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Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, there are clinical trials available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. The majority of the progress made in identifying curative therapies for childhood cancers have been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI (Http: //cancer.gov/clinical_trials/).
Acute myelogenous leukemia (AML) is the most common type of myeloid malignancy of childhood. Between 75% and 85% of children with AML can achieve a complete remission following appropriate induction chemotherapy. Children with newly diagnosed AML have an event-free 5-year survival rate of approximately 50%.[2-4] The most consistent prognostic factor across studies of AML in children is white blood cell (WBC) count at diagnosis. Children who have a WBC count greater than 100,000 per cubic milliliter have a poor prognosis. Additional factors that have been associated with a poor prognosis are:
secondary AML and monosomy 7 karyotype. Children with leukemia cell chromosomal abnormalities t(8;21) and inv 16 have a high likelihood of achieving remission [5-9] and a decreased likelihood of relapse.[8,9] Translocations of chromosomal band 11q23, including most AML secondary to epipodophyllotoxin,[10] are unfavorable in some studies. One exception to the poor prognostic significance of translocation chromosome band 11q23 may be the t(9;11) subtype which may confer an improved prognosis. Patients treated in a series of single institution trials did better if they had t(9;11) than if they had other translocations involving MLL.[11] In several studies, M4 and M5 FAB type, WBC greater than 20,000 per cubic milliliter, and requiring more than 1 cycle to achieve remission, predicted for a short duration of remission.[6,8] Presence of a FLT-3 internal tandem duplication has been demonstrated to be a poor prognostic factor.[12,13]
Acute promyelocytic leukemia (APL) is a distinct subtype of AML and is treated differently than other types of AML. The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoid acid receptor and that leads to production of the PML-RARalpha fusion protein.[14] Clinically, APL is characterized by a severe coagulopathy often present at the time of diagnosis.[15] Mortality during induction due to bleeding complications is more common in this subtype than other FAB classifications.
Children with Down syndrome have an increased risk of leukemia with a ratio of ALL to AML typical for childhood acute leukemia, except during the first 3 years of life when AML (especially M7) predominates.[16] Neonates with Down syndrome may manifest a transient myeloproliferative syndrome (TMS). This disorder mimics congenital AML but improves spontaneously within 4 to 6 weeks. Retrospective surveys indicate that as many as 30% of infants with Down syndrome and TMS will develop AML before 3 years of age.[17] Interestingly, the majority of children with Down syndrome and AML can be cured of their leukemia.[18] Appropriate therapy for these children is less intensive than current AML therapy and bone marrow transplant (BMT) is not indicated in first remission.
The myelodysplastic syndromes (MDS) represent a heterogeneous group of disorders of hematopoiesis leading to variable degrees of pancytopenia and often acute myeloid leukemia (AML). In adults, MDS have been classified by the French-American-British (FAB) group into distinct categories.[19] The FAB MDS classification is not an adequate classification for the syndromes that occur in children. The optimal management of MDS in children has not been well studied in prospective trials.
Juvenile myelomonocytic leukemia (JMML), formerly termed juvenile chronic myeloid leukemia (JCML), is a rare hematopoietic malignancy of childhood accounting for less than 1% of all childhood leukemias.[20] A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia, a disease noted only occasionally in children. Few approaches other than hematopoietic stem cell transplantation have resulted in long-term survival for this disease.[21,22] Children with neurofibromatosis 1(NF1) are at increased risk for developing JMML [23] and up to 14% of cases of JMML occur in children with NF1.[24]
AML,APL AMML AMoL AEL AMKL ALL
M0 (M1-M3) (M4) (M5) (M6) (M7)
Myeloperoxidase - + + - - - -
Nonspecific esterases
Chloracetate - + + -/+ - - -
Alpha-naphthol acetate - - +* +* - -/+* -
Sudan Black B - + + - - - -
PAS - - -/+ -/+ + - +
* These reactions are inhibited by fluoride.
