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www.cambridge.org© in this web service Cambridge University Press
Cambridge University Press978-0-521-19661-1 - Childhood Leukemias: Third EditionEdited by Ching-Hon PuiIndexMore information
Index
Bold page numbers indicate illustrations, italic page numbers indicate tables/boxes
1p32 abnormalities, 1762-CdA, cellular drug resistance,258, 26632P therapy, 4683q abnormalities, 4083q21.3 abnormalities, 1553q26.2 abnormalities, 1554q12 abnormalities, 1575q33.1 abnormalities, 1578p12 abnormalities, 1589p abnormalities, 1429p21.3 abnormalities, 1829q abnormalities, 156in T-ALL, 147
11p15 abnormalities, 15611q23 abnormalities, 142, 143,153–154, 172, 210–214AML with, 401
12p abnormalities, 142, 15614q11.2 abnormalities in T-ALL,14715q22 abnormalities, 21517p abnormalities, 15717q1221 abnormalities, 21520q abnormalities, 15721q22 abnormalities, 157
ABL1 geneactivation, 170in CML, 248in T-ALL, 147
ABL1 tyrosine kinase activity,170absolute neutrophil count, 781G-CSF therapy and, 806parent/patient calculation, 842
accelerated phase of CML, 11
access to carebarriers to, 554–555family income and, 551lack of, distortion of statisticsby, 550, 551measures to improve, 554
acetaminophen, 816acid phosphatase stain, 24acquired immunodeficiencysyndrome (AIDS) and risk ofBurkitt lymphoma/leukemia,386activity, physical, 844acute bilineal leukemia, 32, 36,37, 94, 96, 97acute biphenotypic leukemia, 32,36acute erythroblastic leukemia,27, 91acute erythroid leukemia,subtypes, 91acute kidney injury, 666acute leukemia, 100of ambiguous lineage, 36–37bilineal, 32, 36, 37, 97blood transfusion, 5CD45 and, 81chemotherapy, early attempts,6classification, 21, 23, 28–39,96CD markers, 72, 73future trends, 38–39
diagnosis, 23future trends, 38–39
diagnosis and classification,MPO in, 83Down syndrome and, 93expression profiles, 82flow cytometry, 81genetic factors, 51and infection, 6lineage identification, 80
neuropsychologicalconsequences, 8Pneumocystis pneumonia and,7processes mimicking, 98–102total care, 7undifferentiated, 36, 37
Acute Leukemia Group B, 8acute leukemia of ambiguouslineage (ALAL), 82, 88, 94, 403classification, 94
acute leukemia, mixedphenotype, 88acute lymphoblastic leukemia(ALL)adolescents and young adultswith, 520–525array comparative genomichybridization in, 136B-lineage, submicroscopicmolecular genetics, 182BCR-ABL1 fusion in, 140cellular drug resistance in,258, 257–259, 268childhood, 8–9chromosomal abnormalities,138, 145, 169, 1809p, 142numeric, 137–138other, 142–144structural, 138–140targets for PCR, 633
classification, 28–32future trends, 39immunophenotypic, 29molecular (genetic), 30
clinical presentation, 334–336complications of treatment,524–525continuation treatment,351–352cytogenetics, 142–147cytoplasmic granules, 25development, 177diagnosis, 23
diagnosis andimmunophenotypicclassification, 338–340diagnostic criteria, 29Down syndrome, 504–506epigenetics, 239–245event-free survival, 367genetic classification, 340–342genetics of relapse, 184–185genome-wide associationstudies of, 59glucocorticoids in, 319HSCT in, 532, 533–535indications for, 534MRDmonitoring in, 645second transplant, 535
hyperdiploidy, 51, 137, 340in adolescents, 523drug responsiveness in, 258,268
hypodiploidy, 29, 137, 340,533hypomethylating agents in,245incidence, 431age peak, 57age-specific, 49ethnic and racialdifferences, 49geographic variation, 49sex differences, 49
incidence and distribution,124infant, 353initial classification, 2intensification andreinduction therapy, 349–350L1, 25L2, 25laboratory findings, 336–338methotrexate accumulation in,310molecular genetics, 182–186PCR assay, 642
MRD detection inby flow cytometry, 639–640,646, 645–647
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Cambridge University Press978-0-521-19661-1 - Childhood Leukemias: Third EditionEdited by Ching-Hon PuiIndexMore information
Index
acute lymphoblastic leukemia(cont.)by PCR, 633, 636, 644,642–645
near-haploidy, 137, 335, 340neutropenia prophylaxis, 784normal karyotype, 137outcome, 185as indicator of cancer unitsuccess, 552, 556, 557
pathogenesis andpathophysiology, 332–334pediatric, cytogeneticsubtypes, 30Ph+, 3, 170ploidy, 30precursor T-cell, 28prevalence, 21prognosis and outcome bysubtype, 341prognostic factors, 342–344,643, 647pseudodiploidy, 137rates, national, 50relapse, 367diagnosis of, 367, 643HSCT in, 374–375immunophenotypes in, 369MRDmonitoring in, 643,645new drugs, 375prognostic factors, 367–370,642, 647treatment, 371, 370–376
remission induction, 349monitoring, 643, 645
risk classification, 344risk groups, 342–344risk stratification, 185, 369,643staining, 27subtypes, 2, 28age at diagnosis and, 520classification, 338
supportive care, 344–345, 349as target for treatment indeveloping countries, 552T-lineage, submicroscopicmolecular genetics, 182–184total therapy approach,344–353treatmentfuture directions, 354, 525monitoring by flowcytometry of MRD,645–647monitoring by MRD PCR,642–645principles of, 345results, 346results of St. JudeInternational OutreachProgram, 556–557
with aberrant expression ofmyeloid-associated antigens
(My+ ALL), flow cytometry,94with eosinophilia, 32
acute megakaryoblastic leukemia(AMKL), 27, 34, 401–402abdominal abnormalities,398chromosomal abnormalities,154diagnosis, 92with Down syndrome(AMKL-DS), 217, 218–219,508–513genetic lesions, 220
immunophenotyping, 92molecular genetics, 217–220with t(1;22), 219–220X-chromosome abnormalityand, 51
acute mixed lineage leukemia,94, 354acute monoblastic leukemia, 26,27flow cytometry, 81staining, 24
acute monoblastic/monocyticleukemia, 34acute monoblastic/myelocyticleukemia, immunophenotypes,90–91acute myeloblastic leukemia,flow cytometry, 81acute myelocytic leukemia withmaturation, immunophenotype,89acute myeloid leukemia (AML),9–11, 204, 395–412anthracyclines in, 316array comparative genomichybridization in, 136, 151bone marrow transplantationin, 535–537second transplant, 537
cellular drug resistance in,257, 258, 259, 263, 268chromosomal abnormalities,targets for PCR, 633chromosomal changes,148numeric, 149–151structural, commonrecurrent, 151–154structural, uncommonrecurrent, 154–157
classification, 32–37, 49,147future trends, 39
clinical trial results, 405cross-lineage IG/TCRrearrangements, 125cytogenetic abnormalities, 89,157–158, 205
cytogenetically normal AML,149, 220–225diagnosis, 23differential with MDS, 435immunophenotypingpanels, 88
diagnostic criteria, 29Down syndrome and,508–513dysplastic features and, 23epigenetics, 245–248familial, CEBPα-dependent,296gene rearrangements, 124genetic lesions, 206genetic subtypes, 34–35HSCT in, 532, 536indications for, 534
immunophenotype, 88incidence, 431age-specific, 49geographic variation, 49
initial classification, 2leukocyte antigen expression,89markers, 83, 84minimally differentiated,staining, 24molecular genetics, 204–225PCR assay, 647–648
MRD detection inby flow cytometry, 640, 641,648–649by PCR, 633, 647–648
neutropenia prophylaxis,784not otherwise specified, 400PCR analysis of junctionalregions, 636prevalence, 21prognostic factors, 649rates, national, 51relapsed, 422, 421–425combination therapy in, 315after HSCT, 536MRDmonitoring in, 648
and related precursorneoplasms, 31risk assignment, 649secondary, 713subclassification, 23, 400subtypes, 9, 205, 395cellular drug resistance in,259specific therapies for, 412staining, 24treatment-related, 747–749,751–753
therapy-related, 36topoisomerase IIinhibitor-induced, 153treatment, 10–11monitoring by flowcytometry of MRD,648–649
monitoring by PCR ofMRD, 647–648results of St. JudeInternational OutreachProgram, 557–559
treatment-related, 56clinical presentation,latency, and diagnosis, 749,747–749cytogenetic and molecularaberrations, 738–739treatments and outcome,751–753
vs. MDS, 435algorithm, 435
WHO classification, 9, 204with aberrant expression oflymphoid-associated antigens(Ly+ AML)flow cytometry, 95
with associated eosinophilia,chromosomal abnormalities,157–158with granulocyticdifferentiation, 26with granulocytic sarcoma,chromosomal abnormalitiesin, 151with inv(16), 35, 400with maturation, 33with minimal differentiation,403–404diagnostic criteria, 93immunophenotyping,92–93
with minimal granulocyticdifferentiation, 25with monosomy, FISH, 150with multilineage dysplasia, 33with myelodysplasia-relatedchanges, 35, 88with predominant erythroiddifferentiation, 27with recurrent geneticabnormalities, 88with t(8;21), 34, 398, 400without maturation, 33immunophenotype, 88
acute myeloid leukemia withminimal evidence of myeloiddifferentiation (AMLM0), 33acute myeloid leukemia withpredominant erythroiddifferentiation (AMLM6), 34acute myelomonoblasticleukemia, 663acute myelomonocytic leukemia,26, 33flow cytometry, 81immunophenotypes, 90
acute promyelocytic leukemia(APL), 10, 33, 215–217, 402–403ATRA in, 317–318
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characteristics, 23chromosomal abnormalities,152–153coagulopathy in, 672hypergranular, 23, 26, 33immunophenotypes, 89–90microgranular, 23, 26, 33, 90MRDmonitoring in, 647PML-RARA fusion, 33, 648with PML-RARA fusion, 89relapse in, 422, 424, 648therapy-related, 36treatment, 407–408urgency of diagnosis, 152WHO classification, 399
acute undifferentiated leukemia(AUL), 88, 94immunophenotyping,95–96
acute, use of term, 21acyclovir, 775, 777development, 7
adeno-associated vectors, 594,595, 596–597adenoviral vectors, 595–596adenovirus, 594adjuvant immune therapy,783–784adolescents, ALL treatment,520–525adrenal corticosteroids,lympholytic effects, 4adrenal insufficiency, 661adrenocortical insufficiency,687adult T-cellleukemia/lymphoma, 100immunophenotype, 100
Advisory Committee onImmunization Practices (ACIP),7AF4/MLL fusion transcript, 31affluenceand infection, 57pediatric cancer survival and,551
ageat diagnosiscomplications and, 662secondary cancers and, 730treatment of ALL and,520–525
maternal, and childhoodcancer, 55at treatment, neurocognitiveissues and, 824
airway compression, 661, 670,671
alcohol, maternal consumptionin pregnancy, 55, 56alemtuzumab, 477, 563, 564, 572,623side effects, 573
aleukemic leukemia, 2algorithmdiagnostic, in AMLabnormal promyelocytes, 32blast cells, 32erythroid precursors, 32
FAB classification of AML, 32management oftreatment-related leukemia,750WHO, for classificationof AML, 33
alkaline phosphatase, 80alkylating agents, 725in Burkitt leukemia, 3and chromosomalabnormalities, 56cytogenetic and moleculargenetic changes due to,736–739dentofacial effects, 708early, 4hypersensitivity to, 278, 279in therapy-related AML, 36infertility and, 705new, 622–623-related AML/MDS, 404-related leukemias, clinicalpresentation, 748resistance to, 258secondary cancers and,725–726, 732treatment-related leukemiaand, 726
allergyto asparaginase, 318uric acid levels and, 388
alloantigens, 584allopurinol, 667introduction of, 6xanthine nephropathy and,666xanthine oxidase and, 665
all-trans-retinoic acid (ATRA),90, 215in APL, 10–11, 152, 407, 672first use, 215pharmacodynamics, kinetics,and genetics, 316–318plasma concentration, 317in relapsed disease, 424
alpha-naphthyl acetate esterase(ANA), 24applications, 27
alpha-naphthyl butyrate esterase(ANB), 24, 24, 27
applications, 27amegakaryocyticthrombocytopenia, myeloidneoplasia and, 431aminopterin, trials of, 4AMKL see acutemegakaryoblastic leukemiaAML see acute myeloid leukemiaAML genes,in FPD/AML, 294see also CBF genes, RUNXgenes
AML1 gene, 205in ALL, 340trisomy 21 and, 509
AML1(RUNX1) genein ALL, 138in AML, 148, 150, 151,157amplification in ALL, 144fusions, 155
AML1-CBFA2T3 fusion, 157AML1-ETO fusion transcript,151–152, 648amphotericin B, 6, 782, 783anagrelide, 467, 471analgesics, 815–818procedural, 819
anaplastic large cell lymphoma,102leukemic phase, 101–102immunophenotype, 102
anaplastic lymphoma kinase(ALK), 102anemia, 23in ALL, 337, 344erythropoietin in, 807in JMML, 38in primary myelofibrosis, 473transfusion in, 794
anergy, 583, 588anthracenedione, 10anthracyclines, 10, 265in ALL-DS, 506in AML, 423in AML-DS, 510in APL, 407cardiotoxicity of, 707–708cellular drug resistance, 268mechanisms, 264–265
liposomal, 620MoAb conjugates with, 568new formulations, 621pharmacodynamics, kinetics,and genetics, 316in reinduction therapyin AML, 423in relapsed ALL, 370
in remission inductiontherapy in ALL, 348resistance to, 258secondary AML and, 56treatment-related leukemiaand, 726
antiangiogenic drugs in AML,425anti-aspergillus azoles, 6antibiotics, 6in ALL, 344in AML, 10, 411in APL, 407for bloodstream infections,773in fever and neutropenia, 779,780–781guidelines, 782prophylactic, 785in typhlitis, 681
antibodies, monoclonal, seemonoclonal antibodiesantibody engineering, of MoAbs,573antibody screening panels, 80in ALL, 338
antibody-dependentcell-mediated cytotoxicity, 563,565anti-CD20 antibody, rituximab,390anticoagulation, 678for occluded catheters, 803
anticonvulsants, 817chemotherapy and, 320
antidepressants, tricyclic, 818antiemetics, 829–830antifols, trials of, 4antifungals, 6, 783prophylactic, 785–786
antigen-specific variabledomains, 113antigen specificity, 113, 115antigen targets for MoAb-basedagents, 566antigen-induced somatichypermutations, 116antigen-presenting cells, 582antigenspresentation, 582recognition by immunesystem, 113targets of immunotherapy,583–584
antigen-specific cytotoxicT-lymphocytes, transfer,586–587
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anti-leukemic drugs, 8emergence, 6
antipyretics, in neutropenia, 815antiviral prophylaxis, 785anxiety, 830procedural, interventions for,828–829
APL see acute promyelocyticleukemiaaplastic anemia, 434risk of MDS and, 432
aplastic bone marrow, 99apoptosisanthracyclines and, 264arsenic trioxide and, 11B-cell, 76, 76, 77drugs targeting, 627E2A–HLF and, 172E2A–PBX1 and, 172epigenetics and, 249granulocyte, 78leukemic blasts in precursorB-ALL, 30new drugs related to, 375p53-induced, 385PML and, 215RAS and, 450in severe congenitalneutropenia, 297suicide gene therapy, 604T-cell, 77downregulated, 604
telomere shortening and, 293TP53-mediated, 731
aprepitant, 830AraC 266 see cytarabineara-CTP(1-β-d-arabinofuranoxylcytosine-5′-triphosphate),313–315ARID genesand risk of ALL, 185, 333as susceptibility allele, 298polymorphisms, 60, 60, 298,321
array comparative genomichybridization, 136in ALL, 177in AML, 151, 204
arrhythmias,anthracycline-induced, 316arsenic trioxide, 3, 10in APL, 217, 672in relapsed APL, 424
arsenicals, 3asparaginase, 8, 9, 262action, 262in ALL, 345–348, 349,521
anticoagulation and, 678cellular drug resistance, 262,268mechanisms, 262–263
drug–drug interactions, 319hyperglycemia and, 686in reinduction therapyin relapsed ALL, 370
mechanisms, 318new formulations, 620,621pancreatitis and, 682pharmacodynamics, kinetics,and genetics, 318–319resistance to, 258MLL rearrangements and,257prognosis and, 257
single-dose, 263thrombosis and, 679treatment in ALL, 340
asparagine rescue, 263aspergillosis, 774, 782–783aspirin, 469, 471assaysdonor screening, 801drug cytotoxicity, seecytotoxicityELISA for fungal infection,783low-cost, 552MRD, 410, 422
Association of PediatricHematologists/Oncologists ofCentral America (AHOPCA),557ataxia-telangiectasia, 51,281–283, 336aberrant TCR rearrangementin, 125and B-ALL, 336complications and, 663heritable predisposition, 277and risk of Burkittlymphoma/leukemia, 386
ATM gene, 281, 283ATM protein, 281–282ATM–MRN DNA repairpathway, 282atomic bomb, leukemiaincidence after, 53ATRA see all-trans-retinoic acidattention-deficit interventions,827–828Auer rods, 23in AML, 26, 33, 34in APL, 33, 402myeloblasts, 23MDS, 37staining, 24
autoimmune disease in JMML,452autoimmunelymphoproliferative disorder, 98avascular necrosis of bone inadolescent ALL, 520avidin–biotin–HRP complex, 82azacytidine, 246–247, 620,625in combination therapy, 248
azole antifungals, 6, 686
B-cell acute lymphoblasticleukemia (B-ALL), 122,383–390cellular drug resistance in, 258chromosomal abnormalities,144–146chromosomalrearrangements, 169–172,174TCF3-HLF, 172
clinical features, 338diagnosis, 82expression profiles, 85FISH, 141gene rearrangements, 123,124, 124genetic lesions, 206IG rearrangements, 173–174IG/TCR rearrangements in,123–124MLL rearrangements, 173immunologic classification,376, 127
B-cell precursor ALLcompared with T-cell ALL,339genetic subgroups, 342
B-cell receptors, 75, 76antigen specificity, 113
B-lineage lymphoidmalignancies, incidence anddistribution, 124B-lineage maturation anddifferentiation, 72–77B-lymphocytesIG rearrangements, 116,117in JMML, 449immunoglobulins on, 113maturation, 76flow cytometry studies, 99normal, 75
somatic hypermutations,116
