicular irradiation at 2400 cgy in 12 once-daily fractions (200 cgy per fraction). Maintenance. Maintenance therapy consists of daily oral 6-mercaptopurine, weekly oral methotrexate, monthly intravenous vincristine, and 5-day pulses of oral dexamethasone. Maintenance continues until total duration of therapy is 2 years from the start of interim maintenance for female patients and 3 years from the start of interim maintenance for male patients. Length of treatment differs because male patients have a poorer prognosis than female patients, which can be improved by prolonged maintenance therapy. Therapy for High-Risk Groups. The current very-high-risk ALL COG protocol includes a subset of patients with poor outcomes and an expected 5-year event-free survival (EFS) rate of 45%. This group includes patients with Ph ALL [t(9;22)], hypodiploidy, MLL rearrangement with a slow early response to induction chemotherapy, and induction failures (an M3 [ 25% blasts] bone marrow at the end of induction therapy or MRD 1%). In this group of patients, allogeneic BMT is recommended in first remission for those with matched sibling donors. In addition, protocols for patients with t(9;22) now include the BCR-ABL tyrosine kinase inhibitor imatinib (Gleevec) in combination with intensive multiagent chemotherapy in an effort to improve outcomes for this subgroup. For infants with MLL rearrangement with rapid induction response, treatment currently consists of intensive chemotherapy on high-risk protocols due to excessive treatmentrelated mortality in this subgroup during BMT. Central Nervous System Prophylaxis. The CNS is a sanctuary site for leukemic blasts due to poor penetrance of the CNS by many chemotherapeutic agents. Historically, it was found that without CNS prophylaxis in patients without overt CNS leukemia at diagnosis, these 212 DM, April 2008

12 patients would relapse in the CNS at a high rate even while maintaining bone marrow remission. CNS status is determined by a diagnostic lumbar puncture at the time of diagnosis (CNS 1, 5 WBCs, no blasts on cytospin; CNS 2, 5 WBCs, blasts seen on cytospin; CNS 3, 5 WBCs with blasts on cytospin or overt signs of CNS leukemia such as facial nerve palsy). In the past, CNS leukemia prophylaxis was achieved with cranial radiation, which provides effective prophylaxis but with excessive long-term toxicity, including neurocognitive impairment and increased risk of secondary malignancy. As a result, CNS prophylaxis is currently achieved with repeated doses of intrathecal methotrexate throughout all phases of therapy. Research is ongoing to determine the effect of this treatment on long-term neurocognitive function. Patients with CNS 2 status receive additional doses of intrathecal methotrexate during induction and are subsequently treated with the same regimen as CNS 1 patients. Currently, cranial radiation (1800 cgy) combined with intrathecal methotrexate is reserved for patients with documented CNS 3 disease or patients without CNS disease who have high risk of relapse in the CNS ( cgy), such as T-cell ALL patients. Relapse Treatment. Although the overall outcomes for children with ALL have markedly improved over the past 40 years, the treatment of children who experience relapse remains a significant challenge. The number of children with relapsed acute leukemia equals or exceeds the incidence of most other pediatric tumors. Despite intensive and riskstratified treatment regimens, 15% to 20% of patients relapse, and the vast majority of these children ultimately die of disease. The majority of relapses (75%) occur within 3 years from diagnosis, and treatment and prognosis depend on site of relapse (bone marrow or extramedullary), timing of relapse (months from diagnosis), and immunophenotype. For children enrolled in the Children s Cancer Group (CCG) 1900 series trials between 1997 and 2002, 12% of patients experienced bone marrow relapse, 4% experienced CNS relapse, and 1.3% experienced testes relapse. The 3-year survival rates were 28%, 60%, and 60%, respectively. Second remission rates range from 70% to 90% in different series depending on timing and site of relapse, but the 3-year survival rate for patients with marrow relapse within 3 years of diagnosis is less than 10%. Factors associated with extremely poor outcome include T-cell ALL relapse and early bone marrow relapse (duration of first remission 36 months). Outcomes are somewhat better for isolated CNS or testicular relapse and late bone marrow relapse with B-precursor ALL. DM, April

