Textbook of malignant hematology

Cover......Page 1
Textbook of Malignant Hematology......Page 4
Contents......Page 6
Contributors......Page 10
Preface......Page 16
Lifetime conservation of stem cell activity......Page 26
Ontogeny of the HSC......Page 27
Regulation of HSC quiescence and proliferation......Page 28
Characterization of stem cells......Page 29
Long-term cultures......Page 30
SCID mouse assay......Page 31
Ex vivo expansion of stem cells......Page 32
REFERENCES......Page 33
The concept of the stem cell......Page 38
Epithelial stem cells......Page 39
Skeletal muscle from BM-derived cells......Page 40
Myocardium from BM-derived cells......Page 41
Neural cells from BM-derived cells......Page 42
Potential mechanisms underlying stem cell plasticity......Page 43
Conclusions and future directions......Page 44
REFERENCES......Page 45
Introduction......Page 48
Other signaling pathways......Page 49
Phosphatases and GAPs......Page 50
Severe combined immunodeficiency (SCID)......Page 51
Severe congenital neutropenia (SCN)......Page 52
Activating mutations......Page 53
REFERENCES......Page 54
Introduction......Page 58
Cell division......Page 59
Cyclin-dependent kinases......Page 61
Cyclin-dependent kinase inhibitors......Page 64
Substrates of the cyclindependent kinases......Page 67
Introduction......Page 73
Cyclins......Page 74
CKIs......Page 76
Clinical implications of the analyses of pRb/cyclin-cdk/CKI families......Page 78
REFERENCES......Page 79
Combinations of transcription factors drive lineagespecific gene expression......Page 89
Transcription factors critical for stem cells......Page 90
Transcription factors critical for the formation or function of specific lineages......Page 92
Stem cells, lineage commitment, and plasticity......Page 93
Target cells for transformation......Page 95
Transcription factor genes are common targets in leukemia......Page 96
Translocations involving 21q22 and inversion 16......Page 98
Tyrosine kinase and RAS signaling pathways......Page 100
Genes influencing chromatin structure may be targets for leukemogenic rearrangements......Page 101
REFERENCES......Page 102
Generation of immature B cells......Page 108
Interaction of B-cell progenitors with stromal cells in the bone marrow......Page 110
Development of the basic Ig repertoire in the bone marrow as B cells differentiate......Page 111
Germinal center formation and the acquisition of somatic mutations......Page 112
Conclusions......Page 114
REFERENCES......Page 115
Introduction......Page 117
T- and NK-cell development......Page 118
Mature T and NK cells......Page 123
REFERENCES......Page 126
DC origins and differentiation pathways......Page 128
Monocyte-derived DC......Page 129
Langerhans cells and dermal DC......Page 130
Cytokines inhibiting DC differentiation......Page 131
Signals inducing DC maturation......Page 132
T-cell activation by DC......Page 133
Clinical perspectives......Page 134
REFERENCES......Page 135
Polymorphonuclear neutrophils......Page 138
Function of mononuclear phagocytes......Page 139
Hematopoietic growth factors......Page 140
Growth factor-deficient animals......Page 141
Enhancement of cell survival......Page 142
GM-CSF......Page 143
SCF......Page 144
Role of adhesion molecules......Page 145
REFERENCES......Page 146
Adult erythropoiesis at the cellular level......Page 150
Stem cell factor and its receptor......Page 151
Erythropoietin and its receptor......Page 152
Synergy between EPO and SCF during adult erythropoiesis; role of the glucocorticoid receptor......Page 153
Trans-acting factors that are required for setting up erythropoiesis......Page 154
Trans-acting factors involved in the expression of erythroid-specific genes......Page 155
Cell cycle, apoptosis, and erythroid-specific trans-acting factors......Page 157
BFU-Mk......Page 161