bacteremia, 773, 773catheter-related, 804
bacterial contamination in bloodtransfusions, 801
Barnes, DW, total bodyirradiation, 7barriers to treatment indeveloping countries, 552,554–555basophilia, 23B-cells see B-lymphocytesBCL2 overexpression, 172BCL2 inhibitors, 620BCR tyrosine kinase activity, 170BCR–ABL1, 460activity, 170ALL subtypes and, 181in CML, 249inhibitors, 250see also Philadelphiachromosome
BCR-ABL1 fusion gene, 31, 37,138, 140in ALL, 177in B-ALL, 170–171cellular drug resistance and,258, 263in CML, 248, 460diagnosis of CML, 38effect on outcome, 171in healthy people, 460see also Philadelphiachromosome
behavioral changes,dexamethasone and, 352behavioral issues interventions,827–828bendamustine, 622benign bone marrowlymphocytosis, 98Bennett, JH, linked leukemia towhite blood cells, 1, 11benzene, maternal exposure to,54bereavement care, 848biclonality, 124bilineal leukemia, 354, 403acute, 32, 36, 37, 97
BIM gene, 262bio-ballistic “gene gun”technique, 597bioflavonoids,MLL and, 56biomarker studies, 619biomarkers of genetic instability,61biopsybone marrow, 21in AML, 399dry tap, 92, 473immunohistochemistry, 80
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in MDS, 434procedure, 22specimen preparation, 22
lung, 776biphenotypic leukemia, 36, 94,354, 403acute, 32, 36blasts, 96
birth marks, multiple, childhoodleukemia and, 52birth order, childhood leukemiaand, 55, 57birth weightchildhood leukemia and, 56in Fanconi anemia, 278
bisphosphonates, 479BK virus, 779blast cellsin acute leukemia, 21in ALL, age at diagnosis and,520in AML, 34, 204, 397diagnostic algorithm, 32
in AML with minimaldifferentiation, 403in AMKL-DS, 218L1-type, 28L2-type, 28levels, diagnosis and, 23lineage, 23myeloid differentiation in, 33proliferation, treatment failureand, 3re-accumulation, 3in TMD, 507
blast crisis, 11, 12in CML, 461lymphoid, 249myeloid, 249
blastic plasmacytoid dendriticcell neoplasms, 37, 88, 97–98immunophenotyping, 97
bleedingin ALL, 334in APL, 407disordersFPD/AML, 294in APL, 672in Noonan syndrome, 288therapy-related, in AML,411
as early complication, 672in essential thrombocythemia,469in polycythemia vera, 464, 465platelet count and, 6time, 796
blinatumomab, 568, 620, 623BLM actions, 285BLM gene, 285
blood components, 795support, 794–800
blood evaluation, 2blood findingschronic GVHD, 540in coagulopathy, 672at presentationin ALL, 336–337in AML, 398in APL, 403in CML, 460in essentialthrombocythemia, 469in JMML, 447, 448in MDS, 433in polycythemia vera, 465
in primary myelofibrosis, 473in TMD, 507
blood groups, identification of, 5blood transfusions, 5–6in ALL, 344early use, 3
blood viscosity, 675hyperleukocytosis and, 674
bloodstream, infections of, 773Bloom syndrome, 51, 284–286heritable predisposition, 277
Bodey, GP, neutrophils andinfection, 6body surface area, drug dosageand, 660, 662Boggs, DR, linked neutropeniaand infection, 6bonehealth, treatment effects on, 9lesionsin AMKL, 402in AML, 398
symptoms and signs in ALL,334, 337in adolescents, 520
bone marrowaspiration, 21analgesia, 819, 829in diagnosis of ALL, 338in diagnosis of AML, 399preparing for, 841procedure, 21–22therapy response analysis,410
biopsy, 21in AML, 399dry tap, 92, 473immunohistochemistry, 80in MDS, 434procedure, 22specimen preparation, 22
blasts, in AML, 33CD34+ cells, 605cellularity
in acute leukemia, 23in refractory cytopenia,434
dysplasia, 434evaluation, 2in severe congenitalneutropenia, 297
failurein dyskeratosis congenita,293in Fanconi anemia, 278, 280incidence, 431in MDS, 431–432
fibrosis, dry tap aspiration in,402first associated with leukemia,2flow cytometry, 99folic acid effect on, 4harvest, 532in essential thrombocythemia,470in JMML, 448in MDS, 433in polycythemia vera, 465in primary myelofibrosis, 471,473in systemic mastocytosis, 479leukemic, 2normal hematogones, 98relapsein ALL, 368reinduction therapy,370–376
response, 9sampling, 21–22sites, 22
transplantation, 7, 530–531in AML, 535–537in Burkittlymphoma/leukemia,390in CML, 11gonadal function and, 706growth after, 702–703
bone mineral density, therapyand, 709bortezomib, 620, 626bosutinib, 620, 624Boveri, T, work on genetics ofcancer, 2B-progenitor ALL, generearrangements, 174–175BRAC1 gene, 731BrazilAML in, 559Burkitt lymphoma/leukemiain, 558pediatric cancer managementin, 552, 553St. Jude InternationalOutreach Program in, 557
breakpoint fusion genes, as PCRtargets, 633–634breast cancer-resistance protein(BCRP), cellular drug resistanceand, 268breast-feeding, 57bronchoscopy, 776bronchus, compressed, 670BTG1, 261Burkitt leukemia, 28, 124MYC rearrangement in, 173therapy for, 3see also “mature” B cell ALL
Burkitt leukemia/lymphomatreatment, results of St. JudeInternational OutreachProgram, 557–559
Burkitt lymphoma, 28,383–390abdominal, CT scan, 387endemic vs. sporadic, 386endemic, of the jaw, 387gene rearrangements, 124histology, 384MYC rearrangement in, 173
Burkitt lymphoma/leukemiaendemic, sensitivity tochemotherapy, 558in sub-Saharan Africa, 558
busulfan-based myeloablative therapy,437, 459, 532gonadal damage, 706
cachexia in primarymyelofibrosis, 473cadherins, in CML, epigeneticsand, 250calicheamicin, MoAbconjugated, 624cancerfirst account, 1folic acid and, 4genetic basis of, 2, 3low priority in developingcountries, 550predisposition, 276–278in ataxia-telangiectasia, 281in Bloom syndrome, 285in Fanconi anemia, 278in neurofibromatosis type 1,287in Nijmegen breakagesyndrome, 283in Noonan syndrome, 288in Shwachman–Diamondsyndrome, 291
programs in developingcountries, 552
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cancer (cont.)riskin Diamond–Blackfananemia, 290in dyskeratosis congenita,293
secondarylow thiopurinemethyltransferase and, 313treatment-related, 723–755
in under-5 mortality rate, 551units, creating, 552
Cancer and Acute LeukemiaGroup B, 5cancer units, pediatric,establishing in developingcountries, 552–556cancer, incidence of childhood,geographic variation, 549cancer–testis antigens, 583, 583candidate gene sequencingin B-ALL, 182in relapsed ALL, 184
candidate gene studies, 58–59DNAmethylation, 245
candidiasischronic disseminated, 778systemic, 774, 782
carbenicillin, 6cardiac monitoring, potassiumand, 667cardiofaciocutaneous syndrome,451cardiomyopathy, anthracyclinesand, 707cardiotoxicity, 707–708of anthracyclines, 264, 316,423of chemotherapy, 10cyclophosphamide, 320Down syndrome and, 511drug formulation and, 621
care see nursing care, supportivecarecase–control studies, limitations,61caspase 9, 589, 604inducible (icasp9), 589, 604
cataracts, 707catheters see central venouscatheterscause-and-effect, betweenchemotherapy and secondaryleukemia, 744CBF see core-binding factorCBF genes, 205in FPD/AML, 294
see also AML genes, RUNXgenes
CBFB-MYH11 fusion, 35, 152,157, 206, 209, 401CBFβ–MYH11 fusion protein,209CBL gene, 455CBP(CREBBP) gene, 156CBS gene, 315, 511CD (cluster of differentiation)antigens, 73CD1, 73CD2, 73, 564, 567CD3, 73, 83, 564, 567CD3ε, 564CD4, 73, 564, 567CD4+/CD8+T-cells, 582in graft-versus-leukemiaeffect, 585
CD5, 73, 564, 567CD7, 73, 82, 564, 567CD8, 73CD9, 73CD10, 73, 564CD11, 73CD11a, 564CD13, 73, 83CD14, 73, 79CD15, 73, 78CD16, 73CD19, 73, 82, 400, 564, 568CD20, 73, 564, 568–569, 604,623CD21, 73CD22, 73, 82, 390, 564, 569–570,623CD23, 73, 564, 570CD235a, 75–80, 88–93CD24, 74CD25, 564, 570CD30, 74CD33, 74, 78, 83, 564, 570–571,624in AML immunotherapy, 425
CD34, 74, 84CD34+ cells, 605CD36, 74, 79CD40, 564, 571CD41, 74
CD42b, 74CD45, 74, 80–82, 564, 571CD52, 564, 571, 623CD56, 74, 400CD61, 74CD64, 74, 78CD65, 74, 79CD66, 564, 572CD66c, 74CD68, 74CD74, 564, 572CD79, 74, 117CD79(a/b), 82CD80, 564, 572CD83, 74CD117, 74, 83CD122, 564, 572CD123, 75, 564, 572CD131, 75CD135, 564, 572see also FLT3
CD179, 75CD247, 75CD261, 564, 572CD262, 564, 572CD303, 75CDKN2 genes, 249in ALL, 138, 182inactivation, 141polymorphisms, 59as susceptibility alleles, 298in T-ALL, 146
CEBP genes, 205, 224–225in AML, 149, 408in familial AML, 296leukemia predisposition and,294mutated, 35polymorphisms, 60, 60and risk of ALL, 185as susceptibility alleles, 298
CEBPA-dependent familialleukemiaheritable predisposition, 277
CEBPB-dependent familialAML, 296cell culture, in JMML, 449–450cell cycle arrest, 293cell death, decreased, treatmentfailure and, 3cell kill assays, 259
cell lysisrenal dysfunction and, inBurkitt lymphoma/leukemia,388uric acid levels and, 337
cell metabolism, drugs to target,412cell cycle progression, inhibitors,412cellular drug resistance, 268in ALL, 370in AML, 423assays, 259in CML, 462drugs to target, 627mechanisms, 259, 462anthracyclines, 264–265AraC, 266–267asparaginase, 262–263epipodophyllotoxins,265–266glucocorticoids, 259–262methotrexate, 268thiopurines, 267–268vinca alkaloids, 263–264
prognostic value, 257cellular origins of leukemia, 1cellulitis, 774perianal, 777
central airway compressionsyndrome, 661, 670, 671central nervous system (CNS)in AML, 399, 407infections, 778–779leukemia, 31, 337, 350–351,675–676in AML, 399on-therapy complicationsin, 682
relapse, 9, 30, 338, 367in AML, 421in Burkitt lymphoma/leukemia, 390myelopathy in, 684treatment, 372–373
status at diagnosis, 338therapyin Burkitt lymphoma/leukemia, 389sequelae, 706
tumors, as second cancers, 712central venous catheters, 680,802–803complications, 679, 803–804infections and, 773management algorithm, 680
centroblasts, 76centrocytes, 76cerebrospinal fluid (CSF)in AML, 399analysis, in ALL, 337–338
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in CNS infections, 778in relapsed ALL, 367
Chelyabinsk reactor accident, 53chemoprophylaxis, 785–786see also prophylaxis
chemotherapyin ALL, 342in AML, 10in Burkitt lymphoma/leukemia, 388in CNS relapse, 373combination, in AML, 411dentofacial effects, 708developing new agents, 620,616–627early, 6genotoxic, 56gonadal damage from, 705,709growth and, 701hepatotoxicity, 681hypersensitivity to, 278, 279,284, 287immunodeficiency andinfections, 772immunosuppression from, 7-induced hyperglycemia, 686in infants, 662in JMML, 457–458in MDS, 436MoAb-based conjugates, 563mucositis and, 679neurologic sequelae, 707,824–826pathophysiology, 826–827
postremission, 371–372in relapsed ALL, new drugs,375in relapsed AML, 423-related distress, 829–830responsiveness, 309secondary cancers after,725–728sensitivity toin Down syndrome, 511,513modifying, 598, 604–605
suboptimal, 310Chernobyl reactor accident, 53chest radiography findings, inALL, 337Childhood Cancer TARGETInitiative, 616childhood leukemiaschromosomal abnormalities,59classification, 49epidemiologic studies of, 49first case report, 1frequencies, 122genetic factors, 58–61immunogenotype, 122–126
incidence, 49geographic variation, 50in USA, 49
lineage identification, 80microsatellite instability and,61new agents, 620–627risk factorscongenital, 52environmental, 52–54genetic, 51lifestyle, 54–55studies of, 49, 51
risk stratification protocols,185temporal trends, 50
Children’s Cancer Group, 8Children’s Cancer Study Group,5, 8Children’s Oncology Group, 5, 8genome-wide associationstudies, 60risk classification, 345studies, 51
chimeric antigen receptors, 566,588, 601–603chloroacetate esterase stain, 24,27chloroma, 34, 37, 398, 663intraorbital, 677
chromatinepigenetics, 239glucocorticoids resistance and,262patterns in AML, 225regulation, genetic mutationsand, 246
chromosomal aberrationsin APL, 403clonal, 135in CML, 140in MDS, 431–433nomenclature, 135in PCR assays for MRD, 633TCR in T-ALL, 125
chromosomal abnormalities, 1689p, 142acute myelomonocyticleukemia, 90alkylating agents and, 736–739in ALL, 138numeric, 137–138structural, 138–140
in ALL-DS, 504–505in AML, 148, 149, 157–158,205, 206, 400in ataxia-telangiectasia, 282in B-ALL, 144–146, 206biphenotypic leukemia, 36in Bloom syndrome, 285in childhood leukemias, 51classification of ALL, 30
classification of leukemia by, 2conventional cytogeneticsand, 135diagnosis by, 9immunophenotype-specific,144, 145in familial AML, 296in JMML, 448monoblastic leukemias, 91in Nijmegen breakagesyndrome, 284in polycythemia vera, 466in primary myelofibrosis, 472as prognostic factors in ALL,342in T-ALL, 146–147target in PCR analysis, 633topoisomerase II poisons and,739–744treatment-related, 56
chromosomal fragilityin Bloom syndrome, 285in Fanconi anemia, 279
chromosomal rearrangementsin ALL, 169, 180AML-specific, 400in B-ALL, 170–174in DS TMD/AMKL, 508,509in T-ALL, 176–177
chromosomal translocations,332chromosomesderivative, 135dicentric, 135iso-, 135marker, 135
chronic eosinophilic leukemia,476chronic leukemiaclassification, 21diagnosis, 23
chronic lymphocytic leukemiaincidence and distribution,124initial classification, 2methylation studies, 245prevalence, 21
chronic lymphoproliferativedisorders, 23chronic myelogenous leukemiaBCR-ABL1 fusion in, 140epigenetics, 248–250genomic instability in, 249incidence, 431Ph in, 170
chronic myeloid leukemia(CML), 38, 460–463diagnosis, 38initial classification, 2prevalence, 21
chronic myelomonocyticleukemia and JMML, 38chronic myeloproliferativeneoplasms, leukocytosis in, 23chronic phase, 11chronic proliferative disorders,444–480chronic, use of term, 21cigarette smokingmaternal, during pregnancy,55, 59parental, and childhoodleukemia, 55, 56
citrate dextrose, 5C-KIT gene, 205cladribine, 621drug–drug interactions, 315
class effect of novel agents, 618class switching, ATM and, 282clinical course in JMML,455–456clinical featuresof ALL, 334of Burkittlymphoma/leukemia, 387of thrombosis, 677of TMD, 507
clinical presentationof ALL, 334–336of ALL, age at diagnosis and,520of AML, 397–399with minimaldifferentiation, 403
of CML, 460of essential thrombocythemia,469of JMML, 445–446leukostasis syndrome, 674MDS, 433of polycythemia vera, 464of primary myelofibrosis, 472of systemic mastocytosis, 478of treatment-related leukemiasand MDS, 747–750
clinical resistance to AraC, 314clinical trials, 8in ALL, 346AML, results, 405erythropoietin, 808of G-CSF in ALL, 806of gene therapy vectors, 606immunotherapy, 584, 584–587methodology, 4–5of MoAb agents, 566–573, 574non-randomized, 5patulin, 8phase I, 618phase II, 618
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clinical trials (cont.)phase III, 619randomized, 5Cognitive RemediationProgram, 828
system for new drugs, 617–619clofarabine, 375, 423, 620, 621clonal eosinophilia, 476clonal evolution, 3, 184, 636at relapse, 126
clonal evolution at relapse, 185clonal relationship analysis, 126clonalityassessment, 113IG/TCR rearrangementsand, 119–122by PCR, 119, 606, 636, 645by Southern blotting, 119
in JMML, 449studiesin ALL, 636, 645in essentialthrombocythemia, 468
clonespredominating, 2relapse, 184
Clostridium difficile, 777CML see chronic myeloidleukemiacluster of differentiation, 73 seeCD antigenscoagulation factors in freshfrozen plasma, 799coagulopathies, 661, 672–675fresh frozen plasma use in, 799on-therapy thrombosis,677–679
COBRA assay, 239, 240cognitive function, treatmenteffects on, 9Cognitive Remediation Program(CRP), 828cognitive-behavioralinterventionsfor pain, 819during procedures, 829
collaboration, 8, 9in trials, 5
colony-stimulating factors(CSFs), 784, 805–807combination epigenetic therapy,248, 250combination therapyAraC and fludarabine, 315drug ratio in, 621MoAb-based agents in, 574
combinatorial diversity, 115
commonerythroid–megakaryocyticprogenitor (CFU-EM), 79Common Toxicity Criteria(CTC), 618community educationin Burkitt lymphoma/leukemia, 558non-governmentalorganization and, 555
community participation incancer units in developingcountries, 555complementarity determiningregion 3 (CDR3), 116complement-dependentcytotoxicity, 563, 565complianceadolescents and, 845non-, indicators, 313
complications, 660in AML, 411central venous catheter,803–804in developing countries,554early, 661, 663–677disease factors, 660leukemia factors, 663patient factors, 660–663treatment factors, 660, 663
after HSCT, 537–541infectious, 772–786late, 701–713monitoring for, 846neurocognitive deficits,823–827treatment-related leukemiaas, 723
on-therapy, 661, 677–687in polycythemia vera, 467of stem cell harvesting, 532of treatment for ALL, 524–525
conditioning therapy for HSCTneurocognitive effects, 825secondary cancers and, 729
congenital anomaliesin Fanconi anemia, 278non-genetic, childhoodleukemia and, 51heart defectschildhood leukemia and, 52in Noonan syndrome, 288
congenital heart defect inFanconi anemia, 278congenital leukemias, 94congestive heart failure,anthracycline-induced, 316conjugated monoclonalantibodies, 563
consolidation therapy, 345in ALL, 522
continuation therapy, 9, 345, 845in ALL, 351–352
coping, family, 832copy number alterationsin ALL, 177, 214, 332in AML, 206, 214, 397diagnosis and relapse, 184in T-ALL, 183