13 Treatment of early marrow relapse involves intensive reinduction chemotherapy in an attempt to achieve second remission, followed by myeloablative allogeneic BMT for patients with an acceptable donor. For patients without an unrelated donor, intensive chemotherapy with consideration of phase I/II studies of novel agents is indicated given the extremely poor prognosis for this group, many of whom will relapse again before BMT even when a donor is available. For patients with late bone marrow relapse ( 36 months from diagnosis), research is currently ongoing to determine the role of BMT versus intensive chemotherapy, although for patients with a matched sibling donor, most oncologists would proceed with BMT if the patient achieves second remission. Isolated CNS relapse has a more favorable outcome than bone marrow relapse. In terms of risk stratification, early CNS relapse ( 18 months from diagnosis) is considered similar in prognosis to late marrow relapse, and patients with late CNS relapse ( 18 months from diagnosis) have the most favorable outcome. Patients are treated with weekly intrathecal triple chemotherapy (methotrexate, cytarabine, hydrocortisone) until the CSF is negative for blasts. Craniospinal radiation therapy is also indicated, with a dose of 2400 (cranial)/1500 (spinal) cgy for early CNS relapse and cranial radiation to 1800 cgy for late CNS relapse. In addition, all CNS relapse patients receive intensive systemic reinduction, consolidation, and maintenance chemotherapy because CNS relapse is a harbinger of eventual relapse in the bone marrow. Current studies are ongoing to determine if the cranial radiation dose in children with late CNS relapse can be decreased further to 1200 cgy following 12 months of intensive chemotherapy incorporating agents known to cross the blood-brain barrier (dexamethasone, high-dose methotrexate, asparaginase, and high-dose cytarabine). Testicular relapse is suspected when testicular swelling or mass is noted on physical examination. Relapse should be confirmed with testicular biopsy and evaluation for concurrent bone marrow, and CNS relapse should be undertaken and treated as described earlier. Treatment of isolated testicular relapse (ITR) has historically involved bilateral testicular radiation to 2400 cgy combined with intensive systemic chemotherapy. However, as with isolated CNS relapse, the most significant factor influencing survival following ITR is the length of the first remission. Patients with ITR 18 months from diagnosis have 5-year EFS rates of 45% compared with 60% EFS rate for patients with ITR 18 months from diagnosis. 214 DM, April 2008

14 Testicular radiation is effective at eradicating leukemia, but risk of sterility and endocrine late effects following testicular radiation are significant, with a majority of boys requiring hormonal replacement at some stage for induction of puberty, continuing pubertal maturation, or both. Primary germ cell dysfunction is associated with doses of 1200 cgy, and testicular doses of 2400 cgy result in Leydig cell failure, particularly in prepubertal boys. Current research protocols for patients with late ITR involve the use of intensive systemic chemotherapy including high-dose methotrexate (shown to penetrate the blood-testes barrier) with inclusion of testicular radiation to 2400 cgy only in boys who have persistent biopsy-proven testicular relapse after intensive systemic induction chemotherapy. As in isolated CNS relapse, therapy is combined with intensive systemic chemotherapy for 2 years due to the risk of subsequent bone marrow relapse following ITR. Acute Myeloid Leukemia Acute myeloid leukemia (AML) accounts for 20% of new cases of pediatric leukemia each year. AML represents a biologically heterogeneous group of diseases that arises from abnormal myeloid cell progenitors. Despite aggressive therapy, overall cure rates remain at about 50%. The key to improvement in this group of diseases has been identifying different subgroups of patients based on karyotypic and molecular characteristics. The current approach is to further refine risk-stratification and to develop risk-based or molecularly targeted therapies. The therapy outline is modeled after the St. Jude AML 2002 Consortium Study. Induction. On completion of a diagnostic work-up and evaluation of eligibility for a clinical trial, the next step is to proceed with informed consent. We advocate enrollment in open clinical trials from the Children s Oncology Group or multi-institutional consortia for all eligible patients with consent from the parents or guardians. Induction chemotherapy is started as we await molecular and karyotype testing for risk stratification. Due to the intensity of the induction phase of therapy and the need for supportive care, we advocate the early placement of an indwelling central venous catheter if this can be achieved safely. Therapy consists of anthracyclines (usually daunorubicin or idarubicin [Idamycin]) for 3 days, cytosine arabinosine for 7 to 10 days, and etoposide (Toposar) 1 or thioguanine for 5 days. 1 Not FDA approved for this indication. DM, April