Megakaryocyte precursor cells identified by stagespecific differentiation markers......Page 162
The endomitotic compartment......Page 163
Platelet shedding......Page 164
Regulation of megakaryocytopoiesis by transcription factors......Page 165
Thrombopoietin, a ligand for the Mpl receptor......Page 166
Interleukin-3 and granulocyte-macrophage colonystimulating factor......Page 167
Other hematopoietic growth factors......Page 168
Inhibitory factors......Page 169
Transcription factors and abnormal megakaryocytopoiesis......Page 170
Clinical potentials of TPO......Page 171
REFERENCES......Page 172
DNA repair mechanisms......Page 180
Homologous recombination......Page 181
V(D)J recombination......Page 182
Immunoglobulin class switching......Page 183
Homologous recombination and chromosomal aberrations......Page 184
Non-homologous end-joining and chromosomal aberrations......Page 186
REFERENCES......Page 187
Telomere structure and function......Page 190
Telomere maintenance pathways......Page 191
Telomeres and replicative senescence......Page 192
Acknowledgments......Page 194
REFERENCES......Page 195
The angiogenic process......Page 197
Angiogenic factors......Page 198
Angiogenesis and hematopoiesis......Page 199
Angiogenesis in hematologic tumors......Page 200
Multiple myeloma......Page 201
Acute myeloid leukemia......Page 203
Acute lymphoblastic leukemia......Page 204
Myelodysplasia......Page 205
Lymphomas......Page 206
REFERENCES......Page 207
Epidemiology and associated diseases......Page 212
Cellular tropism and viral receptor......Page 213
Tax protein and its role in leukemogenesis......Page 214
Epidemiology......Page 216
Cytological, immunovirological and molecular features of ATLL......Page 217
Cutaneous lesions......Page 220
Therapeutic aspects of ATLL......Page 221
Viral factors......Page 222
Pathogenesis of ATLL......Page 223
Lymphoproliferative diseases associated with HTLV-2......Page 224
REFERENCES......Page 226
Epstein-Barr virus......Page 232
EBV and immunodeficiency......Page 234
KSHV/HHV8......Page 235
EBV-associated tumors in PID......Page 236
EBV and post-transplant lymphoproliferative disorders (PTLD)......Page 237
EBV and AIDS-related lymphomas......Page 238
REFERENCES......Page 239
Gene rearrangements......Page 243
FISH......Page 244
t(15;17)(q22;q21): PML/RARA......Page 245
t(8;21)(q22;q22): RUNX1-ETO......Page 247
t(8;16)(p11;p13): MOZ-CBP......Page 248
MLL/11q23......Page 249
ETV6/12p13......Page 250
Gene amplification......Page 251
Gene mutation......Page 252
Trisomies......Page 253
The 5q- syndrome......Page 254
t(8)(p11) Myeloproliferative syndrome......Page 255
REFERENCES......Page 256
Mechanisms of oncogene activation and TSG inactivation......Page 259
Methods used to detect genetic alterations......Page 260
Chromosome translocations: prototypic examples......Page 263
Other recurrent mutations in lymphoid malignancies......Page 265
REFERENCES......Page 266
Introduction......Page 268
X-chromosome inactivation patterns......Page 269
Chronic myeloid leukemia......Page 272
Aplastic anemia and paroxysmal nocturnal hemoglobinuria......Page 273
REFERENCES......Page 274
Technical aspects......Page 278
Data mining, interpretation, and storage......Page 279
Prediction of genetic abnormalities......Page 281
Acute lymphoblastic leukemia (ALL)......Page 284
Class prediction......Page 285
REFERENCES......Page 288
Lymphoid malignancies......Page 291
Detection of minimal residual disease......Page 292
Aberrant immunophenotypes as targets for MRD detection......Page 293
T-cell ALL and T-lymphoblastic lymphoma......Page 294
Chronic B-cell leukemias and B-cell NHL......Page 296
Chronic T-cell leukemias and T-NHL......Page 297
Rearrangement of Ig and TCR genes and formation of antigen receptor diversity......Page 298
Secondary rearrangements in Ig and TCR genes......Page 299