copy-neutralloss-of-heterozygosity, 177cord blood, 7stem cell transplantation, 375,530, 531in JMML, 459
core-binding factor (CBF), 207CBFB-MYH11 fusion and, 152in FPD/AML, 295leukemias, 152, 206–210, 400,408secondary mutations,209–210
transcription complex, 169,206–208
corticosteroidsbone mineralization and, 709dose, 319for nausea and vomiting, 830neurocognitive issues and, 825osteonecrosis and, 685resistance, 320see also glucocorticoids
cost–benefit ratio of therapy, 8Costello syndrome, 451Cote d’lvoire, Burkittlymphoma/leukemia, 389cotrimoxazole, 7CpG island hypermethylation inJMML, 456CpG island methylatorphenotype, 239Craigie, D, linked leukemia towhite blood cells, 1cranial irradiation, 350–351in AML, 407in Burkittlymphoma/leukemia, 389in CNS relapse, 372–373CNS tumors and, 712dentofacial effects, 708growth and, 701, 703, 709for intracerebral myeloidtumors, 677leukoencephalopathy and, 684neurologic sequelae, 706–707,823–824pathophysiology, 826
thyroid function and, 702
craniofacial effects of therapy,708craniospinal irradiationin CNS relapse, 372–373growth and, 701thyroid function and, 702
CREB-binding protein(CREBBP)actions, 185mutations, 184
CREBBP genein B-progenitor ALL, 180in relapsed ALL, 184, 333
Creutzfeldt–Jakob disease, bloodtransfusions and, 802CRLF2 gene, 138in ALL, 175, 181, 332in B-progenitor ALL, 180overexpression, 142rearrangements, 39in B-progenitor ALL,174–175outcome and, 175
CRLF2, overproduction, 174,175Cryptococcus neoformans, 778cryptosporidiosis, 777CTchest, 776-guided transthoracic needleaspiration, 776
culturalattitudes, treatment ofpediatric cancer and, 550, 554,557change, and pediatric cancerunit, 556inequality, patterns of,550–552
cure, 7believed impossible, 9first, 3by HSCT, 7national differences, 9rates, 9early, 8in ALL, 332in AML, 10, 408, 411in APL, 412pediatric cancer, indeveloping countries,552
cutaneousinfections, 774–775lesions in AML, 398
CXCL12/CXCR4 signaling, 627cyclic neutropenia, 297cyclin-dependent kinaseinhibitors, 182, 620, 626
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encoding genes methylationstudies, 240–241
cyclins, overexpression, geneticabnormalities and, 142cyclophosphamide, 8in ALL, 521in AML, 10in Burkittlymphoma/leukemia, 388, 558early use, 4gonadal damage, 705, 706as myeloablative therapy, 459pharmacodynamics, kinetics,and genetics, 320–321urinary side effects, 710
CYP genes, 320polymorphisms, 59
cystitis, 779cytarabine (cytosine arabinoside[AraC])in ALL, 521in AML, 404–406, 423in APL, 407Burkitt lymphoma/leukemia,388cellular drug resistance, 266,268mechanisms, 266–267
clinical resistance, 314in CML, 461in AML-DS, 510, 511in hyperleukocytosis, 675in infant ALL, 353for intracerebral myeloidtumors, 677in JMML, 457liposomal, 620metabolism in AML, 408new formulations, 621drug–drug interactions, 315,319pharmacodynamics, kinetics,and genetics, 313–315resistance to, 258sensitivity toin ALL, 32, 342in AML subtypes, 35
in TMD, 507cytochemical analysis, 22–28cytochemical features indiagnosis, 91cytochemical staining, 23bone marrow, 22Burkitt/non-Burkittlymphoma, 383
cytochemistry in AML withminimal differentiation, 403cytochrome P450, 59, 732–733cytogenetic abnormalitiesalkylating agents and, 736–739in AML, 89, 409
in childhood leukemias, 51in “mature” B-ALL, 87in infant leukemia, 56in pro-B-ALL, 85topoisomerase II poisons and,739–744
cytogenetic ploidy analysis, 30cytogeneticsalkylating agent-inducedchanges in, 736–739of ALL-DS, 504–505of AML, 395of AML subgroups, 400of APL, 402of Burkittlymphoma/leukemia, 385conventional, 135in AML, 147, 151
of AML-DS, 508early, 2molecular, 135in cytogenetically normalAML, 220–225
nomenclature, 135of JMML, 449of MDS, 431, 433of polycythemia vera, 466of primary myelofibrosis, 472of treatment-related leukemia,744role in diagnosis of ALL, 185studies, in AML, 399subsets, event-free survivaland, 2topoisomerase IIpoisons-induced changes in,739–744utility, in AML, 151
cytokine receptor-like factor 2,174 see CRLF2cytologic features ofmyelodysplasia, 433cytomegalovirus,transfusion-associated, 800cytopenia, 23causes, 434in Fanconi anemia, 278in MDS, 37pre-ALL, 99refractory, of childhood, 38
cytoplasmic granules, 25, 28ALL blasts, 28APL, 33lymphoblasts, 23monoblasts, 23myeloblasts, 23promyelocytes, 23
cytoplasmic vacuoles, 25in blast cells in ALL, 28in Burkitt leukemia, 28lymphoblasts, 23monoblasts, 23
cytoreductive therapy, 471cytosine arabinoside, 10 seecytarabine (AraC)cytotoxicityassays, 257, 259differential staining ofcytotoxicity, 257fluorometric microculturecytotoxicity assay (FMCA),257methylthiazol–tetrazolium(MTT)-based, 257novel agents, 616
mechanisms of MoAb-basedtherapies, 565, 563–566
dacetuzumab, 564, 571daclizumab, 564, 570danusertib, 620DAPK1, 245dasatinib, 12, 250, 462, 620, 624activity, 425
daunorubicin, 10, 265cellular drug resistance, 264,265in AML, 404–406P-glycoprotein drug resistanceand, 423pharmacodynamics, kinetics,and genetics, 316
Dausset, J, HLA typing andmatching, 7dCK, 314dCK, 267DDC polymorphisms,60, 60deathfrom complications, 660leukostasis syndrome and,673in monoblastic leukemia, 675preparing for, 847
decitabine, 247–248, 620, 625in combination therapy, 248,250as hypomethylating agent,246trials, 244, 250
delayed intensification, 9deletion, definition, 135deletionsin ALL, 175, 179del(5q), 737–738del(7q), 736
demethylating agents, 620demographic risk factors, 54secondary cancers, 730
demographics of Fanconianemia, 278denaturing gradient gelelectrophoresis, 121dendritic cells, 582differentiation, 37expression profiles, 82immunotherapy with, 587leukemias, 37
dental abnormalities, aftertherapy, 708–709depression, 831developing countrieschildhood mortality in, 550establishing pediatric cancerunits, 552–554, 555–556pediatric cancer in, 550results of treatment in,556–559
developmental therapeutics,616–627dexamethasoneadrenal insufficiency and, 687in ALL-DS, 506in continuation treatment inALL, 352dose, 319drug–drug interactions, 319for nausea and vomiting, 830neurocognitive issues and,825osteonecrosis and, 524, 685,710pharmacodynamics, kinetics,and genetics, 319–320in remission inductiontherapy in ALL, 348in spinal cord edema, 676
dexrazoxane, 348, 708secondary leukemia and, 727
diabetes insipidus, 661diagnosisof ALL, 338–340of AML, 397–399of AML with minimaldifferentiation, 403Burkitt lymphoma/leukemia,387of chronic GVHD, 540of CML, 461delayed in poor regions, 554diagnosis and referral phasesof care, 840differentialeosinophilia, 477in essentialthrombocythemia, 470of JMML, 449of mastocytosis, 480of MDS, 434–435in polycythemia vera, 466
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diagnosis (cont.)in primary myelofibrosis,473
fungal infections, 783immunophenotyping panel,338JMML, 448of hypereosinophilicsyndrome, 476of mastocytosis, 478of myelopathy, 684of neurofibromatosis, 455of polycythemia vera, 464primary myelofibrosis, 473pulmonary disease, 776in relapsed AML, 421of TMD, 507of treatment-related leukemiasand MDS, 747–750urgency ofin APL, 152in myelopathy, 684
diagnostic criteriaby FAB category, 29in MDS, 434for systemic mastocytosis, 478
dialysis, 669Diamond, L, antifols work, 4Diamond–Blackfan anemia,290–291heritable predisposition, 277myeloid neoplasia and, 431
dic(9;20), 141in ALL, 141
dietand childhood leukemias, 55in hyperglycemia, 686maternal in pregnancy, 55AML and, 56, 739
neutropenic, 785in pancreatitis, 682during remission inductiontreatment, 349during treatment, 841in typhlitis, 681
differential staining ofcytotoxicity assay, 257differentiation antigens, 583, 583differentiation therapy indrug-resistant AML, 424DiGuglielmo disease, 91diphtheria immunotoxinconjugate, 567diploidy, 30in ALL, 137
discharge, distress and, 846disease-free survival, 5diseases of poverty, 550mortality, by country, 551
under-5 mortality rate and,550
disseminated intravascularcoagulation, 673in AML, 398in APL, 407, 411
distressparental, 832, 843procedural, interventions for,828–829psychological, 830
DNAcopy number alterationin ALL, 178
copy number alteration inALL, 177damage mechanisms, 744–747index, 30lesions in Fanconi anemia, 278methylationrepair, 278in ataxia-telangiectasia, 281ATM–MRN pathway, 282in Bloom syndrome, 284defective, 278in Down syndrome, 509drugs to target, 627gene therapy for, 281in Fanconi anemia, 279, 280in Nijmegen breakagesyndrome, 284
repair genes, 61in family cancer syndrome,730–732polymorphisms, 59, 731
replicationerrors, 278
synthesis, ara-CTP and, 313vaccines, 600–601
DNMT gene, 225mutations, 246, 249
Donne, A, observed high whiteblood cell counts, 1donorlymphocyte infusion in CML,463lymphocyte infusion, 535, 536,585in JMML, 460prophylactic, 585
matched family donor (MFD),459matched sibling donors(MSDs), 530matched unrelated donor(MUD), 459mismatched donor, 531, 532risk, 532screening donors, 531, 800assays, 801
selection, 528–530T-cells, unmanipulated, 585transplants, 531
dose-finding studies, 618molecularly targeted drugsand, 619multiagent regimens, 619
dose-limiting toxicity, 618defining, 619
dosingopioids, 816protocolssecondary cancers and, 729treatment-related leukemiaand, 727, 728
DOT1LinMLL leukemia, 173, 754recruitment, 213
Dounreay (UK), 53Down syndrome (DS), 503ALL in, 504–506CRLF2 in, 505
AMKL with (DS AMKL), 34,217–220, 508–513AML cure rate and, 10AraC metabolism in, 314-associated B-ALL, CRLF2rearrangements in, 174complications and, 663drug sensitivity in, 511incidence of leukemia, 9JAKmutations, 142leukemia risk, 93, 503methotrexate and, 352methotrexate toxicity in, 310MDS and, 38myeloid leukemia related to,34myeloid proliferationsassociated with, 38, 93–94and risk of ALL and AML,150, 503risk of leukemia, 51t(8;14)(q11.2;q32) in, 146transient myeloproliferativedisorder of, 34, 506–508
doxorubicincardiotoxicity, 707pharmacodynamics, kinetics,and genetics, 316
Drosophila, homology with, 168,171, 172MLL, 210RUNX, 206
Drug Development Group(DDG), 617drug resistancecorticosteroid, 320drugs to target, 412, 627genes, therapeutic use, 605primary, definition of, 462
drug–drug interactions, 349AraC in, 315asparaginase in, 319
glucocorticoids, 320synergistic, in AML, 423triazoles, 783vincristine, 320
drugscellular resistance, geneticsand, 257–269cytotoxicity assays seecytotoxicitydevelopment process,616–617current challenges, 619–620
effects, host polymorphismsand, 3metabolismin AML, 408genetic variations and, 732secondary leukemias and,732–734susceptibility to malignancyand, 397
molecularly targeted,624–627new formulation and delivery,621novel for childhood leukemia,620–627resistance 8in AML, 423treatment of relapse and,370
see also cellular drugresistanceresponsiveness, genetics and,257–269targeting apoptosis, 627
DS see Down syndromeduplication, definition, 135dyskeratosis congenita, 292–294,432heritable predisposition, 277myeloid neoplasia and, 431
dysplasiain AML, 33causes, 434multilineage, 32
dysplastic features, diagnosisand, 23
E2A-FB1 fusion, 140in ALL, 138
E2A–HLF actions, 172E2A-HLF fusion, 138, 140E2A–PBX1 actions, 172E2A-PBX1 fusion, 30, 139, 139E2A-ZNF384 fusion, 140ear, nose, and throat infections,776echinocandins, 6, 783
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educationcommunitynon-governmentalorganizations and, 555family, in developingcountries, 555ongoing in St. JudeInternational OutreachProgram, 556, 557parental, in developingcountries, 552patient and family, 841timing, 842
see also trainingeducational attainment, aftertherapy, 826Ehrlich, P, introducedhistochemical staining, 2, 12El SalvadorAHOPCA-1 protocol, 557pediatric cancer managementin, 554treatment of ALL in, 556–557treatment of AML in, 557–559treatment of Burkittleukemia/lymphoma in,557–559
El Salvador–Guatemala–Honduras II (SGH-II) study,556–557El Salvador I (ELS-I) protocol,556–557ELANE, 297electrolyte balancein ALL, 344in tumor lysis syndrome, 664
electromagnetic fields, 54and AML, 397
electroporation, 597, 600Elion, Gwork on acyclovir, 7work on purines, 4, 6work on trimethoprim, 7
embolization,catheter-associated, 804emergency situationsin Burkitt lymphoma/leukemia, 389central airway compression,670fever in neutropenia, 779hyponatremic seizures, 686monoblastic leukemia withhyperleukocytosis, 675pain, 816spinal cord compression, 676
emotional needs, 840empathy, role of, 5encephalitis, 778
endocrine abnormalities inFanconi anemia, 278endocrine complications,on-therapy, 685–687endocrine deficiency, chronicGVHD and, 539endocrine toxicity, late, 701–706endpoints, trialmolecularly targeted drugsand, 619Phase II, 618
enhancer core motif(TGT/cGGT), 206enterococcal infections, 6environmental risk factors,52–54genetic susceptibility and, 61
eosinophilia, 23ALL with, 32bone marrow in AML, 35classification, 475clonal, 476differential diagnosis, 477
eosinophils, in AML withinv(16), 401ephrin family, 242epidemiology, 49–61AML, 396–397Burkitt lymphoma/leukemia,385chronic myeloid leukemia, 460essential thrombocythemia,468–469hyperglycemia, 686JMML, 445–446of leukemia in Downsyndrome, 503MDS, 430–432molecular, 58osteonecrosis, 685of polycythemia vera, 464of primary myelofibrosis, 472treatment-related cancers,724–725trends in diagnostic practiceand, 49, 50
epigeneticchanges in leukemia, 2, 3regulation, drugs to target, 412therapy, 754in CML, 250combination, 248in JMML, 457in myeloid leukemia,246–248
epigeneticsof ALL, 239–245in AML, 245–248in CML, 248–250definition, 239
genetics and, 246glucocorticoid responsivenessand, 262of MDS, 245–248
epipodophyllotoxins, 265cellular drug resistancemechanisms, 265–266drug–drug interactions, 319pharmacodynamics, kinetics,and genetics, 316–317secondary AML and, 713secondary cancers and, 729,732sensitivity to, in AMLsubtypes, 35therapy-induced leukemiaand, 56, 404, 726–727
epratuzumab, 569Epstein–Barr virus, 386–387-associated genes, futuretherapy and, 390blood transfusions and, 802lymphoproliferative disorder,586–587HSCT and, 537
ERG, 219, 510deletions, 182
erythremic myelosis, 91erythroblasts, characteristics, 23,24erythrocytosis, in differentialdiagnosis of polycythemia vera,466erythroid maturation, 79and differentiation, 80
erythroid precursorsin AML, 34diagnostic algorithm, 32erythropoietin and, 33
erythroleukemia, 34, 91staining, 24
erythropoietin, 807clinical trials, 808levels in erythrocytosis, 466in primary myelofibrosis, 474
esophagitis, 777essential thrombocythemia,468–471and AML, 470and myelofibrosis, 470WHO diagnostic criteria for,468
estimated risk of relapse, 9ethics of randomization, 5ethnic and racial differencesin ALL, 334, 339, 342in essential thrombocythemia,468in incidence of AML, 396
in leukemic subtypes, 340in osteonecrosis, 685secondary cancers and, 730
etiology, 49–61infant leukemia, 56–58treatment-related leukemia,744–747
ETO, 207etoposide, 265, 388in AML, 404–406cellular drug resistance, 265drug–drug interactions, 319in JMML, 457leukemogenicity, 56resistance to, 258secondary cancers and, 732treatment-related leukemiaand, 726
ETS2 protein, 509ETV6-RUNX1 fusion, 333in ALL, 177, 340in B-ALL, 169–170
ETV6–RUNX1, role inleukemogenesis, 170European Medicines EvaluationAgency (EMEA), 617event-free survival, 5in ALL, 367adolescents, 523age at diagnosis and, 520,523
in ALL-DS, 505in AML, 149, 153, 204, 410in APL, 11, 215B-lineage leukemia, 321in DS AML, 510HSCT andin ALL, 533–535in AML, 535–536
improvement in, 9in JMML, 456, 459methotrexate plasmaconcentration and, 310relapse category and, 369in relapsed ALL, 368, 369risk group and, in relapsedALL, 369, 370variability, 2
EVI1 overexpression, 155evolution, leukemia, 11exchange transfusionin ALL, 344in AML, 411for hyperleukocytosis, 675
expansion of T-cells, 585, 588expression profilesB-ALL, 85B-lineage, 72–77Burkitt lymphoma, 384CDmarker, 72
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expression profiles (cont.)myelocytic and monocyticlineages, 78–79T-lineage, 78
extramedullarydisease, 34, 676hematopoiesis, 467, 472tests for, 473treatment, 474
leukemic tumors, 663manifestationsin AML with inv(16), 400in relapsed ALL, 367
myeloid tumors, 398relapse, in AML, 421
extravasation, 804
FAB see French–American–BritishFaces Pain Scale, 814, 815facilities, in developingcountries, 554faggot cells, 402familial AML, 397CEBPβ-dependent, 294–296
familial MDS, 432familial monosomy 7, 51familial Noonan syndrome, 454familial patterns, 52familial platelet disorder (FPD),294heritable predisposition, 277with propensity for AML(FDP/AML), 294–295
familial thrombocytopenia,myeloid neoplasia and, 431familyadjustment, 832, 843, 845in relapse, 847
cancer syndrome genemutations, 730–731education, 552in developing countries, 555
