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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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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

852






Index

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

853






Index

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

854






Index

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

855






Index

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

856






Index

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

857






Index

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

858






Index

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

859






Index

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

860






Index

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

861






Index

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

862






Index

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

863






Index

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

864






Index

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

865






Index

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

866






Index

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

867






Index

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

868






Index

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

869






Index

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

870






Index

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

871






Index

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

872






Index

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

873






Index

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

874






Index

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

875






Index

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

876






Index

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

877






Index

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

878






Index

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

879






Index

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




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