The use of monoclonal antibodies to determine cell surface antigens of AML cells is helpful to reinforce the histologic diagnosis. Various "lineage-specific" monoclonal antibodies that detect antigens on AML cells should be used at leukemia diagnosis, along with a battery of lineage-specific T- and B-lymphocyte markers to help distinguish AML from ALL and mixed lineage or biphenotypic or biclonal leukemias. Various cluster designations (CD) that are currently thought to be relatively lineage specific for AML include CD33, CD13, CD14, CDw41 (or platelet antiglycoprotein IIB/IIIA), CD15, CD11B, CD36, and antiglycophorin A. Lineage-associated B-lymphocytic antigens CD10, CD19, CD20, CD22, and CD24 may be present in 10% to 20% of AMLs, but monoclonal surface immunoglobulin and cytoplasmic immunoglobulin heavy chains are usually absent; similarly, CD2, CD3, CD5, and CD7 lineage-specific T-lymphocytic antigens are present in 20% to 40% of AMLs.[7-9] The expression of lymphoid- associated antigens by AML cells is relatively common but has no prognostic significance.[7,8]
Immunophenotyping can also be helpful in distinguishing some FAB subtypes of AML. Testing for the presence of HLA-DR can be helpful in identifying APL. Overall, HLA-DR is expressed on 75% to 80% of AMLs but rarely expressed on APL. In addition, APL cases with PML-RARalpha were noted to express CD34/CD15 and demonstrate a heterogenous pattern of CD13 expression.[10] Testing for the presence of glycoprotein Ib, glycoprotein IIB/IIIa, or Factor VIII antigen expression is helpful in making the diagnosis of M7 (megakaryocytic leukemia). Glycophorin expression is helpful in making the diagnosis of M6 (erythroleukemia).[11]
Molecular probes and newer cytogenetic techniques (e.g., fluorescence in situ hybridization (FISH)) can detect cryptic abnormalities that were not evident by standard cytogenetic banding studies.[13] This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia chromosome in children with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML.
FAB morphologic classification in peripheral blood and bone marrow findings in
the myelodysplastic syndromes
-------------------------------------------------------------------------------
RA RARS RAEB RAEB-T CMML
Anemia + + + + +
Granulocytopenia +/- +/- Usually + Usually + +/-
Thrombocytopenia +/- +/- Usually + Usually + +/-
Marrow dysplasia
erythroid +/- +/- Usually + Usually + +/-
myeloid +/- +/- Usually + Usually + +/-
megakaryocytic +/- +/- Usually + Usually + +/-
Auer's rods - - - +/- -
Ringed sideroblasts 15% - + +/- +/- +/-
Peripheral blasts <or=1% <or=1% <5% May be >5% <5%
Abnormal marrow blasts <5% <5% 5-20% 5-30% <5-20%
Peripheral monocytosis - - - - +
(>1 x 10(to the 9th)/L
RA= refractory anemia
RARS= refractory anemia with ringed sideroblasts
RAEB= refractory anemia with excess blasts
RAEB-T= refractory anemia with excess blasts in transformation
CMML= chronic myelomonocytic leukemia
However, in children RARS is rare. RA, RAEB and RAEB-T are more common. Syndromes not covered by the BFM MDS classification include Juvenile Myelomonocytic Leukemia (JMML, formerly, Juvenile Chronic Myeloid Leukemia) and Infantile Monosomy 7 syndrome. JMML shares some characteristics with adult CMML,[15-17] but is a distinct syndrome (see below). The Infantile Monosomy 7 Syndrome includes children less than 4 years of age at diagnosis with any type of myelodysplasia and monosomy 7. This entity shares many characteristics with JMML and may be best considered a subset of this disease. Older children with monosomy 7 and characteristics of MDS should be classified by the FAB MDS classification.
Category Item
Minimal Laboratory criteria 1. No Ph chromosome, no bcr-ab1
rearrangement
(All 3 have to be fulfilled) 2. Peripheral blood monocyte count > 1 x 10
(to the 9th)/L
3. Bone marrow blasts < 20%
Criteria for definite diagnosis 1. Hemoglobin F increased for age
(At least 2 must be fulfilled) 2. Myeloid precursors on peripheral blood
smear
3. White blood count > 10 x 10(to the 9th)/L
4. Clonal abnormality (including monosomy 7)
5. GM-CSF hypersensitivity of myeloid
progenitors in vitro