support of, 5FANC genes, 279, 280FANCD2–FANCI complex, 279,280Fanconi anemia, 51, 278–281complications and, 663heritable predisposition, 277myeloid leukemia in, 430, 431myeloid neoplasia and, 431
Farber, S, 12antifols work, 4total care, 7
farnesyltransferase inhibitors,458, 620, 624
fatigue, 844FBXW7, 183fentanyl, 819transdermal, 816
fetal exposure to drugs, 333fetal loss and childhoodleukemia, 55feverin ALL, 334, 344in AML, 411definition, 779management guidelines,781and neutropenia, 779–781priority admission for, 842
FHIT, 267FIP1L1-PDGFRA fusion, ineosinophilic disorders, 476–477FISH see fluorescence in situhybridizationFLACC pain score, 814,815flavopiridol, 620, 626flora, microbiologic, changes in,and infection, 772flow cytometry, 2, 9, 80, 639acute leukemias, 81, 94–97in AML, 32anaplastic large celllymphoma, 102assay of MRD, 410B-cell maturation, 99for detection of relapse inALL, 368in diagnosisof ALL, 338of AML, 88, 90of APL, 89
DNA index, 30future directions, 102hepatosplenic T-celllymphoma, 101limitations, 642lineage assessment, 23in MRDmonitoring, 641,638–642, 646, 645–649normal pediatric bonemarrow, 80permeabilization in, 83
FLT3 223, 222–224in AMKL, 220
FLT3 gene, 205, 223activating mutations, 223in ALL, 138, 142, 173, 332in AML, 150, 152, 408–409in APL, 152duplication, 9internal tandem duplications(ITDs), 409
mutations, 30, 32mutation affecting tyrosinekinase domain, 223, 224
fluconazole, 782fludarabine, 423, 437drug–drug interactions, 315as myeloablative therapy, 459
fluidbalance in ALL, 344overload, transfusion and, 794
fluorescence in situhybridization (FISH), 136in AML, 149, 151, 152analysis, 139, 141, 150interphase, identifieschromosomal changes, 2MLL and, 153MLL probe, 154pediatric ALL, 30role in diagnosis of ALL, 185with TEL-AML1 probe, 144
fluorometric microculturecytotoxicity assay, 257foamyvirus, 594folatedeficiency effects, 4depletionin Down syndrome, 311neurocognitive effects, 827
effects, 4maternal supplementation inpregnancy, 54, 58pathwaygenetic polymorphisms, 58,311methotrexate and, 309
Food and Drug Administration(FDA), 617formulations, drug, 619new, 621
forodesine, 375, 622foundations seenon-governmental organizationsFowler’s solution, 3“FPC” prognostic scoring systemin MDS, 436FPD see familial platelet disorderFrench–American–British (FAB)classificationALL, 28–29AML, 23, 32, 204algorithm, 32
MDS, 37, 429fresh frozen plasma, 799Fuller, H, first diagnosis ofleukemia, 1, 11funding
for cancer units in developingcountries, 555, 556for patients, in Brazil, 553
fungal infections, 6, 775,781–783after HSCT, 537ear, nose, and throat, 776myeloablative therapy and,527pre-existing, 663pulmonary, 775
gabapentin, 817galiximab, 564, 572gammaretroviral vectors, 593gamma-secretase inhibitors, 183,620ganciclovir, 604gastrointestinalcomplicationsinfections, 776–778on-therapy, 679–682
features of JMML, 446GATA1, 93, 205, 218, 512in AML, 151in DS AMKL, 217, 218, 508,509, 511and trisomy 21, 219
GATA1 proteins, 218–219, 508,509, 511G-CSF, 805–807clinical trials, 806in neutrophil recovery, 411pre-leukapheresis, 800prophylactic, in ALL, 345secondary leukemia and, 727in severe congenitalneutropenia, 297therapy, MDS and, 431
GCSF gene, 260G-CSF receptors, in severecongenital neutropenia, 297gemcitabine, 423gemtuzumab ozogamicin, 10,404, 564, 565, 571, 620, 624in AML, 412in relapsed AML, 425side effects, 573
gender differences in side effects,824gene expression profilein AML with minimaldifferentiation, 403MLL-rearranged ALL, 173
gene expression profiling, 136in ALL, 39, 734in AML, 204future trends in diagnosis, 38
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in JMML, 456leukemia, 3MLL PTD, 214pediatric ALL, 39prognostic implications, 39
gene marking, 605–606gene silencing, 599gene therapyas cause of leukemia, 606–607Epstein–Barr virus genes and,390in Fanconi anemia, 280host modification, 601–605protocols, 607tumor cell modification,597–601vectors, 594, 593–597
gene transfer, 589, 593–607gene, suicide, 589, 604genesaberrantly expressed, as PCRtargets, 634breakpoint fusion, as PCRtargets, 633–634mutations, in family cancersyndrome, 730–731rearrangementsand cellular drug resistance,257–259cross-lineage, 123, 125pediatric ALL, 30processes, 113–119in T-ALL, 145, 146in utero, 144, 509
GeneScan analysis, 121, 122, 123sensitivity, 128
genetic abnormalitiesin advanced CML, 249in ALL, risk of relapse and,342in AML, 88, 397, 409in AML subtypes, 33, 35, 399acquired, 51, 52in Burkitt lymphoma/leukemia, 385in FDP/AML, 295inherited, 51, 52leukemia classification by, 30in precursor T-ALL, 32pro-B-ALL, 85submicroscopic moleculargenetics in, 136
genetic abnormalitiesin DS AMKL, 220in TMD, 220
genetic alterationsin ALL, 180, 181, 182in B-progenitor ALL, 170and cellular drug resistance,257–259DNAmethylation and, 246
DNA repair errors and, 278in JMML, 450–455in leukemia, 2, 3in leukemic blast cells, 332in T-ALL, 170secondary, 184
genetic classificationof ALL, 30–32
genetic classification of ALL,340–342genetic instabilityin cancer, 2MDS and, 432
genetic lesions in AML, 397genetic mechanisms of heritablepredisposition, 277genetic predispositionin cancer, 276to secondary leukemias,730–735for treatment-relatedleukemia, 730
genetic susceptibility, 58–61environmental risks and, 61
genetic syndromes, 51geneticsof cancer, early work, 2cellular drug resistance and,257–269in CML, 460epigenetics and, 246of relapse, in ALL, 184–185role of in acute leukemias, 52
genome-wideassociation studies, 60, 59–61in ALL, 177of susceptibility alleles, 298,735
methylation profile study inchronic lymphocyticleukemia, 245profiling, 177in ALL, 173in AML, 204in B-ALL, 178in relapsed ALL, 184in T-ALL, 183
sequencingin ALL, 182cytogenetically normalAML, 221future trends, 186
genomic instability, 61in CML, 249
gentamicin, 6germline mutations, 276in Diamond–Blackfan anemia,290in dyskeratosis congenita, 294in familial AML, 296
in family cancer syndrome,730in FPD/AML, 295heritable conditionsdiagnosed by, 279in JMML and Noonansyndrome, 446, 450–452, 454,455leukemia predisposition and,278in NBN, 284in NF1, 286, 451in RAS–MAPK pathway, 286,450, 452
germline polymorphisms inleukemogenesis, 333Gloor, W, first cure by, 3glucocorticoid receptors, 259,260cellular drug resistance and,259–261complex with glucocorticoidGCR genes
glucocorticoids, 259adrenocortical insufficiencyand, 687bone mineralization and, 709cellular drug resistance, 268mechanisms, 259–262
complex with glucocorticoidreceptor, 259, 260in continuation treatment inALL, 352hyperglycemia and, 686neurocognitive effects, 827osteonecrosis and, 710pharmacodynamics, kinetics,and genetics, 319–320in remission inductiontherapy in ALL, 348resistance to, 257, 258, 259,370MLL rearrangements and,257
thrombosis and, 679glutathione S-transferasesanthracyclines and, 265oxazaphosphorines and, 320
glycolysis, glucocorticoidresistance and, 261glycosyl phosphatidylinositol, 79GM-CSF, 411, 805hypersensitivity, in JMML, 449in neutrophil recovery, 411receptor-targeted therapy, 458
Goldin, A, multiagent therapy, 8gonadal function, 705–706after transplant, 706
graft engineering, ex vivo,533
graft-versus-host disease(GVHD), 7acute, 538–539grading, 539
CD13 and, 83chronic, 539–541grading, 540
in CML, 11in Fanconi anemia, 280in JMML, 459neurocognitive effects, 825in relapsed AML, 424source of stem cells and,530–531suicide genes in, 604transfusions and, 796
graft-versus-leukemia effect,412, 425AML and, 423cellular mechanism, 584in JMML, 459KIR mismatching and, 529reduced-intensityconditioning and, 532suicide genes and, 604
graft-versus-lymphoma effect,390Gram-negative bacteria, 6, 773in catheter infections, 804in typhlitis, 777in urinary tract infections, 779
Gram-positive bacteria, 6, 773resistant, 6
granular ALL, 28granulocyte colony-stimulatingfactor see G-CSFgranulocyte transfusion, 784,799granulocyte–macrophagecolony-stimulating factor seeGM-CSFgranulocytes, 78granulocytic component inAML, 33, 34granulocytic sarcoma, 34, 398diagnosis, 28
grief, 840, 848growthafter therapy, 701–702, 703chemotherapy and, 701control, PML and, 215factor, use in HSCT, 605failure, 7hormonecranial irradiation and,701deficiency, after total bodyirradiation, 703methotrexate and, 701therapy, 703
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GST polymorphisms, 59, 408Guatemala, treatment of ALL in,556guidelinesfor management of febrileneutropenic patients, 779for management of patientswith persistent fever, 781regarding the duration ofantibiotic, 782supportive care, 541for use of blood products, atSt. Jude Children’s ResearchHospital, 802for use of high-dosemethotrexate, 559WHO, on pain therapy, 815
GVDH see graft-versus-hostdisease
HAGE, 250harvestingof bone marrow, 532of PBSC, 532
HAX1, 297healthbehaviors, in survivors, 846indicators in under-5mortality rate, 550inequality, measures of, 550insurance for survivors, 846prioritiesin developing countries,550, 555twinning programs and, 555
statistics in developingcountries, 550
hematogonesexpansion, 98immunophenotype, 98
hematologic malignanciesin ataxia-telangiectasia,281–283in Bloom syndrome, 284–286C/EBPα-dependent familialAML, 296Diamond–Blackfan anemia,290–291dyskeratosis congenita,292–294in Fanconi anemia, 278–281FPD/AML, 294–295genetic mechanisms, 276heritable predisposition,276–298in Nijmegen breakagesyndrome, 283–284Noonan and Noonan-likesyndromes, 288–289severe congenital neutropenia,296–298
Shwachman–Diamondsyndrome, 291–292
hematopoiesisCD117 in, 83CD33 in, 83extramedullary, 467, 472tests for, 473treatment, 474
fetal trisomy 21 and, 219MLL rearrangements and, 173MLL in, 210role of CBF, 206–208RUNXmutations and, 208,209RUNX–CBF complex in, 295
hematopoietic cells, leukemictranformation, 332hematopoietic differentiationprograms, 213hematopoietic failure inleukemia predispositionsyndromes, 278hematopoietic growth factors,805–809hematopoietic mosaicism inFanconi anemia, 279hematopoietic stem celltransplantation (HSCT), 7,527–541in ALL, MRDmonitoring in,645in AML, 406–407in Burkittlymphoma/leukemia, 390in CML, 463in Diamond–Blackfan anemia,291in dyskeratosis congenita, 294in Fanconi anemia, 280in FPD/AML, 295growth after, 702–703indications for, 534in JMML, 288, 456, 458–460indications for, 458
in MDS, 437neurocognitive issues and, 825in Nijmegen breakagesyndrome, 284pregnancy after, 706in primary myelofibrosis, 475relapse aftergene marking in, 605suicide genes for, 604
in relapsed ALL, 374–375in relapsed AML, 423–424second, in JMML, 460secondary cancers after,729–730in severe congenitalneutropenia, 297see also donors for HSCT
hematopoietic stem cells
CBF and, 210MLL and, 210
hematopoietic system, generearrangements and, 176hematoxylin & eosin stain, 22hemocytic lymphohistiocytosis,449hemoglobin concentration, 794hemophagocytosis, 449hemorrhagein APL, 672as early complication, 672platelet count and, 796platelet transfusion reducesdeath from, 6
heparin, 671, 672, 678, 679in venous catheter, 804
hepatic complicationsafter HSCT, 538pre-existing, 663of therapy, 710–711
hepatic symptoms and signs inALL, 334, 337hepatitis, 662, 710, 777transfusion-associated, 800,800, 801
hepatomegalyin JMML, 446in primary myelofibrosis, 473
hepatosplenic T-cell lymphoma,101leukemic phase, 101
hepatotoxicity, 681hereditary thrombocythemia,470heritablecancer risk, 276predispositionhematologic malignancies,276–298to leukemias, geneticmechanisms, 277
herpes simplex virus (HSV), 775,777type 1 (HSV-1), 594HSV-tk suicide gene, 604
herpesvirus, 9as gene therapy vector, 597
heteroduplex analysis, 121, 122,124, 127diagnosis of relapse vs.secondary, 127IGK-Kde rearrangements, 123sensitivity, 128
HispanicsALL in, 342APL in, 49, 396
CRLF2 alteration in, 333secondary cancers in, 730
histamine receptor antagonists,479histochemical staining of bonemarrow, 22histology of Burkitt lymphoma,383, 384histone code alterations, 245, 249histone deacetylase, 625inhibitors, 245, 248, 249, 475,620, 625, 753, 754in combination therapy, 248
histone H3 lysine methylation,79histone methyltransferases, 626histone modifications, 225Hitchings, Gwork on purines, 4, 6work on trimethoprim, 7
HLAencoding genes, 528genomic map, 528-matchedfamily donor, for HSCT, 437unrelated donor, for HSCT,437
matching in HSCT, 528, 529HLA-DR, 564, 573Hodgkin disease, nitrogenmustard in, 3Honduras, treatment of ALL in,556honestyimportance of, 840in palliative care, 847
hopeimportance of, 840in relapse, 847
hopelessness, parental distressand, 843, 845horseradish peroxidase, 80, 82hospital facilities, in developingcountries, 554outcome and, 555, 556, 558
host modification by genetherapy, 601–605HOX genes, 32, 176, 213in ALL, 142expression profiling, 39overexpression, 213in precursor T-ALL, 32rearrangements, 171, 176regulation, 210, 213repression of, 217in T-ALL, 125, 126, 146upregulation, 213
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inMLL-rearranged ALL,173
HOX transcription factorsrearrangements and, 176roles, 171
HOXA9, 754HPRTmutations as biomarkers,61Hsp90 inhibitors, 620, 626HSCT see hematopoietic stemcell transplantationHughes, WT, work onPneumocystis pneumonia, 7human immunodeficiencyviruses (HIV) and bloodtransfusions, 801human leukocyte antigen (HLA)matching in HSCT, 528sibling compatibility, 7typing and matching, 7
human T-cell leukemia virus-1blood transfusions and, 800,801associatedleukemia/lymphoma, 100
humor, 840Hungerford, DA, Philadelphiachromosome, 11hydrocarbons, maternalexposure, 54hydrocortisone, 687hydroxyurea, 471, 675in polycythemia vera, 467in primary myelofibrosis, 474
hygieneeducation on, 842hand, importance of, 785
hypercalcemia, 661, 670hypercellularity, 23MDS, 37
hypercoagulability, 673hyperdiploidy, 30in ALL, 51, 137, 185, 340CD45 and, 81precursor B-ALL with, 30
hypereosinophilia syndrome,336, 475–477hyperglycemia, 661, 686–687hyperhydration, 667hyperkalemia, 666, 667, 669spurious, 674
hyperleukocytosis, 675hypermethylation in JMML, 456hypermethylator phenotype, 245
in ALL, 239in AML, 246
hyperphosphatemia, 666, 667,669spurious, 674
hypersensitivity to asparaginase,317–318hyperuricemia, 665, 667, 669hyperuricosuria, 6hyperviscosity, 673, 674hypnosis, during procedures, 828hypocalcemia, 666, 669, 669in tumor lysis syndrome, 666
hypodiploidy, 30, 533in ALL, 137, 340
hypoglycemia, 661, 687hypomethylating agents,244–245, 246–248, 250in combination therapy, 248in JMML, 457in MDS, 436, 753
hyponatremia, 686hypoplastic bone marrow, 99hypothyroidism, radiationtherapy and, 702hyroxdyurea, 11
iAMP21, 138, 144, 175icasp9, 589, 604ICH S9, safety guidance, 619idarubicin vs. daunorubicin, 404IDH genes, 222, 246idiopathic pneumoniasyndrome, 538ifosfamide, 388pharmacodynamics, kinetics,and genetics, 320–321
IG genes, 113complexes, 114rearrangements, 116in B-ALL, 123, 145,144–146, 173–174in B-progenitor ALL,174–175cross-lineage, 125during lymphoiddifferentiation, 116–119PCR analysis, 120junctional regions in, 635,637, 634–638secondary, 116, 118somatic hypermutations in,116
IG/TCR genescombinatorial diversity, 115rearrangements, 114
aberrant and oncogenic,125–126in ALL, 123–124in AML, 125antigen specificity and, 113,115–116clonality detection basedon, 119–122, 126–128diagnostic applications, 126during lymphoiddifferentiation, 116–119frequencies, 124in lymphoid leukemia, 113,126processes, 113–119
secondary rearrangements,116, 117
IGH@ gene in ALL, 145, 175IGH@-CRLF2 fusion, 174IGH@-ID4 fusion, 146IGH@-MYC in B-ALL,144–146IGH@-PAX5 fusion, 145IgM B-cell receptor, 76, 82IKZF genes, 138, 221in ALL, 182alterations, in ALL, 178in precursor B-ALL, 332deletions, 140, 171, 175polymorphisms, 60, 60, 321and risk of ALL, 185, 333susceptibility allele, 298
imatinib, 9, 11, 171, 620action, 250, 425in ALL, 140, 186, 354, 533in chronic eosinophilicleukemia, 476clinical trials, 461in CML, 250, 461–462large granular lymphocytesand, 100in polycythemia vera, 468resistance to, 477
immune competence, B-cellmaturation, 76immune response, appropriate,delayed exposure to infectionand, 57immune systemimpairment, infections and,772modification, gene therapy for,601recognition of tumor cells,582–584
immune-mediated cytotoxicity,563immunization, 786anti-tumor, 600see also vaccination
immunoassays for fungalinfections, 776immunoblotting, in diagnosis ofataxia-telangiectasia, 282immunodeficiencyin ataxia-telangiectasia, 281,283in Bloom syndrome, 285prolonged, after HSCT, 539and risk of Burkittlymphoma/leukemia, 386in survivors, 711
immunofluorescent microscopy,80immunogenicity of MoAbs,573immunogenotype, childhoodleukemias, 122–126immunoglobulinsB-lineage and, 82encoding genesin Burkitt lymphoma/leukemia, 385
