Adult Acute Lymphocytic Leukemia

Biology and Treatment
1. Auflage 2010
ISBN: 978-1-60761-707-5
Verlag: Humana Press
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 388 Seiten

The current explosion of new areas of controversy in the treatment of acute lymphocytic leukemia in adults and young adults makes this comprehensive book a much needed reference for hematologists and oncologists. This book assembles leading authorities from around the globe to cover the full spectrum of ALL subtypes and their treatments. Specific topics of discussion include indications for allogeneic bone marrow transplant in first complete remission, the role of minimal residual disease in making treatment decisions, the treatment of young adults, and the treatment of Philadelphia chromosome positive ALL with the advent of the tyrosine kinase inhibitors. This is the first book to focus exclusively on the adult ALL patient. It provides a complete overview of diagnosis, molecular pathogenesis, evaluation, and treatment for this important patient population.

Autoren/Hrsg.

Inhaltsverzeichnis

1;Preface;7
2;Acknowledgement;9
3;Contents;11
4;Contributors;13
5;Chapter 1: A Perspective on the Treatment of Acute Lymphoblastic Leukemia in Adults;17
5.1;How Can Results Be Improved in Adults?;18
5.1.1;Focus on Subgroups of Patients;18
5.1.2;What Can Be Learned from Pediatric Protocols and Can This Be Applied to Adults?;18
5.2;Future Considerations;20
5.2.1;Why Are Patients with Leukemia Cured?;20
5.3;Conclusions;21
5.4;References;21
6;Chapter 2: Acute Lymphocytic Leukemia – Clinical Features and Making the Diagnosis;24
6.1;Presentation: Signs, Symptoms and Laboratory Features;1
6.1.1;Superior Vena Cava Syndrome/Mediastinal Mass;24
6.1.2;Neurological Complications;1
6.1.3;Testicular Involvement;25
6.1.4;Other Organ Involvement;26
6.1.5;Hyperleukocytosis and Leukostasis;26
6.1.6;DIC;27
6.1.7;Metabolic Complications;27
6.1.8;Lactic Acidosis;28
6.2;Making the Diagnosis;28
6.2.1;Morphologic Assessment;29
6.2.2;Cytochemical Assessment;30
6.2.3;Immunophenotypic Assessment;30
6.2.4;Genetic Analysis;31
6.2.5;Gene Expression Profiling;34
6.2.6;Minimal Residual Disease;34
6.3;Differential Diagnosis;35
6.4;References;35
7;Chapter 3: The Biology of Adult Acute Lymphoblastic Leukemia;40
7.1;Introduction;40
7.2;Epidemiology;40
7.3;Biology of ALL;40
7.3.1;The Philadelphia Chromosome, t(9;22);417.3.1.1;Are p210 and p190 BCR-ABL Different?43
7.3.2;Ikaros;44
7.3.3;Mixed Lineage Leukemia;44
7.3.4;Chromosomal Changes Affecting Multiple Other Genes Involved with the Cell Cycle;45
7.3.5;MYC in Mature B Cell Leukemia;45
7.3.6;Genome-Wide Expression Analysis;45
7.3.7;T-ALL;46
7.3.8;Recurrent Translocations in T-ALL;46
7.3.9;Deletions, Duplications, and Mutations in T-ALL;47
7.3.10;Gene Expression Changes in T-ALL;48
7.3.11;Aberrant Lymphocyte Development;49
7.3.12;Recombinase Activating Genes (RAG);49
7.3.13;Oligoclonality and Clonal Evolution;50
7.4;Conclusion;52
7.5;References;52
8;Chapter 4: Minimal Residual Disease in Acute Lymphoblastic Leukemia;60
8.1;Introduction;60
8.2;Techniques for Detecting Minimal Residual Disease;60
8.3;PCR Methods;61
8.3.1;PCR for Recurrent Translocations;61
8.3.2;PCR for Antigen Receptor Rearrangements;61
8.4;Flow Cytometry Methods;63
8.5;Comparing PCR to Flow Cytometry–Based MRD;66
8.6;The Prognostic Significance of MRD;67
8.7;Efforts to Incorporate MRD into Frontline ALL Trials;69
8.8;Applications of MRD Testing in Relapsed ALL;69
8.9;Factors Limiting the Use of MRD for Therapeutic Decisions;70
8.10;Conclusions;70
8.11;References;71
9;Chapter 5: Cytogenetics;76
9.1;Introduction;76
9.2;Cytogenetic Techniques and Nomenclature;76
9.2.1;Conventional Cytogenetic Analysis;77
9.2.2;Cytogenetic Terminology;77
9.2.3;Fluorescence In Situ Hybridization;80
9.3;Chromosomal Abnormalities in Adult B-Cell Precursor ALL (BCP-ALL);81
9.3.1;t(9;22)(q34q11.2)/BCR-ABL1/Philadelphia Chromosome81
9.3.2;t(4;11)(q21q23)/MLL-AF4 and Other 11q23/MLL Translocations82
9.3.3;t(1;19)(q23p13)/TCF3-PBX183
9.3.4;High Hyperdiploidy (51–65 Chromosomes);83
9.3.5;Low Hypodiploidy (30–39 Chromosomes)/Near-Triploidy (60–78 Chromosomes);84
9.3.6;Complex Karyotype;84
9.3.7;Other Chromosomal Abnormalities;85
9.4;Chromosomal Abnormalities in Adult Mature-B ALL;85