A distinctive characteristic of JMML leukemia cells is their spontaneous proliferation in vitro without the addition of exogenous stimuli, an ability that results from the leukemia cells being hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF).[20] While the majority of children with JMML have no detectable cytogenetic abnormalities, a minority show loss of chromosome 7 in bone marrow cells.[18] Children with myelodysplastic syndrome and monosomy 7 have sometimes been considered to have "Monosomy 7 Syndrome," defined by age less than 4 years and by loss of chromosome 7.[16,21] However, recent data provide limited support for the concept of monosomy 7 as a distinct syndrome, and instead support considering children with clinical features of JMML as having one disorder without regard to the presence or absence of chromosome 7.[22]
Treatment is ordinarily divided into 2 phases: 1) induction (to attain remission) and 2) postremission consolidation/intensification. Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic bone marrow transplantation (BMT). For example, the current U.S. nationwide trial (CCG-2961) uses induction therapy followed by two courses of chemotherapy, one utilizing high-dose cytarabine.[1] A pediatric AML regimen developed by the United Kingdom Medical Research Council (MRC) utilizes three or four courses of chemotherapy following the initial course of remission induction chemotherapy.[2,3]
Maintenance therapy is not part of most pediatric AML protocols with the exception of the Berlin-Frankfurt-Munster (BFM) protocols. In aggressively treated AML, maintenance therapy does not appear to be of value.[4] Treatment of AML is usually associated with severe and protracted myelosuppression and other complications. Treatment with hematopoietic growth factors (G-CSF, GM-CSF) has been used in an attempt to reduce the toxicity associated with severe myelosuppression but does not influence ultimate outcome.[5] Virtually all adult randomized trials of hematopoietic growth factors (G-CSF, GM-CSF) have demonstrated significant reduction in the time to neutrophil recovery,[6-9] but varying degrees of reduction in morbidity and little if any effect on mortality.[5]
Because of the intensity of therapy utilized to treat children with AML, children with this disease must have their care coordinated by specialists in pediatric oncology, and they must be treated in cancer centers or hospitals with the necessary supportive care facilities (e.g., to administer irradiated, filtered, or cytomegalovirus-negative red blood cell and platelet transfusions; to manage infectious complications; and to provide emotional and developmental support). With increasing rates of survival for children treated for AML comes an increased awareness of long-term sequelae of various treatments. For children who receive intensive chemotherapy, including anthracyclines, continued monitoring of cardiac function is critical. Periodic renal and auditory examinations are also suggested. In addition, total-body irradiation before bone marrow transplant increases the risk for growth failure, gonadal and thyroid dysfunction, and cataract formation.[10]
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
The two most effective drugs used to induce remission in children with acute myeloid leukemia (AML) are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[1-3] For example, the CCG DCTER regimen utilizes cytarabine, daunorubicin, dexamethasone, etoposide, and thioguanine and is given as two 4-day treatments separated by 6 days.[3] The German Berlin-Frankfurt-Munster (BFM) Group has studied cytarabine and daunorubicin plus etoposide (ADE) given over 8 days,[2] and the United Kingdom Medical Research Council (MRC) has studied a similar ADE regimen given over 10 days.[1] The MRC has also studied cytarabine and daunorubicin given with thioguanine (DAT).[1] A randomized trial that included both children and adults comparing either etoposide or thioguanine given with cytarabine and daunorubicin (i.e., ADE versus DAT) showed no difference between the thioguanine and etoposide arms in remission rate or disease-free survival.[4]
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[1-3] although idarubicin has also been used.[5] A randomized study in children with newly diagnosed AML comparing daunorubicin and idarubicin (each given with cytarabine and etoposide) observed a trend favoring idarubicin, but the small benefit for idarubicin in terms of remission rate and event-free survival was not statistically significant.[5] Similarly, studies comparing idarubicin and daunorubicin in adults with AML have not produced compelling evidence that idarubicin is more efficacious than daunorubicin.[6] In the absence of convincing data that another anthracycline produces superior outcome to daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML.