see also IG genesin JMML, 448moleculesjunctional diversity,116repertoire, 115, 115–116structure, 113
surface membrane-bound(SmIg), 113
immunohistochemical assaysbone marrow, 22, 80procedures, 82
immunophenotypesin AML, MRD assays and,410, 640, 648AML with minimaldifferentiation, 403AML with t(8;21), 400in APL, 403Burkitt lymphoma/leukemia,384, 383–385leukemia, 2for MRD studies, 639multilineage lymphomyeloid,213in relapsed ALL, 369
immunophenotypicclassification, 29–30immunophenotyping, 78of ALL, 338–340of AML, 397B-ALL, 85Burkitt lymphoma, 383future directions, 102methods, 80–84MRD assays base on, 638panel, 80, 82in ALL, 338
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immunosuppressionagentsin chronic GVHD, 540in GVHD prophylaxis, 539
chemotherapy-induced, 7Pneumocystis pneumonia and,7pre-HSCT, 532
immunosuppressive therapy, inMDS, 436immunotherapy, 582–589adjuvant, 783–784in AML, 412, 425modulating therapies, 783
immunotoxins, 390, 566anti-CD19, 568
incidenceadrenocortical insufficiency,687ALL, age at diagnosis and, 520AML, 396, 396APL, 396ataxia-telangiectasia, 281Burkitt lymphoma/leukemia,386childhood cancer, geographicvariation, 549CNS leukemia, 676coagulopathy, 672Diamond–Blackfan anemia,290early complications, 660essential thrombocythemia,468ethnic and racial differencesin Bloom syndrome, 284in Fanconi anemia, 278in Nijmegen breakagesyndrome, 283
GVHD, 459hematologic malignancies,431hyperleukocytosis, 673JMML, 430, 445late complications of GVHD,539leukoencephalopathy, 684leukostasis syndrome, 673mastocytosis, 477MDS, 430mucositis, 679Noonan syndrome, 288osteonecrosis, 685Ph+ CML, 460polycythemia vera, 464post-transfusion hepatitis C,801primary myelofibrosis, 472relapse in AML, 408secondary cancers, 712,724–725Shwachman–Diamondsyndrome, 291thrombotic complications, 677
incidence trends in leukemia,49–50income, family, access to careand, 551infant ALL, 353infantschemotherapy in, 662leukemia in, 56–57etiology, 56–58
infection, 772–786acute leukemia and, 6after HSCT, 537ALL and, 57in ALL, 334, 344in AML, 411in ataxia-telangiectasia, 281catheter-related, 6, 803–804as cause of death, 6childhood leukemias and, 58in chronic GVHD, 540exposure pattern, 57fungal, 6hepatitis C, 710myeloablative therapy and,527pre-existing, 663prevention, 842nursing care and, 841
secondary, 6in severe congenitalneutropenia, 296, 297susceptibility to, in Downsyndrome, 506therapy-related, in ALL, 349,353transfusion-associated, 800,800–802viral, 7imitates JMML, 449
infectious diseases, mortalityfrom, in developing countries,550infertilityafter HSCT, 539alkylating agents and, 705
influenza, 785informationhealthy lifestyle, 846need for, 840, 842, 843in palliative care, 848in relapse, 847
patient/parent handbook, 844receptiveness to, 840reinforcing, 845
inherited bone marrow failure inMDS, 432inherited genetic variation, riskof ALL and, 185inosine triphosphatepyrophosphatasepolymorphisms, 3
inotuzumab ozogamicin, 9, 620,623insecticide exposure, 59integrin inhibitors, 620intensification therapy, 345in ALL, 349–350, 522in AML, 406MRD detection as criterion,649
intent to treat, 5interferon-α, 11in CML, 12, 461in JMML, 457in polycythemia vera, 467in primary myelofibrosis, 474
interferon-gamma, recombinanthuman, 784interindividual variability, 321in drug response, 343
interleukins, 8091β , in JMML, 4492, 6032 receptor, 5643 receptor, 57210, in JMML, 44915, 321modified T-cells, 603
SNPs in, 321International OutreachProgram, St Jude Children’sResearch Hospital, 555results for ALL, 556–557results for AML, 557–559results for Burkittlymphoma/leukemia, 557–559
International Prognostic ScoringSystem for MDS, 436, 436International Randomized Studyof Interferon and STI571 (IRIS),12intracellular NOTCH1 protein(ICN1), 183intrachromosomal amplificationof chromosome 21 (iAMP21),144, 175intracranial myeloid tumors, 676intrathecal therapyin AML, 407in Burkitt lymphoma/leukemia, 389CNS status and, 338leukoencephalopathy and, 684MoAb-based, 574sequelae, 706triple, 350in relapsed ALL, 371
inversiondefinition, 135inv(3)/t(3;3), 155
inv(7)(p14q34), 125inv(14)(q11q32), 125inv(16), 152, 206, 400inv(16) cytogeneticabnormalities, 9inv(16)(p13;q22), 35, 90, 742,749inv(19)(p13.3q13.4), 140
ionizing radiationhypersensitivity to, 278, 279,287paternal exposure,preconceptually, 53X-raysin utero, 53postnatal, 53
IQ score, neurotoxicity and,823–825iron overload, 796irradiationof blood products, 796in CNS relapse, 372–373cranialCNS tumors and, 712growth and, 701, 709leukoencephalopathy and,684neurologic sequelae,706–707
craniospinal, 9growth and, 701
early use, 3immunodeficiency andinfection, 772neuraxis, 9regimen for HSCT, 424resistance to, nitrogenmustard used in, 3in testicular relapse, 373thyroid function and, 702total body, 7, 532
isochromosomes, 135isocitrate dehydrogenase 1, 222isolation from infection,784–785isotype-dependent C exons,113
JAK, 22JAK2 inhibitors, 475
JAK genes, 205in ALL, 138in DS AMKL, 219in essential thrombocythemia,468mutations, 142CRLF2 alterations and, 174,181
in polycythemia vera, 464in primary myelofibrosis, 472in T-ALL, 147
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JMML see juvenilemyelomonocytic leukemiaJamshidi needle, 22Janus kinase (JAK) tyrosinephosphatase, 81in AMKL, 220
Japan, leukemia incidence, 53Japanese Childhood AMLCooperative Study AML99, 400jaundice, 662junctional diversity, 116junctional region-specificoligonucleotide probes, 128juvenile myelomonocyticleukemia (JMML), 38, 429,445–460characteristics, 23, 445, 446,447in neurofibromatosis, 287, 446in Noonan syndrome, 289incidence, 431
kappa-deleting element (Kde),114, 117rearrangements, 118, 123, 124
Karon, M, advocatedtruthfulness, 7karyotypealterations, in ALL, 168complex, 158leukemic cells, 30
karyotyping, value in ALL, 340killer cell immunoglobulin-likereceptor (KIR)genomic map, 528mismatching, 528, 541
KIR genes, 529KIT genes, 400in AML, 152, 408in mastocytosis, 477
Knudson’s “two-hit” model, 453Kostmanngranulocytic leukemia, 51syndrome, 296heritable predisposition,277
Krivit, W, Down syndromework, 9
laboratory findingsin ALL, 334, 336–338in AML, 398in Burkittlymphoma/leukemia, 388in coagulopathy, 672in essential thrombocythemia,470
in JMML, 445–448leukostasis syndrome, 674in polycythemia vera, 465–466in primary myelofibrosis, 473
lactate dehydrogenase, leukemiccell burden and, 337lactoferrin, as marker ofmaturation, 79Landsteiner, K, identification ofblood groups, 5large granular lymphocyteleukemia, 100immunophenotype, 100
large granular lymphocytes, 100latency of treatment-relatedleukemias and MDS, 724,747–750lead, parental exposure, 54Leder stain, 22Legius syndrome, 452lenalidomide, 753lentiviral vectors, 594lentivirus, 594LEOPARD syndrome, 450lestaurtinib, 620leucovorin rescue, 310, 352leukapheresisin ALL, 344in AML, 411for hyperleukocytosis, 675results, 345
leukemia researchcandidate gene approach, 58future trends, 61genome-wide associationstudies, 59–61SNPs, 58–59
leukemia stem cells in AML, 397leukemia(s)in ataxia-telangiectasia, 281in Bloom syndrome, 285cellular origins, 1chromosomal abnormalities, 2classification, 2, 9, 21, 22,28–39, 72future trends, 39modern approach, 21, 28
coining of term, 1congenital, 94CBF, 10development of, hostpolymorphisms and, 3diagnosis, 21, 22, 72in Down syndrome, 503–513in dyskeratosis congenita, 293epigenetic changes, 3establishing diagnosis, 23
familial platelet disorder and,294, 295in Fanconi anemia, 279first treatments, 3frequency, by country, 549gene expression profiles, 3gene therapy-induced,606–607genetic changes, 3identification, flow cytometryfor, 80immunophenotype, 2mixed lineage, 37Moabbased therapeutics in,564as model for drugdevelopment, 616in neurofibromatosis, 287in Nijmegen breakagesyndrome, 284pathobiology, 39pathogenesis, 332predisposition syndromes, 278refractory, 11research, future trends, 186in severe congenitalneutropenia, 297in Shwachman–Diamondsyndrome, 291subtypes, 3susceptibility alleleinheritance and, 298therapy-related, 723–755management algorithm, 750
undifferentiated, 128leukemia-initiating cells inAML, 397leukemic blasts, 81, 96in ALL, 339in AML, 397in APL, 402chromosomal changes, 2, 332
leukemic cellsaccess to CNS, 676burden, 339lactate dehydrogenase and,337reducing, 344, 411
cytogenetics in AML, 147karyotypes, 30in leukostasis, 674lysis, 337
leukemic growth, folic acid and,4leukemic infiltration of otherorgans, 663leukemic masses, 663leukemic transformation, 332leukemogenesisin ALL, 177, 333in AML in utero, 397
chromosomal alterations and,168, 205in Down syndrome, 509, 510,512ETV6–RUNX1 and, 170gene therapy-related,606–607HOX proteins and, 172HOX gene regulation in, 213inherited genetic variationand, 185MLL rearrangements and, 173MLL-mediated, 213PML–RARα-mediated, 216RUNX, 209stepwise nature, 178TCF3–HLF and, 172treatment-induced, 725in trisomy 21, 218in utero, 333, 509
leukoencephalopathy, 684leukocytesexpression profiles, 81subsets, stainingdiscriminates, 2
leukocytosisin chronic leukemia, 23in chronic myeloproliferativeneoplasms, 23in essential thrombocythemia,471in JMML, 38leukemia distinguished from,1
leukoencephalopathy, 661, 683leukopenia, 23leukostasis, 661, 673, 674pulmonary, 675syndrome, 675
leucovorin rescue, renalimpairment and, 663licensing of new drugs, 617lidocaine, 819lifestyle education for survivors,846lifestyle factors, 54–55Li-Fraumeni syndrome, 730LIM proteins, actions in T-ALL,176lineageanalysis of differentiation, 126,128assessment, cytochemicalstaining, 23assignment, 22commitment, AML classifiedby, 32development, 80identification
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lineage (cont.)immunophenotyping panel,80screening panels, 338
megakaryoblastic, in AMLsubtypes, 34promiscuity,MLL generearrangements and, 213–214switches, 37, 97, 421
lintuzumab, 563, 571liposomes, as vectors, 597Lissauer, H, used Fowler’ssolution, 3LMO genesoverexpression, 172in T-ALL, 125, 126, 147, 176
lonafarnib, 620Loutit, JF, total body irradiation,7low- and mid-income countriessee developing countrieslumbar punctureanalgesia, 819, 829anticoagulants and, 678diagnostic, 338, 672platelet count and, 798preparing for, 841traumatic, 338, 676, 798
lumiliximab, 564, 570lung biopsy, 776lung function, chronic GVHDand, 539LYL geneschromosomal aberrations inT-ALL, 125expression in T-ALL, 126expression profiling, 39in precursor T-ALL, 32in T-ALL, 147
LYL1 overexpression, 176lymph nodes in ALL, 334, 337,337, 670lymphoblastic lymphomainvolving bone marrow, 23lymphoblastic T-cellmalignancies, 124lymphoblastscharacteristics, 23, 24count, 23identified, 2staining, 24
lymphocyte maturation, CD45and, 81lymphoid blasts, 23crisis, 249
lymphoid differentiation, IG/TCRrearrangements during, 116, 118
lymphoid leukemias, IG/TCRrearrangements in, 113, 126lymphoid malignancies,MYCrearrangement in, 173lymphomagenesis, 385, 386lymphomasin ataxia-telangiectasia, 281in Bloom syndrome, 285frequency, by country, 549malignant, frequencies, 122morphologic, immunologic,and cytogenetic (MIC)classification, 383–384in Nijmegen breakagesyndrome, 284nitrogen mustard in, 3Revised European–AmericanLymphoma (REAL)classification, 384as target for treatment indeveloping countries, 552
lymphoproliferations, diagnosis,126
MAD–MAX dimer, 385maintenance therapy in ALL,522major histocompatibilitycomplex (MHC), role in antigenpresentation, 582Malawi, Burkitt lymphoma/leukemia in, 558malignancy, secondary, 711–713HSCT and, 539treatment-related, 723–755
malnutrition, 660MAP kinase dysregulation, 286neurofibromatosis type 1, 287in Noonan syndrome, 289
MAPK signaling, 220marijuana, maternal use, 55markers for MRD studiesin ALL, 639, 639–640in AML, 640, 640
mastocytosisclassification, 478–479systemic, 477WHO classification, 478
maternal age and childhoodcancer, 55maternal reproductive historyand childhood leukemia, 55maturation, leukemiaclassification by, 32“mature” B-ALLchromosomal abnormalities,144
flow cytometry, 81immunophenotype, 86–87
MAX (MYC-associated factorX), 174maximally tolerated dosemultiagent regimens, 619phase I trials define, 618
MCL1, glucocorticoid resistanceand, 261, 262MDM2 polymorphisms, 734MDR genes, 320therapeutic use, 604
MDS seemyelodysplasticsyndromemeasles vaccination, 7MECOM gene activation, 155mediastinal structures,compression, 671, 672, 670–672MEF2D-DAZAP1 fusiontranscript, 139megakaryoblastic leukemiadiagnosis, 80differentiating, 92staining, 24
megakaryoblastsin AML subtypes, 34characteristics, 23, 24staining, 27in TMD, 218
megakaryocytedysplasia, 23, 38hyperplasia, 23
megakaryocytic-erythroid progenitor, 92maturation, 79and differentiation, 80
melphalan, as myeloablativetherapy, 459memory B-cells, 77menarche, ALL treatment and,705meningitis, 778mepolizumab, 477mercaptopurine, 8in ALL, 521cellular drug resistance, 266,267in continuation treatment inALL, 351–352early use, 4hypoglycemia and, 687in hyperdiploid ALL, 269in JMML, 457low-cost regimen, 553metabolism, 312polymorphisms affect, 3
pharmacodynamics, kinetics,and genetics, 311–313precursor B-ALL sensitivityto, 30secondary cancers and, 734toxicity, 313
mesenchymal cells inasparaginase rescue, 263, 319metabolic complications, early,663–670metal dusts and fumes, maternalexposure, 54metamyelocytes, 79methadone, 817methicillin, 6methotrexate, 8, 266, 268in ALL, 521bone mineralization and, 709in Burkitt lymphoma/leukemia, 388, 558cellular drug resistance, 266,268mechanisms, 268
in continuation treatment inALL, 351–352drug–drug interactions, 319early use, 4guidelines for use, in Brazil,559high-dosage, in ALL, 349in hyperdiploid ALL, 269, 340in intensification therapy inALL, 349for intracerebral myeloidtumors, 677low-cost regimen, 553mucositis and, 681neurocognitive effects, 825,827neurologic sequelae, 707pharmacodynamics, kinetics,and genetics, 309–311postinduction intensification,9precursor B-ALL sensitivityto, 30resistance to, 258sensitivity to, in Downsyndrome, 506
methylated CpG amplification,242, 243methylationaberrantin adult ALL, 240, 239–242in CML, 248impact of, 241in pediatric ALL, 242
analysis, assays for, 242arrays, 242impact on prognosis, 240, 241patternsage and, 242
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in ALL, 240, 242profilein ALL, 239in AML, 246
studiesin chronic lymphocyticleukemia, 245in MDS, 246in pediatric ALL, 244single gene, in ALL, 239
therapy targeted at, 244–245methylation inhibitors, 625methylator phenotype, CpGisland, 239methyl-bis-(β-chloroethyl)amine in lymphoma, 3methylphenidate, 827methylthiazol–tetrazolium(MTT)-based assays, 257methyltransferaseencoding gene mutations, 246,733in CML, 249
inhibitors, 475, 620, 625, 627in JMML, 456
Mexico, management ofpediatric cancer in, 551miceArid5b knockout, 185Cbf genes, 206, 208, 209Runx1, 208
Cbl-deficient, 455cdkn2amutant, 183Cebpa knockout, 224clonal evolution studies, 184Dnmt1mutations, 225drug screening in, 616AMKL-DS studies, 218GATA1 knockout, 219Mll knockout, 210MLL studies, 173, 740, 741MYC gene studies, 385Nf1-deficient, 453NPM-ALKmodels, 221Pax5 studies, 178Ras studies, 453RASi gene mutations, 224Rbm15 knock-out, 220RUNX-null, 295tumor suppressor genes in,183tumor vaccine models, 599
microsatellite instability, 61microtubules, vinca alkaloidsand, 263midostaurin, 620milatuzumab, 564, 572minimal residual disease(MRD), 2, 9in ALL, 525
HSCT and, 533, 535in AML, 410bone marrowtransplantation and, 535,536
in APL, 410assays, 410, 422detection by PCR, 368gene transfer therapies aimedat, 593methylation studies of, 241as prognostic factor, 343, 368,642in relapsed AML, 422risk stratification and, 525testing and monitoring, 636,641, 644, 646, 632–649therapeutic efficacy assessedby, 616
minor histocompatibilityantigens, 583mitoxantrone, 404, 726mixed lineage leukemia, 403molecular genetics, 210–214and partial tandemduplications, 214secondary mutations, 214
mixed phenotype acuteleukemia, 88, 94, 403diagnosis, 95immunophenotype, 95
MKL1, actions, 220, 221MKL1–RBM15 fusion product,220MLLactions, 172, 210-mediated leukemogenesis,213structure, 211
MLL genes, 31, 35, 210in ALL, 138, 332in AML, 150CD79 and, 82fusion partners, 212, 213, 740AF10 fusion, 154AF4 fusion, 214, 333AF9 fusion, 213ELL fusion, 212, 214ENL fusion in precursorT-ALL, 32GAS7 oncogene, 213in PCR assays, 633
rearrangements, 51, 142,153–154, 172, 205, 211,739–741, 745AML classified by, 400cellular drug resistance and,257, 262, 267emergence duringchemotherapy, 745in ALL, 213, 340
in AML, 185, 210, 213, 401,409in B-ALL, 172–173in infant leukemias, 51, 56in leukemogenesis, 177, 213in secondary leukemias, 333in T-ALL, 176leukemia-associated, 317on chromosome 11q23,210–214partner genes, 143PCR analysis of, 633