Junctional regions as PCR targets for MRD detection......Page 300
Sensitivity of PCR analysis of junctional regions......Page 302
TCR and Ig gene rearrangements in T-ALL......Page 303
Oligoclonality and clonal evolution of Ig and TCR gene rearrangements......Page 304
PCR analysis of Ig genes in mature B-cell malignancies......Page 305
Chromosome aberrations as PCR targets for MRD detection......Page 306
ALL......Page 307
NHL......Page 308
Real-time quantitative PCR......Page 309
Detection of CNS involvement in ALL patients......Page 311
Detection of bone marrow involvement during initial staging of NHL......Page 312
ALL......Page 313
Clinical value of MRD detection for assessment of early response to first-line cytotoxic treatment in childhood ALL......Page 314
Clinical value of continuous MRD monitoring in childhood ALL......Page 315
Clinical value of MRD detection before and/or after stem cell transplantation in childhood ALL......Page 316
Value of MRD monitoring in B-CLL patients treated with SCT......Page 317
Negativity or persistence of low MRD levels in FL patients in complete remission after SCT......Page 318
MM......Page 319
Conclusions......Page 320
REFERENCES......Page 321
Introduction......Page 333
Measurement of DNA ploidy by flow cytometry......Page 335
Molecular biology......Page 336
Cytogenetics and FISH in AML......Page 337
Basis of MRD detection in AML......Page 338
Clinical results......Page 339
Molecular monitoring of PML-RARα transcripts in AML with t(15;17)(q22;q21)......Page 341
Molecular monitoring of AML1-ETO transcripts in AML with t(8;21) (q22;q22)......Page 342
Other chromosomal translocations: 11q23 aberrations, t(6;9)(p23;q34), and t(9;22)(q34;q11)......Page 343
Myelodysplastic syndromes......Page 344
RT-PCR......Page 345
REFERENCES......Page 347
Extrinsic resistance......Page 351
ABC proteins......Page 352
Acute myetoid leukemia......Page 353
Lung resistance protein/major vault protein......Page 354
p53 and proteins regulating the cell cycle......Page 355
Anti-apoptosis proteins and signals......Page 356
Resistance to cytarabine......Page 357
REFERENCES......Page 358
The Skipper experiments......Page 361
Relative dose intensity (RDI)......Page 362
Examples of dose intensification not requiring stem cell transplantation......Page 363
Chemotherapy infusion and ‘third spacing’......Page 364
REFERENCES......Page 365
The history of antibody therapy......Page 367
Recombinant antibodies......Page 368
Effector functions of mAbs......Page 370
Signaling functions of antibodies......Page 371
Obstacles in antibody therapy......Page 373
Clinical use of unlabeled antibodies......Page 374
Immunotoxins......Page 377
Targeting of anticancer drugs by the use of antibodies......Page 380
Radioimmunotherapy......Page 381
Purging strategies......Page 386
Anti-idiotypes and idiotype vaccination......Page 387
Targeting T cells to tumor cells by using bifunctional antibodies......Page 389
Targeting solid tumors......Page 392
Suppression of B-cellular immune responses......Page 393
Suppression of T-cell responses......Page 394
REFERENCES......Page 396
Immunotherapy of cancer......Page 403
Cytokines; genetically engineered tumor cells......Page 404
Peptide-based vaccines for the induction of antitumor T-cell immunity......Page 405
Optimal antigen presentation; dendritic cells......Page 406
Genetically engineered, molecularly defined vaccines......Page 407
Transfer of in vitro expanded tumor-reactive T lymphocytes......Page 409
REFERENCES......Page 410
Mutations in receptor tyrosine kinases......Page 415
c-Kit......Page 416
Flt3......Page 417
PDGFRβ......Page 418
Ras......Page 419
PI3K......Page 421
Signaling components as therapeutic targets......Page 422
BCR-ABL-positive leukemias......Page 423
Inhibitors of Ras......Page 424