The intensity of induction therapy influences the overall outcome of therapy. The CCG 2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better event-free survival than standard timing induction therapy (4-day treatment courses separated by two weeks or longer).[3] The MRC Group has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.[1] Another way of intensifying induction therapy is by the use of high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2-3 gm/m2/dose) compared to standard-dose cytarabine,[7,8] a benefit for the use of high-dose cytarabine compared to standard-dose cytarabine in children was not observed using a cytarabine dose of 1 gm/m2 given twice daily for 7 days with daunorubicin and thioguanine.[9]
Randomized trials evaluating hematopoietic growth factors during induction therapy for patients with AML have not been performed in children, and so the potential benefit of these agents for children with AML must be extrapolated from the adult experience. Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in attempts to reduce the toxicity associated with prolonged myelosuppression.[10] Treatment with hematopoietic growth factor generally begins within a day or two following the completion of cytotoxic therapy and continues until granulocyte recovery. A reduction of several days in the duration of neutropenia with the use of either G-CSF or GM-CSF has been observed.[10] Most, but not all, randomized studies showed statistically significant reductions in the duration of hospitalization and antibiotic use in patients receiving hematopoietic growth factors.[10] However, significant effects on treatment-related mortality or overall survival were rarely observed.[10]
The leukemia cells from patients with APL are especially sensitive to the differentiation-inducing effects of all-trans retinoic acid (ATRA). The basis for the dramatic efficacy of ATRA against APL is the ability of pharmacologic doses of ATRA to overcome the repression of signaling caused by the PML RARalpha fusion protein at physiologic ATRA concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis.[17] Most patients with APL achieve a complete remission when treated with ATRA, although single agent ATRA is generally not curative.[18,19] A series of randomized clinical trials have defined the benefit for combining ATRA with chemotherapy during induction therapy and also the utility of employing ATRA as maintenance therapy.[20-22] With the use of ATRA and chemotherapy, the 2-year survival rates for patients with APL have improved from approximately 40% to 50-80%.[20,22] Induction therapy for the current nationwide trial for children and adults with APL utilizes ATRA with standard-dose cytarabine and daunorubicin, and consolidation therapy employs ATRA with daunorubicin.[23]
There is an uncommon variant of APL associated with t(11;17) resulting in a PLZR-RARalpha fusion protein. This variant does not respond well to ATRA and has a worse prognosis than APL with t(15;17).[24-26]
Arsenic trioxide has also been identified as an active agent in patients with APL, with 70 to 90% of patients achieving remission following treatment with this agent.[27,28] There are limited data on the use of arsenic trioxide in children, though published reports suggest that children with APL have a response to arsenic trioxide similar to that of adults.[27,29] Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes),[30] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[31]
Nationwide studies in progress:
C9710 - a phase III randomized intergroup study organized by CALGB in which all patients receive concurrent ATRA and chemotherapy during the induction and consolidation phases of therapy and also receive ATRA as maintenance therapy. One-half of patients 15 years or older receive an additional two courses of arsenic trioxide during the induction phase in order to evaluate the role of arsenic trioxide in patients with newly diagnosed APL. Children less than 15 years do not receive arsenic trioxide. During maintenance phase, patients are randomly assigned to receive ATRA alone or to receive ATRA plus daily 6-mercaptopurine and weekly methotrexate.
Transient Myeloproliferative syndrome (TMD) is a disorder primarily found in Down syndrome patients during the newborn period. It is characterized by an uncontrolled proliferation of myeloblasts. These blasts are frequently of megakaryocytic origin with varying degrees of differentiation and are clonal in nature. Information regarding the presentation and natural course of this disease is lacking. TMD can be distinguished from congenital AML primarily by its spontaneous resolution. Thus, TMD is managed with supportive care only during the first few months of life.
Nationwide studies in progress:
The Children's Oncology Group (COG) is studying the treatment of children with Down syndrome. This study will evaluate the efficacy of reduced dose chemotherapy for Down syndrome patients diagnosed with AML or MDS. The goal is to maintain or improve the current excellent outcome with less late effects. The second goal is to increase the understanding of the natural history of TMD and facilitate epidemiologic investigations of leukemia in Down syndrome.
Nationwide studies in progress:
The Children's Cancer Group (CCG) phase II trial (#2961) (see above for study outline). Children with myelodysplastic syndrome are eligible. According to the study schema, patients are treated according to protocol therapy if treatment with chemotherapy is indicated. If immediate transplantation is indicated, the patients are followed. Patients who do not require immediate therapy are also followed.
Based upon these laboratory observations, 12 patients with JMML were evaluated in a pilot study using cis-retinoic acid (C-RA).[39] Of ten evaluable patients, responses were as follows: 2 CR, 3 partial responses (PR), 1 minimal response (MR), 4 progressive disease (PD). Toxicity was minimal. Responses were relatively slow and most children who experienced progressive disease did so within a few weeks of C-RA treatment.
Transplantation seems to offer the best chance of cure for JMML.[40,41] A summary of the outcome of 91 patients with JMML treated with transplantation in 16 different reports is as follows: thirty-eight patients (41%) were still alive at time of reporting, including 30 of the 60 (50%) patients who received grafts from HLA-matched or one-antigen mismatched familial donors, 2 of 12 (17%) with mismatched donors, and 6 of 19 (32%) with matched unrelated donors.[42]
Nationwide studies in progress:
Children's Oncology Group (COG) (#P9920): a phase II window evaluation of the farnesyl transferase inhibitor (R115777) followed by 13-cis retinoic acid, cytosine, arabinoside, and fludarabine plus hematopoietic stem cell transplantation in children with juvenile myelomoncytic leukemia.