recombinome, 740partial tandem duplication(PTD), 154fusion protein, 214
tandem duplication, 214in therapy-induced leukemia,56in therapy-related AML, 36in utero exposures and, 56
Moabs seemonoclonalantibodiesmodal number, 135molecular analysis in ALL, 30molecular classification of ALL,30–32molecular cytogeneticsin AML, future trends, 225cytogenetically normal AML,220–225
molecular geneticsalkylating agent-inducedchanges in, 736–739in ALL, 182–186PCR assay of, 642
in AMKL, 217–220in AML, 204–225PCR assay of, 647–648studies, 399
MLL gene, 210–214targets for PCR, 633topoisomerase IIpoison-induced changes in,739–744of treatment-related leukemia,744
molecularly targeted therapy,624–627for treatment-relatedleukemias/MDS, 753
monoblastic leukemiaschromosomal abnormalities,91leukostasis syndrome in, 675
monoblastic neoplasms,immunohistochemistry, 91monoblasts, 675in AML subtypes, 33characteristics, 23, 24staining, 24, 27
monoclonal antibodies (MoAb),375–376, 563–574, 623–624agentsanti-CD19, 568anti-CD20, 568–569anti-CD22, 569–570anti-CD25, 570anti-CD33, 570–571clinical trials of, 566–573cytotoxicity, 565mechanisms of, 563–566side effects and limitations,573–574
bispecific, 565conjugates, 564, 565polyspecific, 566
monocyte maturation, 78and differentiation, 78–79
monocytesin AML subtypes, 33in JMML, 449
monocytic component in AML,33monocytic differentiation, 34in AML subtypes, 35in therapy-related AML, 36
monocytosis, 23in JMML, 447
monosomy 5, 7, 736, 737–738AML and, 397in JMML, 448, 457in MDS, 429, 432, 434in ALL, 141in AML, 149, 155FISH, 150
morphine, 816morphologic analysis,22–28in relapsed ALL, 367specimen preparation,22
morphologic classificationin ALL, 28–29MDS, 37
morphologic diagnosis,22–28morphologic featuresof APL, 33in diagnosis, 91erythroleukemia, 91
healthy pediatric B-cells,98MDS, 38
morphologic, immunologic, andcytogenetic (MIC) classification,30acute leukemias of ambiguouslineage, 36–37in AML, 32, 33, 34in AML subtypes, 34, 35
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morphologic, immunologic, andcytogenetic (cont.)in AML with myelodysplasia,35in APL, 33blastic plasmacytoid dendriticcell neoplasms, 37lymphoma, 383–384myeloid sarcoma, 37therapy-related AML, 36
mortalityage-adjusted, for AML, 396child, in various countries,550, 551supportive care and, 660
moxetumomab pasudotox, 620,623MOZ genes, 155in AML, 148
MPLin AMKL, 220in essential thrombocythemia,469
MPL genes, 205, 220, 295, 468in primary myelofibrosis, 472
MPO seemyeloperoxidaseMPO polymorphism, 59MRD seeminimal residualdiseaseMRN complex, 282, 284MRP1 seemultidrug resistanceproteinMTHFR polymorphisms, 58, 733mTOR inhibitors, 620, 626MTR polymorphisms, 58MTRR polymorphisms, 58mucosal lesions, infections and,772mucositis, 662, 679–681, 776,844after HSCT, 537care in, 844
multiagent therapy, 8multidrug resistance, 370AML relapse and, 423-associated protein (MRP),259, 268drugs to target, 627
multikinase inhibitors, 620multi-organ impairment, 7multiple myeloma, incidenceand distribution, 124multiplex pyrosequencingassays, 242muromonab, 564, 567, 623
mustard gas, trials with, 3mutationsin AML, 397, 408in Bloom syndrome, 285in CEBPB-dependent familialAML, 296class I, 205class II, 205in DS TMD/AMKL, 508, 509in dyskeratosis congenita, 292in essential thrombocythemia,468family cancer syndrome,730–731in Fanconi anemia, 278in FPD/AML, 295gain-of-function, 276inherited, 276in JMML, 450–455leukemia-associated, 208–210in mastocytosis, 477multiple, for leukemogenesis,205, 332in neurofibromatosis type 1,287in Noonan syndrome, 288, 289in primary myelofibrosis, 472in RASopathies, 286in severe congenitalneutropenia, 297in Shwachman–Diamondsyndrome, 292secondaryin CBF leukemia, 209–210in mixed lineage leukemia,214topoisomerase II poisonsand, 739–744
tumor suppressor genes, 385MVP/LRP, anthracyclineresistance and, 264MYB in T-ALL, 146MYC genes, 28, 340in ALL, 145in Burkitt lymphoma/leukemia, 384, 385rearrangements, in B-ALL,173–174in T-ALL, 125, 147
MYC proteinin B-ALL, 145overproduction, 385roles, 174
MYC proto-oncogene, NPMand, 222MYC–MAX heterodimers, 385myeloablative therapy, 7, 532choice of, 532growth after, 703in JMML, 459in MDS, 436, 437mortality in, 527
second, 535secondary cancers and, 730
myeloblastoma, 398, 677myeloblasts, 23, 33in AML, 33, 34characteristics, 23, 24count, diagnosis based on, 23expression profiles, 78identified, 2staining, 24, 27
myelocytic maturation, 78, 79and differentiation, 78–79
myelodysplasiaclassification, 30cytological features, 433-related changes, AML with,35
myelodysplastic syndrome(MDS), 36, 37–38, 429–437adult vs. pediatric, 429azacytidine trials in, 246–247bone marrow transplantation,536characteristics, 23chromosomal abnormalities,149classification, 21decitabine in, 247–248in Down syndrome, 34, 508dysplastic features and, 23epigenetics, 245–248incidence, 431preleukemic, therapy-related,36treatment-relatedclinical presentation,latency, and diagnosis, 750,747–750cytogenetic and molecularaberrations, 738–739management algorithm, 750treatments and outcome,751–753
vs. AML, 435algorithm, 435
myelofibrosisin AML subtypes, 34primary, 471–475
myeloid blast crisis, 249myeloid blasts, 23myeloid cell tumors, 676myeloid differentiationin AML, 204in APL, 402CEPBβ and, 296minimal, in AML, 33
myeloid leukemiaof Down syndrome (ML-DS),34, 88, 429, 430, 432, 508epigenetic therapy, 246–248in Fanconi anemia, 430, 431
leukostasis in, 673incidence, 431
risk of tumors, 676myeloid neoplasia, 430WHO classification of, 444
myeloid neoplasms,therapy-related, 88myeloid neoplasms,treatment-related, 36myeloid proliferations associatedwith Down syndrome, 38immunophenotyping,93–94
myeloid sarcoma, 37, 88myeloid-associated antigenexpression in ALL, 339myeloid-to-erythroid cell ratio,23myelopathy, 661, 684myeloperoxidase (MPO), 24in AML, 26as marker of maturation, 79,83staining, 24applications, 24
myelopoiesis, disorders of,severe congenital neutropenia,296myeloproliferative disorders(MPD), 444–480myeloproliferative neoplasm,characteristics, 23myelosuppressive agents, 6
Nageli, O, identified myeloblastand lymphoblast, 2naphthol AS-D chloroacetate, 24narcotics, 5natural killer cellsactivity in HSCT, 530in graft-versus-leukemiaeffect, 425in transplantation, 541large granular lymphocytes,100leukemia, 97
nausea and vomiting,controlling, 829–830NBN gene, 283, 284N-CoR co-repressor complexCBF-mediated transcriptionand, 208lymphoid development and,170
near-haploidy, in ALL, 137, 335,340
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needs framework, supportivecare, 839–848nelarabine, 9, 375, 620, 622neoplasmshematopoietic and lymphoid,diagnosis, 80precursor B-cell, 385second, 711–713, 724
Neumann, E, associatedleukemia with bone marrowchanges, 1neuro-cardio-cutaneous facialsyndromes, see RASopathiesneurocognitive deficits, aftertherapy, 823–827interventions, 827–828
neurofibromatosis, 286–288neurofibromatosis type 1 (NF1),51, 451, 452–454and JMML, 446heritable predisposition, 277
neurologic complications,on-therapy, 682–685neurologic sequelae to therapy,706–707neuron-specific enolase, 92neuropathic pain, 815, 817adjuvant analgesics, 817–818
neuropathy, vincristine-induced,349neuropsychologicalconsequences, 8neuropsychologic impairmentglobal, 823–825specific, 825–826
neurotoxicityintrathecal AraC and, 315methotrexate-induced, 352new nucleoside analoguesand, 622vincristine-associated, 320
neutropeniacyclic, 297and CNS infections, 778definition, 779ear, nose, and throat infectionsand, 776and fever, 6, 779–781infection and, 772, 779–781bloodstream, 773pulmonary, 775
lack of inflammatory responsein, 774, 778, 779prophylaxis, 805–807severe congenital, 296–298heritable predisposition,277
typhlitis and, 777
neutrophilia, 23in CML, 38
neutrophils, 79expression profiles, 78infections and, 772level of, and infection, 6recovery of, outcome and, 6
NF1 tumor suppressor gene, 287Nijmegen breakage syndrome,283–284aberrant TCR rearrangementsin, 125heritable predisposition, 277
nilotinib, 12, 250, 462, 620, 624N-nitroso compounds, 55nociceptive pain, 814NOL1-E2A fusion, 140non-erythroid cells in AML, 33non-governmental organizationcancer units in developingcountries, 555funding from, 556support access to care, 554in Brazil, 553
non-Hodgkin lymphoma, 23,386incidence and distribution,124
non-ionizing radiation, 54non-specific esterase stain, 24non-steroidal anti-inflammatorydrugs, 815non-viral vector systems, 597Noonan syndrome, 288–289, 450heritable predisposition, 277JMML in, 446
Noonan-like syndrome,288–289, 451heritable predisposition, 277JMML in, 446
normal-karyotype ALL, 137NOTCH genes in T-ALL, 183NOTCH proteins, actions,183–184NOTCH1 inhibitors, 620NOTCH1:CSL complex, 183Nowell, PC, Philadelphiachromosome, 11NPM (nucleophosmin), 221actions, 221, 222in cancer, 221in cytogenetically normalAML, 221–222
NPM genesin AML, 149, 409
mutated, 35NPM-ALK fusion oncogene, 222NQO1 gene polymorphisms, 59,733NR3C1 gene, 320nuclear bodies, roles, 215nuclear falloutstudies, 53weapons tests, 53
nuclear power plants, studies ofleukemia near, 53nucleic acid amplificationtesting, 801nucleofection, 597nucleophosmin, see NPMnucleoside analogues, 266cellular drug resistance, 266novel, 375, 621–622
nucleoside transporterspolymorphisms, 3NUP214-ABL1 fusion, 183NUP98 gene, 156, 742, 749nursing care, 839, 839–848nutritionduring treatment, 841maintaining good, 660standard of, at diagnosis,complications and, 660
obatoclax, 375obesityafter ALL therapy, 704–705in APL, 402complications due to, 660dosing and, 660
oblimersen, 620, 626ocularinvolvement in ALL, 334, 335late effects, 707
ofatumumab, 620, 623oligoclonality, 127, 636B-ALL, 123T-ALL, 125
oligonucleotides, antisense, 598,754oncogenesmechanisms, 332transcription factors as, 168translocations and, 168
oncolytic viruses, 597oncoretroviral vectors, 593ondansetron, 830opioids, 816–817dosing, 816
side effects, 818sustained release, 816as syrups, 816
oralcomplications, 345, 775, 776side effects, 709
osteonecrosis, 662, 685, 710therapy-related, 524
other ambiguous lineageleukemias, 94, 96outcomein ALL, 185age at diagnosis and, 520,523in El Salvador, 556MRD predicts, 642, 643, 647
in SGH-II study, 557in ALL-DS, 505ALL subtypes, 341in AML, 535–536in developing countries, 559MRD predicts, 648, 649
in APL, 410in Burkitt lymphoma/leukemia, 389,390cancer, in Brazil, 553cellular drug resistance and,257cognitivechemotherapy and, 824cranial irradiation and, 824
determinants of, 5in DS AML, 508, 510heterogeneity of, 3host factors affecting, 3HSCT andin ALL, 533–535in AML, 10, 408–410source of stem cells and,530–531
of HSCTin AML, 424in CML, 463
in MDS, 436HSCT and, 437relapse and, 437
MLL and, 172neurocognitive, HSCT and,825nutrition at diagnosis and,660in osteonecrosis, 685in primary myelofibrosis, 474in treatment-relatedleukemias, 751–753parental functioning and, 832,843, 845prediction, gene expressionprofiling and, 38after relapse, 9traumatic lumbar punctureand, 338
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ovarian functionALL treatment and, 706transplant and, 706
oxazaphosphorines, 320–321oxygen steal, hyperleukocytosisand, 674
p14/15/16 proteins, actions, 182p14ARF gene, 182, 249p15 methylation studies,240–241pediatric, 244
p16INK gene, 182, 249p19ARF inactivation, 183p210BCR-ABL, see BCR–ABL1P2RY8-CRLF2 fusion, 174p53degradation, NPM and, 222-induced apoptosis, 385in MDS, 434ribosomal biogenesis and, 291role in ALL, 370stability, PML and, 215vinca alkaloids and, 264
p57 methylation studies,240–241pediatric, 244
p73 methylation studies, 241,240–241pediatric, 244
packed red cell transfusions,794–796pain management, 814–819, 845principles, 814procedural, 828–829
palliation and bereavementphases of care, 843, 847–848pancreatitis, 662, 682panobinostat, 620, 625paracetamol see acetaminophenparentalcigarette smoking andchildhood leukemia, 56coping, 832in relapse, 847
distress, 845education, 841in developing countries, 552
exposure to chemicals, 54, 56post-traumatic stress, 831tobacco smoking andchildhood leukemia, 55
partial tandem duplications(PTD), 214partial uniparental disomy, 136pathogenesis
of AML, 397of mastocytosis, 477of pain, 814of polycythemia vera, 464primary myelofibrosis, 472
pathology of Burkitt lymphoma/leukemia, 383–385molecular, 385
pathophysiologyof ALL, 332–334CNS leukemia, 676of leukostasis, 673, 674of MDS, 433neuropsychosocialimpairment, 826–827tumor lysis syndrome, 664
patulin, 8PAX5 genein ALL, 181in precursor B-ALL, 332in progenitor B-ALL, 180fusions, 138, 141in B-ALL, 177
PAX5, roles, 178PBX1 complexes, roles, 171PBX1, 171PCR see polymerase chainreactionPEBP genes in FPD/AML, 294Pediatric Oncology Group, 5, 8Pediatric Preclinical TestingProgram, 616pegfilgrastim, 807pentamidine isethionate, 7pericarditis–myocarditissyndromeanthracyclines-induced, 316
Periodic acid–Schiff (PAS) stain,24peripheral blast cell count, inrelapsed ALL, 369peripheral blood stem cells,530–531, 605harvesting, 532
personnelin Brazil, 553in developing countries, 552,554, 555
pesticides, parental exposure, 54,56PETHEMA protocols, Spain, 239P-glycoproteincellular drug resistance and,259, 268, 423inhibitors, 620, 627therapeutic use, 604
Ph see Philadelphia chromosomepharmacodynamicsin AML treatment, 408definition, 309of anti-leukemic therapies,309–321phase I trials assess, 618
pharmacogeneticsof anti-leukemic therapies,309–321definition, 309
pharmacogenomicsin AML treatment, 408definition, 309
pharmacokineticsin AML, 410of anti-leukemic therapies,309–321definition, 309phase I trials assess, 618
phases of carebereavement,diagnosis and referral,palliation and bereavement,prediagnosis,recurrent disease,rehabilitation and treatment,survivorship,see also supportive care;supportive care needsframework
PHF6 gene, 184Philadelphia chromosome (Ph),140biphenotypic leukemia, 36in CML, 248diagnosis of CML, 38identification of, 11-positive ALL, 31, 336, 353relapse in, 369therapy in, 3
-positive CML, 460in T-ALL, 147t(8;14)(q11.2;q32) and, 146see also BCR-ABL1
phlebotomy, in polycythemiavera, 467physical examination, in ALL,334PICALM-MLLT10 fusion, 177Pinkel, D, 12St. Jude Children’s ResearchHospital, 8
Pizzo, PA, antibiotic andantifungal use, 6plasma concentrations ofmethotrexate, 310toxicity and, 310
plasmablasts, 77
platelet countbleeding risk and, 6, 796increment, 798platelet transfusion and, 798
platelet disorder, familial seefamilial platelet disorderplatelet-lowering therapy, 471platelet transfusions, 6, 673,796–799evaluating response to, 799in thrombosis, 678
platinum analogues, 726, 727plerixafor, 620, 627ploidy, 340definition, 137
PLZF protein, 217PLZF–RARα fusion protein, 217PMLarsenic and, 217roles, 215
PML gene, 215PML-RARA fusion, 10, 33, 89,152, 215–217in APL, 402
PML–RARα fusion protein, 215,216, 217Pneumocystis jirovecipneumonia, 7, 9, 775in chronic GVHD, 540prophylaxis, 345, 711, 785
pneumonia, 775syndrome, idiopathic, 538
political inequality, patterns of,550–552polycythemia vera, 463–468WHO diagnostic criteria for,464
polyglobulia, secondary, 466polymerase chain reaction(PCR), 9, 632–633B-ALL, 124for detection of relapse inALL, 368IG/TCR gene rearrangements,117, 119, 120–122, 120–122,127diagnostic clonality studies,126–128limitations, 121sensitivity, 128
in MRDmonitoring, 410, 636,637, 638, 632–638, 644,642–645, 647–648MLL and, 153, 154molecular targets, 633procedures, 120quantitative, 2
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real-time quantitative, 633,637TaqMan, 637, 638, 644
reverse transcriptase, 633identifies chromosomalchanges, 2in AML, 151, 152pediatric ALL, 30role in diagnosis of ALL,185
polymorphismsALL and, 333and response to therapy, 408GCR genes, 260inherited, susceptibility toALL and, 185linked to development ofleukemia, 3, 731, 732–734linked to drug effects, 3receptor, methotrexate toxicityand, 311susceptibility to malignancyand, 397treatment response and, 321see also single nucleotidepolymorphisms
ponatinib, 620population mixing, andchildhood leukemias, 57posaconazole, 786postinduction intensification, 9posterior reversibleencephalopathy, 684postremission chemotherapy,371–372post-traumatic stress, 831–832potassiumhyperkalemia, 666, 667hyperleukocytosis and, 674
povertyaccess to care and, 555diseases of, 550by country, 551
under-5 mortality rate and,550treatment abandoned due to,554
power lines, electromagneticfields, 54PRAME, 250, 634pre-ALL syndrome, 99pre-B-ALLimmunophenotype, 85, 86late transitional, 86
pre-B-cell receptor, 75, 75, 76pre-B-leukemia, clinical features,338precursor B-ALL, 28, 29, 84–87