Conclusions......Page 425
REFERENCES......Page 426
Retroviral vectors......Page 431
Adenoviruses......Page 432
Adeno-associated viruses (AAV)......Page 433
Correction or deletion of underlying defects......Page 434
DNA vaccines......Page 436
Artificial T-cell receptors......Page 437
T-cell modification to improve survival or overcome tumor evasion mechanisms......Page 438
Sensitivity of host cells to cytotoxic drugs......Page 439
In autologous stem cell transplantation......Page 440
Summing up......Page 441
REFERENCES......Page 443
Identification of donors suitable for allogeneic BMT—the HLA gene complex: the major determinant of histocompatibility in human BMT......Page 448
Minor alloantigen systems contributing to graft rejection and GVHD following BMT in humans......Page 449
Sources of allogeneic hematopoietic cells for transplantation......Page 450
The pre-engraftment period......Page 451
Acute and chronic GVHD......Page 452
T-cell-depleted marrow transplants for prevention of GVHD......Page 454
GVL: enhanced resistance to leukemia conferred by marrow allograft and augmentation by posttransplant adoptive cell transfer......Page 455
Infections in the early stages of immune reconstitution......Page 457
Infections in the later stages of immune reconstitution......Page 458
Late complications of marrow transplants......Page 459
Acute myeloid leukemia......Page 460
Transplantation for ALL in second or greater remission or relapse......Page 463
Chronic myeloid leukemia......Page 464
Myelodysplastic syndromes......Page 466
Multiple myeloma......Page 467
Unmodified marrow grafts from partially matched related donors......Page 468
Transplants of unmodified marrow from unrelated donors......Page 469
Allogeneic cord blood transplants from related and unrelated donors......Page 470
T-cell-depleted HLA non-identical related and HLA-compatible unrelated marrow grafts......Page 472
Non-myeloablative/reduced-lntensity conditioning regimens for allogeneic transplantation......Page 474
REFERENCES......Page 475
Incidence and mortality......Page 491
Geographical variation......Page 492
Epidemic of NHL......Page 495
Age curves and cohort of birth......Page 496
Childhood leukemia......Page 497
The lymphomas......Page 498
The leukemias......Page 499
NHL, other than Burkitt lymphoma......Page 501
Leukemias......Page 502
Survival in European and US populations......Page 503
REFERENCES......Page 504
Epidemiology and risk factors......Page 507
Diagnosis and classification......Page 509
Clinical manifestations......Page 511
Laboratory findings......Page 512
Differential diagnosis......Page 513
Prognostic factors......Page 514
Acute lymphoblastic leukemia......Page 515
Induction of remission (early therapy)......Page 516
Central nervous system involvement......Page 517
Higher-risk non-Hodgkin lymphoma (advanced-stage disease)......Page 518
Acute lymphoblastic leukemia......Page 519
Supportive care......Page 520
REFERENCES......Page 521
Morphology......Page 525
Cytogenetics......Page 526
Laboratory evaluation......Page 527
Infection prophylaxis......Page 529
Remission induction therapy......Page 530
Intensification therapy......Page 532
High-dose chemotherapy......Page 533
Therapy for relapsed and resistant leukemia......Page 534
Matched unrelated SCT......Page 535
Prognostic factors......Page 536
B-lineage ALL......Page 537
Minimal residual disease......Page 538
Anti-CD20......Page 539
REFERENCES......Page 540
Epidemiology......Page 546
Biology......Page 548
Disease transformation......Page 549
Prognosis......Page 550
Treatment approaches......Page 552
Biology......Page 553
Biology......Page 554
Treatment......Page 555
Prognosis......Page 556
Biology......Page 557
Treatment......Page 558
Biology......Page 559
Diagnosis......Page 560
Diagnosis......Page 561
REFERENCES......Page 562