15 Some pilot and front-line studies are using chemotherapy with or without gemtuzumab ozogomycin (Mylotarg). This drug is an anti-cd33 monoclonal antibody conjugated with ozogomycin. It is not known at this time whether its use during induction will result in an increased relapse-free survival. Most induction regimens result in remission rates of 85% to 90% when repeated twice. The use of time-intense induction (timing a second induction during early count recovery after the first induction) usually results in prolonged hospital stay for nearly all patients during the induction phase. This allows timely and intense supportive care in the inpatient setting. Family members and the patient undergo HLA typing because a matched sibling hematopoietic stem cell transplant may be indicated for very high-risk factors (monosomy 7, 7q-, primary induction failures) or high-risk factors (FLT3-ITD, MDS-AML, M6 and M7 subtypes, and RAEB-T). A matched unrelated donor may also be considered for very-high-risk patients. The FAB-defined APML subtype is the only subtype of AML with molecularly targeted therapy. The induction regimen for this subtype of AML includes all-trans-retinoic acid (ATRA) in combination with anthracyclines, cytosine arabinoside, and arsenic. Consolidation. With the induction of a remission, the next phase of therapy includes typically three courses of consolidation. Common combination therapies include mitoxantrone (Novantrone) and cytosine arabinoside, high-dose cytosine arabinoside with L-asparaginase, 1 cytosine arabinoside and etoposide, 1 and 2-CdA (2-chlorodeoxyadenosine, Leustatin) 1 with cytosine arabinoside. In this setting, patients with very-high-risk or high-risk factors may proceed with a hematopoietic stem-cell transplant if a matched sibling donor is available. In addition, for very-high-risk patients, a matched unrelated donor transplant may be considered because the outcome on chemotherapy alone is very poor. Maintenance. Maintenance therapy fails to demonstrate any benefit following intense induction and consolidation therapy, except in the molecularly targeted APML subtype. ATRA is continued during maintenance. Central Nervous System Therapy. Central nervous system prophylaxis is achieved using intrathecal cytosine arabinoside at diagnosis, followed by triple intrathecal therapy (cytosine arabinoside, hydrocortisone, and methotrexate) during each subsequent course of therapy. Intrathecal therapy is used in most protocols because of the historical observation that many patients develop CNS relapse in the absence of CNS prophylaxis. Hematopoietic Stem Cell Transplantation. Hematopoietic stem cell transplantation results in a statistically significant survival advantage 216 DM, April 2008

16 compared with chemotherapy alone, specifically for patients with high or very high risk factors. Due to the morbidity and mortality associated with transplantation, it is not recommended for patients with good risk factors, such as inv(16) t(8;21) or t(15;17), even those who have a matched sibling donor. For patients with favorable risk factors, transplantation is reserved for the relapse setting or second remission. In contrast, patients with highor very-high-risk factors may be candidates for a matched sibling donor transplant in first remission. For patients with very-high-risk factors, a matched unrelated donor in first remission may be indicated due to the inferior outcome using chemotherapy alone. In the relapsed patients, matched and unmatched donor transplantations are less controversial because the outcome with chemotherapy is very poor. The preparative regimens for transplant usually include high-dose chemotherapy (busulfan, 1 cyclophosphamide, cytarabine arabinoside) or total body irradiation with high-dose chemotherapy. Relapse Treatment. Most relapses occur in the bone marrow. The prognosis is very poor for those who relapse less than 1 year from remission ( 10% survival). Those who relapse longer than 1 year from remission fare better but still with dismal outcomes ( 20% to 30% survival). The treatment approach is to use chemotherapy to achieve remission and to follow chemotherapy with hematopoietic stem-cell transplantation. Reinduction therapy usually consists of mitoxantrone and etoposide 1 or L-asparaginase 1 with high-dose cytarabine arabinoside. Once a remission is achieved with chemotherapy, the use of any available matched or mismatched donor is recommended, including cord blood stem cells. Other active agents include 2-CdA 1 or gemtuzumab ozogomycin. Two new drugs that will be available for children with refractory and relapsed AML through the Children s Oncology Group include the combination of clofarabine (Clolar) 1 (a novel nucleoside analogue) with cytosine arabinoside and the combination of lestaurtinib 2 (an FLT3 inhibitor) with idarubicin and cytosine arabinoside. Relapse in extramedullary sites is less common. CNS relapses will require administration of intrathecal therapy and craniospinal irradiation. It is unclear whether systemic therapy and hematopoietic stem cell transplantation result in increased relapse-free survival. For soft-tissue relapses (granulocytic sarcoma), local and systemic therapy followed by a stem cell transplant, similar to the approach for bone marrow relapse, are indicated. A cornerstone for the success of AML therapy has been the 1 Not FDA approved for this indication. 2 Orphan drug in the United States. DM, April