cellular drug resistance in,258, 263chromosomal abnormalities,145CRLF2 in, 332E2A-PBX1 fusion transcript,30expression profile, 82FISH, 139gene rearrangements, 124in adolescents, 523PCR analysis of junctionalregions, 635polymorphisms and, 60with BCR-ABL1, 31with genetic abnormalities,30–32with hyperdiploidy, 30with hypodiploidy, 32withMLL rearrangements,31with TEL-AML1, 30
precursor B-cell neoplasms, 385precursor natural killerleukemia, 87immunophenotype, 87
precursor T-ALL, 29chromosomal abnormalities,32diagnosis, 83expression profiles, 83polymorphisms and, 60
prediagnosis phase of care, 840,843predispositionto AML, 397cancer, 276–278hematologic malignancies,276–298heritable, 277leukemia, 298syndromes in leukemia, 278see also susceptibility
prednisoloneadrenal insufficiency and,687dose, 319resistance to, 258prognosis and, 257
prednisone, 8in AML, 10early use, 4in reinduction therapy inrelapsed ALL, 370in remission inductiontherapy in ALL, 348osteonecrosis and, 685pharmacodynamics, kinetics,and genetics, 319–320
pre-existing conditions, 663pregnancy in survivors, 706
preleukemic myeloproliferativedisorder (MPD), chromosomalabnormalities, 150preleukemic phasetreatment-related leukemias, 749preleukemic syndrome, 99prenatal leukemogenesis, 509,645pre-T-cell receptor (pre-TCR),78
β receptors, 77prevalence of neurofibromatosistype 1, 286prevention of infection, 784–786primary cytogenetic lesions, 135primary myelofibrosis, 471–475WHO diagnostic criteria for,472
pro-B-ALLflow cytometry, 81genetic abnormalities, 85immunophenotype, 85, 84–86
probes, in FISH, 136procedures, pain managementfor, 819, 828–829prognosisALL subtypes, 341in Burkitt lymphoma/leukemia, 390cellular drug resistance and,257MDS, 435–436refractory AML, 422in relapsed AML, 421response to treatment and, 2translocation and, 9
prognostic factorsdrug plasma concentration as,310for neurologic sequelae, 706in ALL, 342–344, 525, 643in AML, 408–410, 649in APL, 410, 648in Burkitt lymphoma/leukemia, 389in CML, 461, 463in DS AML, 510in essential thrombocythemia,470infant ALL, 353in JMML, 455–456in MDS, 436MRD as, 3, 410, 642, 643, 647,649in pancreatitis, 682in primary myelofibrosis, 474in relapsed ALL, 369, 367–370in relapsed AML, 422in TMD, 507
progressionof AML, 435of essential thrombocythemia,470of MDS, 435, 435–436
progressive multifocalleukoencephalopathy (PML),779promonocytes in AML, 34promyelocytesabnormal, in APL, 23characteristics, 23hypergranular, 33leukemic, 402
prophylaxis, 785–786after HSCT, 537antibiotic in AML, 411CNS leukemia, 682CNS, in Burkittlymphoma/leukemia, 389GVHD, 538, 540in MDS, 437for neutropenia, CSFs as,805–807platelet transfusions, 798thrombosis, 679
propofol, 819, 829proteasome inhibitors, 620,626protein tyrosine phosphatasePTPN11 (SHP-2), 454PTPN11 gene, 205, 289, 454
protocol II, 9protocolsexperimental, 4gene therapy, 607
PRV1 gene, 464pseudodiploidy, 30in ALL, 137
Pseudomonas aeruginosa, 6,774, 777Pseudomonas exotoxin A, 566pseudo-Pelger–Huet change,38psychologic interventionsfor pain and distress, 829for parents, 832
psychologic adjustment,830psychosocial issues, 7, 9,823–833psychosocial support, inBrazil, 553pubertyeffects of therapy on, 702radiation therapy and,706
public healthpriorities in developingcountries, 550, 555system, changes in, andpediatric cancer unit, 556
pulmonary infections,775–776
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prophylaxis (cont.)pulmonary leukostasis, 675pulmonary sequelae oftherapy, 708pure erythroid leukemia, 91immunophenotyping, 91
purine analogues, 423in JMML, 457
pyrimidine analogues, 10
RAD001, 475RAD51 gene, 731radiationin therapy-related AML, 36injury to hypothalamic–pituitary axis, 701, 709natural background, 53paternal exposure,preconceptually, 53testicular, 705X-raysin utero, 53postnatal, 53
radiation therapyand puberty, 706CNS tumors and, 712dentofacial effects, 708for intracerebral myeloidtumors, 677in primary myelofibrosis, 474neurologic sequelae, 706–707,823–824pathophysiology, 826
treatment-related cancersafter, 728
radiograph see X-raysradioisotope–MoAb conjugates,566radiotherapyearly use, 3risk of leukemia after, 53
radon exposure, 54RAF kinases, 458RAGs, 114randomized phase II trial, 618rapamycin, 620, 626Rapid Access to InterventionDevelopment (RAID), 617retinoic acid receptor α (RARα)in APL, 152–153, 215gene RARA, 205, 215
RAS genes, 205, 224, 286in AML, 152, 425in JMML, 452–453KRAS, 452NRASmutations in AML, 209NRASmutations in in JMML,452
RAS pathway activation, 289,450RAS proteins, 224, 287, 450therapy targeted at, 458
RAS-associated autoimmunelymphoproliferative diseases,452rasburicase, 388, 667RAS–MAPK pathway, 286, 287,450in JMML, 451–453therapy targeting, 458
RASopathies, 286, 450RB1 gene, 276RBM15 protein, 220, 221RBM15-MKL1 fusion, 92, 154,220-mediated leukemogenesis,221
reactive thrombocytosis, 470receptors, polymorphisms incorticosteroid resistance and,320methotrexate toxicity and, 311
recombinase, 114recombinase-activating genes,114recombination signal sequences,114reconsolidation therapy, 9recovery, maximizing chance of,5recurrent disease phase of care,843, 846red blood cellsin JMML, 448preservation of, 5transfusions, 794–796in Diamond–Blackfananemia, 291
reduced-intensity conditioning,280, 532second, 535, 537
refractory anemia, 430with excess of blasts, 429, 430,435with ringed sideroblasts, 429
refractory cytopenia, 435of childhood, 38, 430
refractory leukemia, 11clonal evolution and, 3
rehabilitation, treatment and,phases of care, 840–846reinduction therapy, 9in ALL, 349–350, 522in AML, 423
in bone marrow relapse,370–376in Burkitt lymphoma/leukemia, 390
relapsein ALL, 367diagnosis of, 367, 643HSCT in, 374–375MRDmonitoring in, 643prognostic factors, 367–370,642, 645treatment, 371, 370–376
in AML, 422, 421–425MRDmonitoring in, 648
in APL, 424, 648bone marrow, reinductiontherapy in, 370–376in Burkitt lymphoma/leukemia, 390category, event-free survivaland, 369of CML, 463clonal evolution and, 3, 184,185, 636CNS, 9, 350in ALL, 372–373in Burkittlymphoma/leukemia, 390myelopathy in, 684
combination therapy in, 315epigenetics of, 240estimated risk, 9genetics of, in ALL, 185in JMML, 459, 460in MDS, 437methotrexate plasmaconcentration and, 310outcomes after, 9re-accumulation of blasts at, 3recurrent disease phase ofcare, 846risk ofin ALL, 342, 643in AML, 410, 648in APL, 648HSCT and, 533–535in JMML, 459in MDS, 437methotrexate systemicexposure and, 310methylation studies of, 240myeloablative therapy and,532therapy based on in AML,204
testicular, in ALL, 373time to, definition, 368vs. secondary malignancy,IG/TCR clonality studies, 127
relationships, family–staff, 840remission, 5in AML, 10complete, in ALL, 349early experience, 8
induction, 9rate, 5treatment, initial responseto, 2
induction therapy, 840in ALL, 345, 645: initialresponse to, 643in AML, 404–406infection related to, 349initial response to, 343in MDS, 436, 437side effects, 349
rates in APL, 215renal failure, 669renal impairment, 669from hyperuricosuria, 6in Burkitt lymphoma/leukemia, 389infection, 779pre-existing, 663tumor lysis syndrome and,664–670
resistance to MoAb-basedagents, 574resolution, spontaneous, inJMML, 455resources, scarce national, limittreatment, 553, 554responsebone marrow, 9early rapid, 9early vs. late in ALL, 523evaluation, 3, 9
retinoblastoma, epidemiology,276retinoic acid, 10, 457see all-trans-retinoic acid,
retroviral vectors, 593, 594,595Revised European–AmericanLymphoma (REAL)classification, 384RFC1 polymorphisms, 58rhinosinusitis, 776ribonucleotide reductaseinhibitor, 11ribosome biogenesisabnormal, 289Diamond–Blackfan anemia,290–291dyskeratosis congenita,292–294Shwachman–Diamondsyndrome, 291–292
genetic mutations in, 290ribozymes, 598ricin–MoAb conjugate, 564, 565,568
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riskassignment in AML, 649classificationALL, 344AML, 408, 410, 410
-directed therapy in ALL, 332,345factors, 52for AML, 396–397for Burkitt lymphoma/leukemia, 385for chronic GVHD, 540congenital, 52disease, for earlycomplications, 660environmental, 52–54, 61genetic, 51for hyperglycemia, 686, 687for infection, 772leukemia, for earlycomplications, 663for leukostasis, 673lifestyle, 54–55for myelopathy, 684for neurocognitiveimpairment, 824for pancreatitis, 682for early complications,660–663reducing, fortreatment-related cancers,729studies of, 49, 51for thrombosis in essentialthrombocythemia, 470for thromboticcomplications, 677for traumatic lumbarpuncture, 338treatment, for earlycomplications, 660, 663for treatment failure inCML, 463for treatment-relatedcancers, 725, 727for tumor lysis syndrome,668for typhlitis, 681
groupsin ALL, 342–344, 345in relapsed ALL, 369, 369,370
of ALL, 185of donation, 532of leukemiaDown syndrome and, 151,503TMD and, 151
of MDS, 431of relapsein ALL, 643in AML, 410, 648in APL, 648CNS, 350estimated, 9
HSCT and, 533–535in JMML, 459in MDS, 437myeloablative therapy and,532therapy based on, in AML,204
of second malignancy, 711growth hormone therapyand, 704
of thrombosis, 678of treatment-related cancers,724–725, 726after chemotherapy, 727after HSCT, 729after radiation therapy, 728genetic variation and,734
of tumor lysis syndrome, 664,667stratificationin ALL, 369, 525, 643groups, 369protocols, in childhoodALL, 185
risk-based therapy in essentialthrombocythemia, 471rituximab, 390, 563, 564,568–569, 620side effects, 573
Robertson, OH, preservation ofred blood cells, 5Romanowsky stain, 24in AML, 26bone marrow, 22
romidepsin, 620, 625Rous, P, preservation of RBCs, 5Rowley, JD, Philadelphiachromosome, 11RT-PCR see polymerase chainreactionRUNX genes, 206in AMKL-DS, 219in FPD/AML, 295leukemia predisposition and,294rearrangements, 208–210in AML, 206in CML, 209
see also AML genes, CBF genesRUNX proteins, 206–208in FPD/AML, 295
RUNX1in AML, 397iAMP21 and, 175translocation, 741
RUNX1–CBFβ complex, 207RUNX1–ETO fusion protein,208–209
RUNX1-RUNX1T1 fusion, 34,207–209, 648RUNX1-RUNX1T1 expressionin AML with t(8;21), 400
safety of drugsnew guidance, 619phase I trials assess, 618
sarcoma, myelocytic ormonocytic, diagnosis, 80SBDS gene, 292SBDS protein, actions, 292Shwachman syndrome, 51Shwachman–Diamondsyndrome, 291–292heritable predisposition, 277MDS and, 38
screening, donor, fortransfusions, 800, 801secondary chromosomalaberrations, 135secondary malignancy, 711–713,723IG/TCR clonality studies todistinguish from relapse, 127treatment-related, 723–755
sedation, procedural, 819, 829seizures, 661, 682Sellafield (UK), 53sensitivityof MRD assay by flowcytometry, 640of MRD PCR analysis, 637,637–638, 647
serum response factor, 220severe congenital neutropenia,296–298heritable predisposition, 277myeloid neoplasia and, 431risk of MDS and, 431
sexual development, aftertherapy, 702shelterin, 293SHMT1 polymorphisms, 58SHP-2 see protein tyrosinephosphatase PTPN11Shwachman–DiamondsyndromeMDS in, 431myeloid neoplasia and, 431
siblingadaptation, 832donor transplants, 11, 374,406, 530HLA-compatible, 7, 374
side effects
anticipating, 841drug compliance and, 845in continuation therapyin ALL, 352
of G-CSF, 806of methadone, 817of MoAb-based agents,573–574nausea and vomiting, 829–830neurocognitive deficits,823–827off-target, in immunotherapy,584, 603of opioids, 818red cell transfusion, 796remission induction therapy,349in survivors, 701–713of treatment for ALL, 524–525
signal transduction inhibitors inAML, 425signaling pathwaysin JMML, 450inhibitors, 412
SIL-TAL1 fusion, 146, 176single nucleotidepolymorphisms (SNPs), 38ALL and, 60arrays for classification ofALL, 39candidate gene studies, 58–59childhood leukemia andgenome-wide associationstudies, 59–61corticosteroid resistance and,320definition, 136genotyping microarrays, 177in folate metabolism pathway,58, 311in interleukin-15, 321and methotrexate toxicity, 311and predisposition toleukemia, 53, 735in thiopurinemethyltransferase, 311in xenobiotic metabolismpathway, 58treatment response and, 321see also polymorphisms,
single-strand conformationpolymorphism analysis, 121skeletal abnormalities aftertherapy, 709–710skin lesionsin chronic GVHD, 540infections, 772, 774–775in JMML, 446rash, antimetabolites and, 352,352
Skipper, HE, multiagent therapy,8
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small cell tumors, differentiating,81SmIg gene rearrangements, 124SmIg–CD79, 117SNP see single nucleotidepolymorphismssocietal attitudestreatment of pediatric cancerand, 550, 555twinning programs and, 555
socioeconomicchange, and pediatric cancerunit, 556inequality, patterns of,550–552
soft tissue infections, 774–775solvents, parental exposure to, 54Soni, SS, neuropsychologicconsequences of treatment, 8sorafenib, 620, 625Southern blotanalysis of IGH genes, 119in precursor B-ALL, 127
B-ALL, 124IG/TCR gene rearrangements,119–120diagnostic clonality studies,126–128
procedures, 119Southwest Oncology Group, 5spinal cord compression, 676spinal lipomatosis, 661, 684spleen in ALL, 334splenectomyin JMML, 458in polycythemia vera, 468in primary myelofibrosis, 474
splenomegalyin JMML, 446in polycythemia vera, 467in primary myelofibrosis, 473
Src kinase dephosphorylation, 81St. Jude Total Therapy Study XV,342St. Jude Children’s ResearchHospital, 8diagnostic criteria, 92genome-wide associationstudies, 60International OutreachProgram, 555results for ALL, 556–557results for AML, 557–559results for Burkittleukemia/lymphoma,557–559
“St. Jude pneumonia”, 7
Total Therapy studies, 337Total-XS protocol, 310
staff, in developing countries,552, 554, 555staging, Burkitt lymphoma/leukemia, 387stainingbone marrow, 22histochemical, introductionof, 2
staphylococcal infection, 6catheter-related, 773
Staphylococcus aureus, 6, 774statistical power of trials, 5stem cell factor, 605stem cell transplantation seehematopoietic stem celltransplantation
stem cells, 7gene marking in, 605sources, 530, 531
Streptococcus spp., 774Streptococcus viridansin AML, 411prophylaxis, 785
stressors, family, duringtreatment, 845Subbarow, Y, antifols, 4subclones, 2formation, 127at diagnosis, 124
IG/TCR clonality studies, 126,127
subgroupsAML, 400–404MDS, 429
submicroscopic moleculargenetics, 136future trends, 158in ALL, 173in AML, 204in B-ALL, 182in T-ALL, 182–184
sub-Saharan Africa, Burkittlymphoma/leukemia in, 558subtype-specific treatment, ofAPL, 412Sudan Black B stain, 24, 24, 29applications, 27
suicide genes, 589, 604sulfamethoxazole, 7sunitinib, 620superinfection, 6superior mediastinal syndrome,337
superior vena cava syndrome,337, 661, 671, 671, 672supportblood component, 794–800for family in Brazil, 553patient, in Brazil, 553venous access, 802–803
supportive care, 5–8in ALL, 344–345, 349in AML, 411in Brazil, 553definition, 839in developing countries,outcome and, 554, 556–558hematologic, 794–809in hyperleukocytosis, 675mucositis and, 681in myelopathy, 685supportive care needsframework, 839, 839–848survival due to, 660in tumor lysis syndrome,667
supportive care needsframework, 839, 839–848suppressor of cytokine signalingproteins in CML, 249Surveillance, Epidemiology, andEnd-Results (SEER) program(US), 50survivalin ALLadolescents, 523age at diagnosis and, 520,523cancer treatment in Brazilassessed by, 552
in ALL-DS, 505in AML, 395, 396bone marrow transplantationand, in AML, 536early therapies, 8in essential thrombocythemia,470HSCT andin ALL, 533–535in AML, 424, 535–536mismatched donor,
in JMML, 456, 457HSCT and, 456
in MDS, 436, 436HSCT and, 437
pediatric cancer, wealth and,551in polycythemia vera, 467postrelapse in AML, 422in primary myelofibrosis, 474quality, 8ratesin AML, 10, 408in CML, 12
remission and, 5
in treatment-relatedleukemias, 751–753
survivin, 435antagonists, 620, 627
survivorsconcerns in, 846psychosocial issues for, 823
survivorship phase of care, 843,846susceptibilityalleles, leukemia risk and, 298to cancer, genetic variationand, 732drug metabolism and, 397,735genetic, 58–61environmental risks and, 61
see also predispositionsyndrome of inappropriatesecretion of antidiuretichormone (SIADH), 661, 686systemic exposure, risk of relapseand, with methotrexate, 310systemic inflammatory responsesyndrome in AML, 411systemic mastocytosis, 477
T-ALL see T-cell acutelymphoblastic leukemiaT-cell acute lymphoblasticleukemia (T-ALL), 9, 122cellular drug resistance in, 258chromosomal abnormalities,146–147chromosomalrearrangements, 176–177classification, 87immunologic, 87
compared to B-cell precursorALL, 339flow cytometry, 81gene rearrangements, 124, 125aberrant and oncogenic, 125
genetic subgroups, 342IG/TCR genesPCR analysis of junctionalregions, 635rearrangements, 124, 127
immunophenotype, 87, 87outcomes, 146Ph+, 147treatment, 354