The use of BMT in first remission has been under evaluation since the late 1970s. Recent prospective trials of transplantation in children with AML suggest that greater than 60% to 70% of children with matched donors available who undergo allogeneic bone marrow transplantation during their first remission experience long-term remissions.[6,7] Prospective trials of allogeneic transplantation compared to chemotherapy and/or autologous transplantation have demonstrated a superior outcome for patients who were assigned to allogeneic transplantation based on availability of a family 6/6 or 5/6 donor.[6-10] In the MRC trial the difference (70% vs 60%) did not reach statistical significance but the numbers of patients enrolled did not give the study the power to demonstrate this difference.[7] Several large cooperative group clinical trials for children with AML have found no benefit for BMT over intensive chemotherapy.[6-8,10]
Two approaches have emerged for the use of allogeneic BMT in first remission. In the first approach, patients with favorable prognostic features at diagnosis are transplanted only after relapse. The Berlin-Frankfurt-Munster (BFM) group uses a combination of day 15 marrow response (<5% blasts), FAB subtype (M1 and M2 with Auer Rods, M3, or M4Eo) to define a good risk group.[11] Similarly, the United Kingdom Medical Research Council (MRC) has identified a group of good risk patients with a 7-year survival of 78%. The patients in this group include those with t(8;21), t(15;17), FAB M3, inv 16.[7] This most likely identifies an equivalent group of patients included in BFM standard risk group. The second approach is to offer allogeneic BMT to all patients who have a suitable donor. The current Children's Oncology Group (COG) studies assign all patients with suitable matched family donors to bone marrow transplantation. Of note, patients with Down syndrome, APL and FAB M3 or t(15;17), are treated on a separate protocol. The role of alternative donor transplants (unrelated marrow or cord blood) in first remission of AML has not been established.
Although maintenance chemotherapy has been incorporated into pediatric AML therapy and continues to be used in BFM trials, no data demonstrates that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration.
1. In the Children's Cancer Group (CCG) phase III study (#2961), children with
AML are treated with multiagent induction chemotherapy. Induction consists of
5 drugs (idarubicin, etoposide, dexamethasone, cytarabine, and 6-thioguanine)
given on days 0 to 3 followed by 5 drugs (daunorubicin, etoposide,
dexamethasone, cytarabine, and 6-thioguanine) given on days 10 to 13. When
white blood cell and platelet counts recover, children are randomly assigned to
consolidation consisting of the same sequence of 5 and 5 drugs or to
fludarabine/cytarabine/idarubicin. CNS prophylaxis consists of intrathecal
cytarabine. G-CSF is given from 2 days after completion of induction and
consolidation until the absolute neutrophil count is greater than 1500.
Children with matched-related donors are assigned to allogeneic marrow
transplant intensification. Transplant cytoreduction consists of age-adjusted
busulfan and cyclophosphamide. Children without a donor are given high-dose
cytarabine/L-asparaginase (Capizzi II) and additional intrathecal cytarabine.
After recovery from cytarabine, children are randomly assigned to interleukin-2
or standard follow-up care.[12,13]
The CCG-2961 study is also evaluating immune-modulatory therapy using IL-2. The rationale for immune-modulatory therapy is the observation that a graft versus leukemia effect is responsible for some of the efficacy of allogeneic transplantation. Patients are randomized to receive interleukin-2 versus observation alone after completion of consolidation chemotherapy.[14]
Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with other agents, including mitoxantrone,[4] fludarabine plus idarubicin, [5,6] and L-asparaginase.[7] The standard-dose cytarabine regimens used in the MRC AML 10 study for newly diagnosed children with AML (cytarabine plus daunorubicin plus either etoposide or thioguanine) have produced remission rates similar to those achieved with high-dose cytarabine regimens.[3]
For children with recurrent acute promyelocytic leukemia (APL), the use of arsenic trioxide or regimens including all-trans retinoic acid should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in patients with recurrent APL, with 70% to 90% of patients achieving remission following treatment with this agent.[8,9] There are limited data on the use of arsenic trioxide in children, though published reports suggest that children with APL have a response to arsenic trioxide similar to that of adults.[8,10] Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes),[11] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[12]
The selection of further treatment following the achievement of a second remission depends on prior treatment as well as individual considerations. Consolidation chemotherapy followed by stem cell transplantation is often employed, though there are no definitive data as to the contribution of these modalities to the long-term cure of children with recurrent AML.[1] Clinical trials, including new chemotherapy and/or biologic agents and/or novel bone marrow transplant (autologous, matched or mismatched unrelated donor, cord blood) programs, should be considered. Information about ongoing clinical trials is available from the NCI (Http: //cancer.gov/clinical_trials/).
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