17 participation of the majority of de novo childhood AML patients in clinical trials. As we better understand the biology of this disease and the number of available targeted agents increase, it will be very important to offer phase I and phase II studies to as many patients as possible so we can further improve the outcomes of all childhood AML patients who relapse. Atypical Manifestations. Rarely, AML manifests as congenital leukemia or extramedullary leukemia (skin, gingival, chloromas, or CNS). Congenital leukemia occurs in the first few weeks of life and can manifest as leukemia cutis. The skin lesions might spontaneously disappear, but they usually reappear with bone marrow involvement. Skin and CNS leukemia are more common in infants than in older children. At diagnosis, only 5% to 15% of patients present with CNS disease. They commonly are asymptomatic; however, some present with headache, vomiting, papilledema, or cranial nerve palsy. For patients who present with chloromas (myeloblastomas or granulocytic sarcomas), these are commonly found in the head or neck region. These lesions can result in later bone marrow involvement. All patients with atypical manifestation need systemic therapy as outlined previously. These atypical manifestations can also occur in relapse. Acute Complications. Tumor lysis syndrome, hyperleukocytosis, and transfusion support are discussed in the supportive care section. Infections. Due to severe and prolonged neutropenia, patients are at risk for bacterial infections (viridans streptococcal infection after high-dose cytarabine arabinoside) and fungal infections (candidemia and aspergillosis). Dental examination and oral hygiene during and after chemotherapy are routinely recommended to prevent -hemolytic streptococcal infection. Fungal prophylaxis is recommended; agents available include fluconazole (Diflucan) and voriconazole (Vfend). These antifungal drugs should be used with caution due to drug interactions. Routinely, patients are started on trimethoprim-sulfamethoxazole (TMP-SMX; Septra) for Pneumocystis jiroveci pneumonia (PCP; formerly Pneumocystis carinii pneumonia) prophylaxis. The dose is 150 mg/m 2 /day in two divided doses 3 days per week. Febrile Neutropenia. The definitions of fever can vary slightly; we use any fever higher than 38.3 C or higher than 38 C that persists for 1 hour with an absolute neutrophil count less than 500. We treat empirically with ceftazidime (Fortaz) and vancomycin (Vancocin) at the commonly recommended doses to treat gram-positive and gram-negative organisms. Extended coverage is strongly recommended if viridans streptococcal sepsis or typhilitis is suspected. 218 DM, April 2008