T-cell leukemiaclinical features, 339immature thymocyte, 339mature thymocyte, 339prothymocyte, 339
T-cell lymphoblasticlymphomas, 122gene rearrangements, 124
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T-cell neoplasms, aberrant TCRrearrangements in, 125T-cell receptor excision circle(TREC), 115T-cell receptor (TCR), 78antigen specificity, 113, 603encoding genes, 113gene transfer, 603immunoglobulins on, 113molecular structure, 113
T-cell receptor gene see TCRgenesT-cellsactivation, 583chimeric antigen receptorsspecificity, 602CD4+/CD8+, 582in graft-versus-leukemiaeffect, 585
depletion, 531, 533, 537, 539,586gene marking, 606immunotherapy, 584, 584–587lineageexpression profile, 83maturation anddifferentiation, 78
maturation, 77modification by gene therapy,601–604suppression, overcoming,589Th1/Th2 and Tc1/Tc2 subsets,585
T-lineage lymphoidmalignanciesincidence and distribution,124
TAL genesexpression profiling, 39in precursor T-ALL, 32in T-ALL, 125, 146, 176
TAL1actions, 176overproduction, 126, 176
TAL1–E2A, actions, 176TALE proteins, 171, 213tandem duplication,MLL, 214TCF3-HLF fusion, 186in B-ALL, 172
TCF3–HLF, actions, 172TCF3-PBX1 fusion, 333TCF3–PBX1, actions, 172TCL1 gene, 282TCR see T-cell receptorTCR genes, 88, 114complexes, 114expression, 77
rearrangements, 115, 115, 116,118, 145aberrant, 125cross-lineage, 123, 125diagnostic studies, 127during lymphoiddifferentiation, 116–119in precursor B-ALL, 123junctional regions in PCRanalysis, 635, 637, 634–638oncogenic, 125PCR analysis, 120secondary, 116in T-ALL, 125, 146, 176in T-ALL and T-LBLsubgroups, 125transcription factors and,126
TCR moleculescombinatorial diversity, 115junctional diversity, 116repertoire, 115, 115–116
TdT see terminaldeoxynucleotidyl transferaseTEL gene, 156rearrangements, 144, 142–144,157in AML, 148
TEL-AML1 fusion, 51, 143in ALL, 30and relapse, 370
cellular drug resistance and,263
telomerase complex genes, 293telomeres, 293dyskeratosis congenita and,432length, analysis, 294maintenance, dyskeratosiscongenita and, 293
temozolomide, 622temperature gradient gelelectrophoresis, 121temperature, monitoring, 842temsirolimus, 375teniposide, 265, 317drug–drug interactions, 319leukemogenicity, 56treatment-related leukemiaand, 727
TER genes, 293, 433terminal deoxynucleotidyltransferase (TdT), 77, 84in gene rearrangements, 116
terminology, changes in,epidemiology and, 49testicular leukemia, in ALL, 334,335, 367
testicular relapse treatment, 373,705TET2 gene, 246, 432tetraploidy, 30therapeutic index, drug toxicityand, 309therapeutic range of teniposide,317therapyadjuvant immune, 783–784alkylator, in Burkittleukemia/lymphoma, 3in ALL, future trends, 354, 525in AML, 204CNS-directed, 350–351consolidation, in ALL, 522continuation, 9, 845in ALL, 351–352
developing new, 620, 616–627differentiation, in AML, 424in AMKL-DS, 510–513early response, 9epigenetic, 246–248experimental, in primarymyelofibrosis, 475for painnon-pharmacological, 818pharmacological, 815–818
for treatment-relatedleukemia, potential, 753–755gene expression profiling and,39growth hormone, 703inadequate, evolution ofleukemia after, 11-induced leukemias, 606–607intensificationin ALL, 522in AML, 406MRD detection as criterion,649
maintenance, in ALL, 522molecularly targeted, 624–627multiagent, 8myeloablativegrowth after, 703in MDS, 436, 437
reinductionin ALL, 522
-related complicationsin ALL, 524–525
-related leukemias, 723–755AML, 36, 404in neurofibromatosis, 287
-related MDS, 404, 437-related myeloid neoplasms,36, 88-related secondary cancers,278remission induction, 840in ALL, 345–349, 643, 645in AML, 404–406infection related to, 349
initial response to, 343in MDS, 437side effects, 349
response to, and outcome,410, 643risk-directed in ALL, 342, 345“species-specific”, 9supportive care, in ALL,344–345undifferentiated, success of, 3see also treatment
thiarabine, 622thioguanine, 10, 267, 312in AML, 404hepatic effects, 710metabolism, 312nucleotides, 311in red blood cells, 311–313
thiopurine methyltransferasedeficiency, 311–313, 663polymorphisms of TPMT, 3,267, 311, 733
thiopurines, 266, 267, 312cellular drug resistance, 258,266mechanisms, 267–268
Thomas, ED, bone marrowtransplant, 7Three Mile Island reactoraccident, 53thrombocythemiaessential, 468–471hereditary, 470
thrombocytopenia, 23in ALL, 336, 344at diagnosis, 672drug-induced, 6in JMML, 38, 448platelet transfusion in, 796
thrombocytopenic bleeding, 6thrombocytosis, reactive, 470thrombolytic therapy, 678for occluded catheters, 803
thrombopoietic growth factors,807thrombopoietin, 809thrombosis, 662, 678,677–679as early complication, 672
thrombotic coagulopathy, 673thrombus formation incatheters, 803thymus, in ALL, 337thyroid cancer, as second cancer,711thyroid function, radiationtherapy and, 702
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time to diagnosis of a secondarymalignancy, 748see also latency
time to relapsedefinition, 368event-free survival and inALL, 368
tipifarnib, 620, 624tissue typing for HSCT, 528–530TLX genes in T-ALL, 146, 147,176T-lymphoblastic leukemia seeprecursor T-ALLTMD 29 see transientmyeloproliferative disordertobacco smokingmaternal, during pregnancy,55, 59parental, and childhoodleukemia, 55, 56
tolerability, drug, phase I trialsassess, 618topoisomerase II, 265anthracyclines and, 265inhibitionby anthracyclines, 56dietary, 56
inhibitor hypothesis, 56, 57poisons and secondaryleukemia, 726–728and resistance toepipodophyllotoxins, 265
topoisomerase II inhibitorsexposure in utero, 333, 739therapy-related AML and, 36
topoisomerase II poisons, 725cytogenetic and moleculargenetic changes due to,739–744DNA damage mechanisms,744–747-related leukemias, 726clinical presentation, 748
total body irradiation, 532cataracts and, 707in Fanconi anemia, 280growth after, 702pregnancy after, 706
total intravenous anesthesia, 819total therapy approach in ALL,344–353toxicities, overlapping, 9toxicityamphotericin B, 783cardiopulmonary, 707–708complications from, 660cyclophosphamide, 320Down syndrome and, 506,511
drug resistance and, 423drug, phase I trials assess, 618endocrine, late, 701–706epipodophyllotoxins, 316, 317gastrointestinal, 311glucocorticoid, 319mercaptopurine, 311, 313methotrexate, 310MoAbs, 573profile, phase II trials and, 618teniposide, 317therapeutic index and, 309thiopurines, 312vincristine, 320
toxicology studies of novelagents, 617toxin–MoAb conjugates, 565toxoplasmosis, cerebral, 778TP53 gene, 205, 249, 730, 734,738trachea, compressed, 670, 671TRAIL receptors, 573trainingin developing countries, 552,555see also education
transcription factorsin AML, 225CEBP, 224HLF, 172gene rearrangements and,172
HOX, 176gene rearrangements and,172roles, 171
in CML, 249rearrangement of encodinggenes, 168in ALL, 168ETV6, 169MYC, 174RUNX1, 169in T-ALL, 176
serum response factor (SRF),220TCR genes and, 126
transcriptional repressors, PLZFprotein, 217transcriptional targeting, 599transcutaneous electrical nervestimulation, 818transforming growth factor-β ,604transfusionin AML, 411associated infections, 800,800–802blood components andindications, 795
coagulopathy and, 673granulocyte, 784packed red cells,794–796platelet, 796–799evaluating response to, 799
reactions, 797refusal of, erythropoietin in,807therapy, 5–6in thrombosis, 678
transient abnormalmyelopoiesis, 88, 93transient leukemia see transientmyeloproliferative disordertransient myeloproliferativedisorder (TMD), 29, 93, 151Down syndrome and, 34,93–94, 506–508in DS AMKL, 218GATA1 in, 217genetic lesions, 220progression, 219
translocation11q23, 94Burkitt, 122definition, 135immunophenotype-specific,145t(8;22)(q24), 385t(1;11)(q21;q23), 35t(1;14)(p32;q11), 176t(1;14)(p32;q11.2), 146t(1;19), 139–140, 340, 342t(1;19)(q23;p13), 30, 171t(1;19)(q23;p13.3), 139t(1;22), 154, 219–220t(1;22)(p13;q13), 92, 94t(1;7)(p32;q34), 125t(10;11), 154t(10;11)(p11.2;q23), 35t(10;11)(p12;q14), 156t(10;11)(p13;q14), 177t(10;11)(p13–15;q14–21), 173t(10;14)(q24;q11), 125t(11;14)(p13;q11), 125t(11;14)(p13;q11.2), 147t(11;14)(p15;q11), 125t(11;17), 33t(11;19)(q23;p13), 154t(12;19)(p13.3;p13.3), 140t(12;21), 142–144, 340t(12;21)(p13;q22), 30, 169t(14;21)(q11;q22), 125t(15;17), 9, 90, 152–153, 742,749t(15;17) (q22;q21), 10t(15;17)(q22;q12), 33t(15;17)(q22q1221), 215t(16;16), 742, 749t(16;16)(p13.1;q22), 35, 152,401t(16;16)(p13;q22), 90, 206t(16;21)(p11.2;q22.3), 157
t(16;21)(q24;q22), 157t(17;19)(q22;p13), 172t(17;19)(q22;p13.3), 140t(19;19), 140t(2;8)(p11;q24), 385t(3;21), 155t(3;5), 155t(4;11), 32, 82t(4;11)(q21;q23), 31, 173t(5;11), 155t(5;14) (q35;q11), 125t(5;14)(q35;q32), 125t(6;11)(q27;q23), 35t(6;14)(p22;q32), 145t(6;7)(q23;q32-q36), 125t(6;7)(q23;q34), 146t(6;9), 155t(6;9)(p23;q34), 90t(7;10)(q34;q24), 125t(7;11)(q34;p13), 125t(7;11)(q34;p15), 125t(7;12), 156t(7;12)(q34;p13), 125t(7;19), 176t(7;19)(q34;p13), 125t(7;19)(q34;p13.2), 147t(7;7)(p14;q34), 125t(7;9)(q34;q32), 125, 147, 176t(7;9)(q34;q34), 125t(8;14)(q11.2;q32), 146t(8;14)(q24.1;q32), 144–146t(8;14)(q24;q11), 125t(8;14)(q24;q32), 174, 385t(8;16), 742, 749t(8;16)(p11.1;p13.3), 155t(8;21), 9, 151–152, 208, 741,749t(8;21)(q22;q22), 34t(8;21)(q22;q22.3), 206t(9;11), 154t(9;11)(p21;q23), 35t(9;11)(p22;q23), 173t(9;14)(p13.2;q32), 145t(9;22), 140, 248, 743, 749t(9;22) (q34;q11), 11t(9;22)(q34;q11), 170t(9;22)(q34;q11.2), 31, 37t(p13;q22), 51t(v;11q23), 31, 37
translocations8q24, 28in ALL, 51, 168, 340in ALL-DS, 504–505in AML-DS, 508detection, 30immunophenotype and, 2in JMML, 448MLL, 739–741, 745in precursor B-ALL, 30prognosis according to, 9RUNX gene, 208topoisomerase II poisons and,739, 746, 749in treatment-related leukemia,739
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transplant-associatedmicroangiopathy, 538transposon-based vectors, 597traumatic lumbar puncture, 338treatmentof ALLcomplications, 524–525future trends 354pediatric vs. adult protocols,521–523, 524
of ALL-DS, 506altering, to reduce risk ofsecondary cancer, 729of AML, 404–411future directions, 411–412
of APL, 407–408initial response in APL, 215
barriers to, 554–555Burkitt lymphoma/leukemia,387–390of CML, 461–463developing new, 616–627early attempts, 3efficacy, remission duration asmeasure of, 5of essential thrombocythemia,471evaluation, approach, 128failure, methotrexate plasmaconcentration and, 310of graduated intensity, 554intervention studies,MRD-based, 649in JMML, 456–460of mastocytosis, 479–480novel, 480
in MDS, 436–437neuropsychologicalconsequences, 8in polycythemia vera, 467–468of primary myelofibrosis,474–475experimental, 475
principles of, in ALL, 345in relapsed ALL, 371CNS, 372–373testicular, 373
of relapsed ALL, 370–376of relapsed AML, 423–425-related cancersafter chemotherapy,725–728epidemiology, 724–725after radiation therapy,728reducing risk of, 729
-related death, 660-related leukemias, 56, 723AML, 404clinical presentation,latency, and diagnosis,747–750cytogenetics and moleculargenetics, 735–744
etiology, 744–747management algorithm, 750preleukemic phase, 749treatment of, 750–755
-related MDS, 404-related mortality inmyeloablative therapy, 527-related toxicity in DS AML,511remission induction, 840resistance, secondary geneticalterations and, 184response, SNPs and, 321results in ALL, 346of thrombosis, 678in TMD, 507treatment and rehabilitationphases of care, 840–846see also therapy
treatment and rehabilitationphases of care, 843triazoles, 783, 786trimethoprim, 7triploidy, 30trisomy 21, 219in ALL, 504in AMKL, 508and hematopoiesis, 219and leukemogenesis, 509, 510,512leukemogenesis in, 218in MDS, 434in TMD, 507
trisomy 8in MDS, 431in ALL, 340in AMKL, 402in AML, 148, 150
trisomy, triple, 137trisomy X, in ALL-DS, 504troxacitabine, 622truthfulness, 7tumor cellsimmune system recognition,582–584modification by gene therapy,597–601
tumor correction, 598, 599tumor lysis syndrome, 6, 661,664–666, 669in AML, 411assessment and managementalgorithm, 668in Burkitt lymphoma/leukemia, 388, 389
tumor necrosis factor-α inJMML, 449tumor suppressor genesinactivation
by aberrant DNAmethylation, 239in neurofibromatosis, 287,453
in MDS, 432mutationsas first hit, 276p53, in Burkitt lymphoma/leukemia, 385
in T-ALL, 183tumor suppressorsNPM, 221p14/15/16, 183
tumor vaccines, 599–600tumorigenesisgene therapy-related, 606RAS-induced, 224
tumors, childhood leukemia riskand, 52tumor-specific antigens,583, 583Turner, JR, preservation ofRBCs, 5twin studies, 52in ALL, 333relapse genetics, 184
twinning programs, 552, 554,555–556results of treatment of ALL,556–557results of treatment of AML,557–559results of treatment of Burkittleukemia/lymphoma, 557–559
two-hit hypothesis, 276, 453typhlitis, 662, 681, 777tyrosine kinase inhibitors, 9, 11,12, 171, 620, 624, 754in AML, 425in CML, epigenetics and, 249,250novel, 375, 462in Ph+ ALL, 3second-generation, 12,624
tyrosine kinases, 222–224activityof ABL, 170of BCR, 170
encoding gene abnormalities,157–158in CML, 249
tyrosine phosphatase (SHP-1) inCML, 249tyrosine phosphatase (SHP-2),454tyrosine protein kinaseinhibitors in CML, 461–463
ubiquitin-proteosome-dependent pathways, inhibitors,412unconjugated MoAb, 563under-five mortality rate,national wealth and, 550United Nations InternationalChildren’s Emergency Fund(UNICEF), 550urate oxidase, 6uric acid levels, 664, 665, 667in ALL, 337, 344in B-ALL, 388
uricolytic agents, in B-ALL, 388urinary side effects of therapy,710urinary tract infections, 779USA, childhood leukemiaincidence, 49, 50
V(D)Jcombinatorial diversity, 115exon, 113, 114coupling, 114somatic hypermutations,116
gene rearrangements, 114,115, 116, 120, 122, 127junctional regions in PCRanalysis, 636, 634–638, 644proto-oncogenes and, 126
recombination mechanism,114, 282
vaccination, 786DNA vaccines, 600–601immunotherapy strategies,425measles, 7repeating, 711tumor vaccines, 599–600varicella, 7
valproic acid, 620, 625vancomycin, 6, 780, 781in venous catheter, 804
varicella, 7, 775in chronic GVHD, 540
varicella zoster virus, 775varicella zoster immunoglobulin, 7vectors, gene therapy, 593–597,606veliparib, 620, 627Velpeau, A, first report ofleukemia, 1vena cava, superior, 671venous access support, 802–803devices, nursing care of, 841
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Vernick, J, truthfulness, 7vinca alkaloids, 263, 264resistance to, 258, 264, 268mechanisms, 263–264
vincristine, 8in ALL, 345, 349, 352, 521in AML, 10cellular drug resistance, 258,263–264intraindividual variability and,320new formulations, 620, 621pharmacodynamics, kinetics,and genetics, 320pharmacology, and outcome, 3in relapsed ALL, 370SIADH and, 686
viral antigens, 583, 583viral infections, 7cystitis, 779after HSCT, 537imitate JMML, 449myeloablative therapy and,527skin, 775transfusion-associated, 800
Virchow, R,cellular origin of leukemia, 1linked leukemia to whiteblood cells, 1“splenic leukemia”, 11
viridans streptococciin AML, 411prophylaxis, 785
virotherapy, 598
visceral pain, 814visilizumab, 564, 567vita cuff, 804vitamins, maternal use inpregnancy, 55von Willebrand factor inessential thrombocythemia, 469voriconazole, 783, 786vorinostat, 185, 620, 625in combination therapy, 248as histone deacetylaseinhibitor, trials of, 248
wealth, pediatric cancer survivaland, 551weightALL therapy and, 704–705drug dosage and, 660, 662
West Nile virus, bloodtransfusions and, 802WHO seeWorld HealthOrganizationWilms’ tumor gene (WT1)in AML, 409in PCR assays for MRD, 634
Wnt/β-catenin pathway, 266wood dust, parental exposure, 54World Health Organization(WHO)classificationof ALL, 29of AMKL, 154
of AML, 9, 23, 147, 155,204, 204, 399, 735:algorithms, 33of AML subtypes, 35, 88of eosinophilic disorders,475of hematopoietic andlymphoid neoplasms, 444of hematopoieticneoplasms, 32, 429of JMML, 445of JMML and chronicmyelomonocytic leukemia,38of lymphoma, 383, 384of mastocytosis, 478of MDS, 434mixed phenotypeleukemias, 37MLL subgroup, 154molecular, 30of MDSof myeloid neoplasms, 444of myeloid proliferations,151of T-ALL, 87of t(5;12), 157of t(9;11), 154
criteriafor essentialthrombocythemia, 468for polycythemia vera, 464for primary myelofibrosis,472
guidelines on pain therapy,815HLA nomenclature, 528
International NonproprietaryName (WHO–INN)committee, 617
Wright stain, 22Wright-Giemsa stain, Burkittlymphoma, 383
xanthine nephropathy, 665xanthine oxidase, allopurinoland, 6, 667xanthogranulomas, in JMML,446xenobiotic pathway geneticpolymorphisms, 58–59X-linked lymphoproliferativediseaseand risk of Burkittlymphoma/leukemia, 386
XPD protein, 731X-rayschest, 776findings in ALL, 337mediastinal mass, 670, 671
as early treatment, 3XRCC1 gene, 731
zebularine, 622zinc finger nucleases (ZFNs),599zoledronic acid, 457zygomycoses, 774, 783
880