Epidemiology......Page 568
Premyeloma conditions......Page 569
Molecular abnormalities......Page 570
Microenvironment......Page 571
Interleukin 6......Page 572
Clinical features......Page 573
Diagnosis......Page 574
Standard-dose chemotherapy......Page 575
High-dose therapy and stem cell transplantation......Page 576
Timing of high-dose therapy......Page 578
Management of patients with renal dysfunction......Page 579
Donor lymphocyte infusions......Page 580
Thalidomide......Page 581
Bisphosphonates......Page 583
REFERENCES......Page 584
Histopathology and correlation with age......Page 590
Staging......Page 591
Early stages......Page 592
Intermediate (early unfavorable) stages......Page 593
Advanced stages......Page 594
Treatment of relapses after chemotherapy......Page 595
Future developments......Page 596
REFERENCES......Page 597
Introduction......Page 600
Etiology and pathogenesis......Page 601
Genetics, etiology and pathogenesis......Page 604
Genetics, etiology and pathogenesis......Page 605
Genetics, etiology and pathogenesis......Page 607
Morphology and immunophenotype......Page 608
Grading and tumor progression in follicular lymphoma......Page 609
Genetics, etiology and pathogenesis......Page 610
Diffuse large B-cell lymphoma......Page 611
Genetics, etiology and pathogenesis......Page 612
Genetics, etiology and pathogenesis......Page 613
Immune-deficiency-associated EBV-positive lymphomas......Page 614
Genetics, etiology and pathogenesis......Page 615
Genetics, etiology and pathogenesis......Page 616
Intestinal T-cell lymphoma......Page 617
CD30+ cutaneous ALCL and lymphomatoid papulosis......Page 618
Staging and treatment evaluation......Page 619
Prognostic factors......Page 620
Wait and see approach vs. chemotherapy......Page 622
Fludarabine......Page 623
Monoclonal antibodies, radio-immunotherapy......Page 624
Localized disease......Page 625
High-dose chemotherapy followed by autologous peripheral blood stem-cell transplantation in first remission......Page 626
Mantle-cell lymphoma......Page 627
REFERENCES......Page 628
Biology and classification......Page 642
Risk group definitions and prognostic features......Page 643
Treatment of AML......Page 644
Remission induction therapy......Page 645
Postremission therapy......Page 646
Treatment of CNS extramedullary disease (EMD)......Page 647
Treatment of relapsed AML......Page 648
Resistance mechanisms for anthracyclines......Page 650
Drug resistance as a prognostic factor......Page 651
Conclusions......Page 652
REFERENCES......Page 653
Concept of AML stem cells......Page 658
FLT3 mutations......Page 659
Diagnosis and classification of AML......Page 660
Immunocytology and cytogenetics......Page 662
Response evaluation after induction therapy......Page 663
Stem cell transplantation......Page 664
Cytogenetics and molecular genetics......Page 666
Initial morphological response to treatment......Page 668
Targeted leukemic cell killing......Page 669
Complications and mortality during remission induction therapy in the elderly......Page 670
Randomized studies in AML to enhance hematopoietic recovery after chemotherapy......Page 671
Refractory disease......Page 672
Novel treatment approaches......Page 673
REFERENCES......Page 674
Clinical features and laboratory findings......Page 682
Molecular genetics of APL......Page 683
Results of intensive chemotherapy......Page 684
Two major adverse effects: retinoic acid syndrome and secondary resistance......Page 685
Treatment after remission......Page 686
Prognostic factors......Page 687
Arsenic treatment......Page 688
Acute promyelocytic leukemia as a model for malignancies......Page 689
REFERENCES......Page 690
Exogenous factors......Page 694
Cytogenetic abnormalities26–36......Page 695
RAS, NF1, PTPN11 mutations in MDS......Page 696