18 Supportive Care Although improved chemotherapy combinations and risk stratification have contributed greatly to better outcomes in childhood leukemias, excellent supportive care and treatment of complications of both the underlying disease and therapy have also played critical roles in the survival of these patients. Important aspects of supportive care include management of hyperleukocytosis, tumor lysis syndrome and metabolic derangements, and infection. Hyperleukocytosis Hyperleukocytosis (WBC 100,000/ L) can lead to clinical symptoms due to leukostasis, a clinicopathologic syndrome caused by the sludging of circulating leukemic blasts in tissue microvasculature due to altered rheology as well as interactions with blood vessel endothelial surfaces. Symptoms are typically neurologic (ranging from confusion and somnolence to stupor and coma) or pulmonary with dyspnea, infiltrates on chest x-ray, and respiratory distress. This syndrome is most common in AML and is rarely seen in ALL, even with markedly elevated WBCs. In general, in an ALL patient, a WBC count greater than 200,000/ L ora WBC count greater than 100,000/ L with clinical symptoms of leukostasis is an indication for intervention. Intervention can include aggressive hydration, cytoreduction with hydroxyurea (Hydrea), 1 or leukopheresis for aggressive removal of circulating blasts until definitive therapy can be initiated. In the AML patient, clinically relevant leukostasis can occur with a WBC of 100,000/ L. Tumor Lysis Syndrome Tumor lysis syndrome (TLS) results from the rapid turnover of malignant lymphoblasts. Cell death leads to release of intracellular contents, leading to hyperkalemia, hyperuricemia with secondary uric acid nephropathy and oliguric renal failure, and hyperphosphatemia with secondary hypocalcemia. In the presence of a high blast burden (WBC 100,000/ L) or extremely rapid cell turnover (Burkitt s leukemia), the ensuing metabolic derangements and uric acid nephropathy can be life threatening, although TLS can occur in any child with acute leukemia. Therefore, at the time of diagnosis (or suspected diagnosis) of ALL, TLS prophylaxis should be initiated with intravenous hydration at 2400 to 3000 ml/mm 2 /day to maintain urine output at greater than 100 ml/m 2 /hour until peripheral blasts and extramedullary disease are reduced. This fluid should be 1 Not FDA approved for this indication. DM, April

19 alkalinized to a target urinary ph of 6.5 to 7.5 to facilitate uric acid excretion. Patients at lower risk of significant TLS (low WBC) should receive allopurinol (Zyloprim) 300 mg/m 2 /day orally in three divided doses throughout the first 4 to 7 days of induction therapy because rapid blast lysis with the initiation of treatment can result in TLS. In fact, prior to the use of allopurinol, acute uric acid nephropathy developed in as many as 10% of ALL patients. In patients at high risk for TLS and subsequent uric acid nephropathy and renal failure, urate oxidase (rasburicase [Elitek]) may be administered intravenously. Urate oxidase rapidly converts uric acid to soluble allantoin; in this case, urinary alkalinization is not necessary. This medication is well tolerated except for infrequent allergic reaction and has markedly reduced the frequency with which Burkitt s leukemia or lymphoma patients require dialysis due to TLS. In addition to management of hyperuricemia, patients must be closely monitored for hyperkalemia and hyperphosphatemia and treated appropriately with binding agents or dialysis (or both) in severe cases. Infection Infection is a major source of morbidity and mortality throughout treatment for leukemia, although it is most prominent during the intensive portions of ALL treatment such as induction and delayed intensification blocks as well as all portions of ALL therapy. In addition to risk of bacterial infection, depression of T cell-mediated immunity can predispose to viral, fungal, and opportunistic infections. Bacterial. The rate of invasive bacterial infection and sepsis increases as WBC, in particular absolute neutrophil count (ANC), falls. Specifically, the risk of serious bacterial infection either with gram-negative rods from the patient s own gastrointestinal tract or gram-positive organisms through damaged oral mucosal surfaces or via central venous catheters, markedly increases when the ANC falls below 500/ L. Because of lack of white blood cells, patients are predisposed to severe infection and might lack the usual clinical signs and symptoms of inflammation (pain, erythema, purulent drainage). Therefore, the clinician must be vigilant for subtle signs of infection, and broad-spectrum antibiotics should be initiated immediately in neutropenic patients who develop fever ( 38.0 C). Various combinations of antibiotics can be used but most commonly includes an antipseudomonal cephalosporin such as ceftazidime or cefipime. For patients with clinical signs of sepsis such as hypotension or specific symptoms (severe mucositis or abdominal pain), antibiotic coverage should be broadened to include additional gram-negative coverage with an aminoglycoside, 220 DM, April 2008

20 gram-positive coverage with vancomycin, and anaerobic coverage with metronidazole or clindamycin. Carbapenems (ie, meropenem) are indicated in children with penicillin or cephalosporin allergy. Children receiving high-dose cytarabine therapy (AML and relapsed ALL patients) have a high incidence of life-threatening streptococcus viridans bacteremia. Any child who has received this therapy and presents with fever and neutropenia should receive intravenous vancomycin as well as ceftazidime regardless of presence of specific symptoms. All patients should receive P. jiroveci prophylaxis with TMP-SMX at a dose of 5 mg/kg/day divided into three doses on three sequential days per week throughout therapy and continue for 6 months from the completion of treatment. For patients with sulfa allergy or who cannot tolerate TMP-SMX, second-line options include inhaled pentamidine (Pentam), oral dapsone (Aczone), 1 or oral atovaquone (Mepron). Viral. Leukemia patients presenting with a rash suggesting primary varicella or shingles reactivation should be admitted to the hospital for intravenous acyclovir (Zovirax) treatment until the lesions are crusted, due to risk of dissemination. Asymptomatic children exposed to a sick contact with primary varicella should receive prophylactic intravenous immunoglobulin (IVIg) or, if available, VZIg (varicella zoster immune globulin). Other viral infections do not require hospitalization or specific therapy unless complications occur (eg, respiratory distress with RSV infection). Patients should receive annual influenza vaccination, but in general, children with leukemia can tolerate routine viral respiratory and gastrointestinal illnesses and do not require specific isolation precautions outside of the hospital. Fungal. Fungal infections represent an area of additional concern for patients being treated for leukemia, mainly during periods of prolonged neutropenia such as ALL induction or any intensive block of AML therapy. The most common pathogens include Candida and Aspergillus species. In neutropenic patients, fever longer than 5 to 7 days despite adequate antibiotic therapy is an indication for the empiric initiation of broad antifungal therapy, usually with liposomal amphotericin B (Ambisome), as well as imaging for occult fungal infection in the sinuses, lungs, liver, or spleen. Treatment of a probable or confirmed invasive fungal infection often requires long-term multiagent antifungal therapy. Current AML protocols include fungal prophylaxis with either fluconazole or voriconazole due to the high risk of infection in this population and the high rate of morbidity 1 Not FDA approved for this indication. DM, April

21 from these infections. Similar prophylaxis should be considered for any child undergoing intensive therapy for relapsed ALL. Hemorrhage Prior to the introduction of ATRA, APML induction therapy was associated with significant treatment related mortality due to hemorrhagic complications. Today the use of ATRA 3 with chemotherapy is usually not complicated by a bleeding diathesis. However, the use of ATRA is associated with the retinoic acid syndrome. This is a syndrome characterized by severe respiratory distress, capillary leak syndrome, and pseudotumor cerebri. This complication is successfully managed with temporary cessation of ATRA and administration of decadron. ATRA is usually restarted at a lower dose once the side effects have resolved. Transfusion Other important aspects of supportive care for children with leukemia include the judicious use of blood component transfusions. In general, packed red blood cell transfusions are recommended for hemoglobin levels less than 8 g/dl or at higher hemoglobin levels if the child is symptomatic (fatigue, headache, shortness of breath, tachycardia). At the time of diagnosis, children are often severely anemic but minimally symptomatic because the anemia has evolved slowly over time. In this setting, blood transfusion should be administered slowly over hours to avoid volume overload. All transfusions should be irradiated to prevent transfusion-related graft-versushost disease (GVHD) and to prevent cytomegalovirus (CMV) exposure. Platelet transfusions are indicated for platelet counts less than 10,000/ L or for bleeding. Platelets should be administered to a platelet count greater than 50,000/ L before diagnostic lumbar puncture to prevent a traumatic tap, which can be difficult to interpret and can introduce peripheral blasts into the spinal fluid. In general, growth factors such as G-CSF (granulocyte colony-stimulating factor, Neupogen) and erythropoietin (Epogen, Procrit) are rarely administered to children being treated for leukemia due to the theoretical risk of stimulating a malignant clone, although G-CSF is becoming an integral part of some highly intensive relapsed ALL protocols. Late Effects of Therapy The success of leukemia therapy comes at a price. Although treatment-related mortality continues to decrease as we implement 3 FDA approved for APL but not ALL, AML, or CML. 222 DM, April 2008