MDS with t(3; 21)(q26; q22) or t(1; 3)(p36; q21)65......Page 697
Clonality in MDS......Page 698
Growth factors and growth factor receptors in MDS......Page 699
Peripheral blood findings......Page 700
Bone marrow aspirate......Page 701
Bone marrow karyotype......Page 702
Refractory anemia with ringed sideroblasts......Page 703
WHO classification of MDS132......Page 704
MDS with t(3; 3)(q21; q26) or inv(3)(q21; q26)138......Page 705
Survival......Page 706
Prognostic scores in MDS36,37,139–142......Page 707
Intensive chemotherapy with or without autologous stem cell transplantation......Page 708
Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor......Page 710
Other drugs in MDS......Page 711
In patients with low or int1 IPSS (or if kanyotype is not available, marrow blasts <10%)......Page 712
Conclusion......Page 713
REFERENCES......Page 714
Etiology and epidemiology......Page 721
The BCR-ABL gene and its variants......Page 722
The role of BCR-ABL in leukemic stem cell dysfunction......Page 724
Laboratory findings......Page 725
Accelerated phase......Page 727
Blastic phase......Page 728
Forms of the disease and atypical presentation......Page 729
Prognosis......Page 730
Chemotherapy......Page 733
Interferons......Page 734
Results of clinical trials with imatinib......Page 736
Stem cell transplantation......Page 739
Treatment of accelerated phase......Page 743
Imatinib......Page 744
High dose chemotherapy......Page 745
Stem cell transplantation......Page 746
Imatinib......Page 747
Imatinib in combination with other antileukemic agents......Page 748
SPIRIT study......Page 749
Practical aspects of treatment......Page 750
REFERENCES......Page 751
Pathophysiology......Page 760
Diagnostic criteria......Page 761
Epidemiology and natural history......Page 762
Therapy......Page 763
Cytoreduction......Page 764
Current therapeutic recommendations and future directions......Page 765
Diagnostic criteria......Page 766
Bleeding......Page 767
Hydroxyurea......Page 768
Anti-aggregation therapy......Page 769
Cellular and molecular pathogenesis......Page 770
Clinical features and diagnosis......Page 771
Prognosis......Page 772
Therapy......Page 773
REFERENCES......Page 774
Overall risk of second malignancy......Page 778
Leukemia......Page 781
Role of chemotherapy......Page 782
Effect of age at treatment......Page 783
Pericarditis......Page 785
Myocardial infarction and cardiac death......Page 786
Effect in patients with HL......Page 789
REFERENCES......Page 790
Introduction......Page 794
Cardiotoxicity......Page 795
Growth......Page 796
Gonadal function and fertility......Page 797
Fertility......Page 798
Cognitive and neuropsychological sequelae......Page 799
Conclusions......Page 800
REFERENCES......Page 801
B-cell PTLD......Page 807
Myelodysplastic syndrome and acute leukemia......Page 809
Conclusions......Page 810
Microvascular retinopathy......Page 811
Chronic obstructive pulmonary disease......Page 812
Osteoporosis......Page 813
Puberty and gonadal failure......Page 814
REFERENCES......Page 815
Biology of EPO......Page 819
Myelodysplastic syndromes......Page 820
Side-effects of EPO......Page 821
Biology of G-CSF and GM-CSF......Page 822
Primary prophylaxis......Page 823
Use of G-CSF and GM-CSF in specific disorders......Page 824
Pegfilgrastim......Page 825
Thrombopoietin......Page 826
REFERENCES......Page 827
Neutropenia......Page 836
Nosocomial infections......Page 837
Epidemiology of infections during neutropenia......Page 838
Minimal microbiological examinations......Page 839
Empiric therapy for first intention......Page 840
Reconsidering therapy during aplasia......Page 841
Pneumonia......Page 842
Central nervous system infections......Page 844
Special considerations for allogeneic BMT/PBSCT recipients......Page 846
REFERENCES......Page 849
FAB classification......Page 852
Index......Page 870