22 better supportive care strategies, an increasing number of survivors suffer from late effects of therapy. The Children s Oncology Group has recently published detailed long-term follow-up guidelines for pediatric oncologists and other physicians ( These guidelines do not supplant disease-specific follow-up care, but they seek to complement and standardize the care of childhood, adolescent, and young adult cancer survivors. All pediatric oncology centers should establish late effects clinics to provide care for the increasing population of survivors. As the number of long-term effects investigators grows, their experience and expertise are integral parts of clinical trial development. The ultimate objective is to modulate the intensity of therapy to maximize its efficacy and to minimize the short-term and long-term sequelae. It is necessary for all cancer survivors to have a record of a summary of their cancer therapy. Most leukemia cancer survivors graduate to long-term follow-up within 4 or 5 years after completing therapy. After this, they need follow-up visits once a year. The most concerning toxicity occurs in the CNS from high-dose methotrexate or cytarabine arabinoside and from intrathecal methotrexate with or without craniospinal irradiation. These patients can experience a lower educational attainment due to diminished cognitive functioning and usually experience a greater need for special education services. Many studies document increased weight and body mass index in survivors of childhood leukemia. There is also now increased awareness of adverse cardiovascular and diabetes risk profiles (the metabolic syndrome) due to leukemia therapy. Patients who receive high cumulative doses of anthracyclines also need yearly follow-up of cardiac function. Fertility is another issue of concern; this is now more commonly addressed with adolescents and young adults at diagnosis if the planned therapy could result in sterility. Psychosocial evaluation continues to be an important part of long-term follow-up because many patients deal with issues of assistance to procure educational resources, job placement, and health insurance. Current Diagnosis History (including family history of blood disorders or cancer) and physical examination. Complete blood count with a manual white blood cell differential and review of the peripheral smear. Chest x-ray (PA and lateral views). DM, April

23 Serum electrolytes, bun, creatinine, uric acid, calcium, phosphorus, LDH, ALT, bilirubin. Coagulation studies: PT, PTT, fibrinogen. Varicella titer (IGG). Bone marrow aspirate and biopsy for morphology, blast cell immunophenotype, cytogenetics, and minimal residual disease studies. Lumbar puncture with csf cell count, morphology on a spun preparation, protein, and glucose. Abbreviations: ALT, alanine aminotransferase; BUN, blood urea nitrogen; CSF, cerebrospinal fluid; IgG, immunoglobulin G; LDH, lactate dehydrogenase; PA, posteroanterior; PT, prothrombin time; PTT, partial thromboplastin time. Want to know more? Get multiple perspectives from more than 300 leading practitioners from over 15 countries on managing hundreds of common disorders affecting every organ system. The 2008 volume of Conn s Current Therapy offers the latest thinking on everything from insomnia and hypertension to smallpox and toxic chemical agents, as well as online access to the complete contents of the 2006, 2007, and 2008 volumes fully searchable, giving you multiple opinions on treatment. In print and online, Conn s consistently offers you the fastest approach to the latest treatments for the most effective results! Annual subscriptions and single-volume books are available at BIBLIOGRAPHY Armstrong SA, Look AT. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 2005;23: Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3: Carroll WL, Bhojwani D, Min D-J, et al. Childhood acute lymphoblastic leukemia in the age of genomics. Pediatr Blood Cancer 2006;46: Chessells JM, Veys P, Kempski H, et al. Long-term follow-up of relapsed childhood acute lymphoblastic leukemia. Br J Haematol 2003;123: Creutzig U, Renhardt D, Diekamp S, et al. AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 2005;19: Gaynon PS. Childhood acute lymphoblastic leukemia and relapse. Br J Haematol 2005;131: Jones LK, Saha V. Philadelphia positive acute lymphoblastic leukemia of childhood. Br J Haematol 2005;130: Kaspers GJ, Creutzig U. Pediatric acute myeloid leukemia: International progress and future directions. Leukemia 2005;19: DM, April 2008

24 Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood 2006;108: Pui C-H, Relling M, Downing JR. Mechanisms of disease: Acute lymphoblastic leukemia. N Engl J Med 2004;350: Pui C-H, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 2003;349: Pui C-H, Evans W. Drug therapy: treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354: 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 1996;334: Rubnitz JE, Razzouk BI, Lensing S, et al. Prognostic factors and outcome of recurrence in childhood acute myeloid leukemia. Cancer 2007;109: 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 2003;101: Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002;100: 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 2001;98: 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 2001;97: DM, April