9.5;Genetic Abnormalities in Adult T-Cell All (T-ALL);86
9.5.1;Activation of TAL1, TLX1, TLX3, and LMO2;86
9.5.2;Gene Fusions;87
9.5.3;Deletions and Mutations;87
9.6;Summary and Future Directions;87
9.7;References;88
10;Chapter 6: Acute Lymphoblastic Leukemia: Epidemiology;91
10.1;Demographic Patterns;91
10.1.1;Incidence;91
10.1.2;Survival;91
10.1.3;Mortality;92
10.1.4;Sex Differences;92
10.1.5;Race Differences;92
10.1.6;Age Differences;92
10.1.7;Parental and Birth Characteristics;92
10.1.8;Socioeconomic Status;93
10.2;Etiology;93
10.2.1;Biological Factors;94
10.2.1.1;Genetic Syndromes;94
10.2.1.2;Acquired Genetic Abnormalities;94
10.2.1.3;Infectious Etiology;94
10.2.2;Physical Factors;95
10.2.2.1;Ionizing Radiation;95
10.2.2.2;Nonionizing Radiation;96
10.2.3;Chemical Factors;96
10.2.3.1;Hydrocarbons;96
10.2.3.2;Pesticides;96
10.2.3.3;Smoking;97
10.2.3.4;Maternal Pharmaceutical Use;97
10.2.3.5;Maternal Alcohol Use;97
10.2.3.6;Outdoor Air Pollution;97
10.2.3.7;Diet;98
10.3;References;98
11;Chapter 7: Prognostic Factors in Adult Acute Lymphoblastic Leukemia (ALL);102
11.1;Introduction;102
11.2;“Classic” Clinical Diagnostic Prognostic Factors;102
11.2.1;Presenting White Blood Count (WBC);102
11.2.2;Age;103
11.2.2.1;Impact of Therapy Received on Age-Related Prognosis;103
11.2.3;Immunophenotype;104
11.2.3.1;T Cell Versus B Cell ALL;104
11.2.3.2;Other Immunophenotypic Markers;104
11.2.4;Specific Clinical Features;105
11.2.4.1;CNS Disease at Diagnosis;105
11.2.5;Cytogenetics;105
11.3;Response to Therapy;105
11.3.1;Time to CR;105
11.3.2;Minimal Residual Disease (MRD);106
11.3.3;Pharmacogenetics;106
11.3.4;Genomics;107
11.4;Prognosis of Relapsed ALL;107
11.5;Conclusions;108
11.6;References;108
12;Chapter 8: The Generalized Care of the Patient with Acute Lymphoblastic Leukemia;110
12.1;Introduction;110
12.2;Metabolic and Hematologic Complications;110
12.2.1;Tumor Lysis Syndrome;110
12.2.2;Hyperleukocytosis;112
12.2.3;Disseminated Intravascular Coagulation (DIC);114
12.2.4;Cytopenias and Transfusion Support;115
12.3;Infectious Complications;115
12.4;Febrile Neutropenia;115
12.4.1;Sepsis;117
12.4.2;Invasive Fungal Infections;118
12.4.3;Herpes Family Viral Infections;119
12.4.4;Respiratory Syncytial Virus (RSV);119
12.4.5;Pneumocystis jiroveci;120
12.5;Issues Related to Specific Antileukemic Agents;120
12.6;Conclusions;121
12.7;References;123
13;Chapter 9: Treatment of Acute Lymphoblastic Leukemia in Middle-Age and Older Adults;128
13.1;Introduction;128
13.2;Recent Clinical Trials;129
13.3;ALL in Older Adults;131
13.4;Clinical Trial Data;135
13.5;Co-morbidities and Complications;136
13.6;Summary;137
13.7;References;137
14;Chapter 10: Pharmacology of Acute Lymphoblastic Leukemia Therapy;140
14.1;Introduction;140
14.2;Glucocorticoids;141
14.2.1;Mechanism of Action;141
14.2.2;Clinical Pharmacology and Pharmacokinetics;141
14.2.3;Adverse Effects;141
14.2.4;Drug Interactions;141
14.3;Methotrexate;142
14.3.1;Mechanism of Action;142
14.3.2;Clinical Pharmacology and Pharmacokinetics;142
14.3.3;Adverse Effects;143
14.3.4;Drug Interactions;143
14.4;6-Mercaptopurine and 6-Thioguanine;143
14.4.1;Mechanism of Action;143
14.4.2;Clinical Pharmacology and Pharmacokinetics;144
14.4.3;Adverse Effects;144
14.4.4;Drug Interactions;144
14.5;Cytarabine;144
14.5.1;Mechanism of Action;144
14.5.2;Clinical Pharmacology and Pharmacokinetics;144
14.5.3;Adverse Effects;145
14.5.4;Drug Interactions;145
14.6;Anthracyclines;145
14.6.1;Mechanism of Action;145
14.6.2;Clinical Pharmacology and Pharmacokinetics;146
14.6.3;Adverse Effects;146
14.6.4;Drug Interactions;146
14.7;Vincristine;147
14.7.1;Mechanism of Action;147
14.7.2;Clinical Pharmacology and Pharmacokinetics;147
14.7.3;Adverse Effects;147
14.7.4;Drug Interactions;147
14.8;Cyclophosphamide;148
14.8.1;Mechanism of Action;148
14.8.2;Clinical Pharmacology and Pharmacokinetics;148
14.8.3;Adverse Effects;148
14.8.4;Drug Interactions;149
14.9;Asparaginase;149
14.9.1;Mechanism of Action;149
14.9.2;Clinical Pharmacology and Pharmacokinetics;149
14.9.3;Adverse Effects;149
14.9.4;Drug Interactions;150
14.10;Nelarabine, Clofarabine, and Forodesine;150
14.10.1;Mechanism of Action;150
14.10.2;Clinical Pharmacology and Pharmacokinetics;150
14.10.3;Adverse Effects;151
14.10.4;Drug Interactions;151
14.11;Imatinib, Nilotinib, Dasatinib;151
14.11.1;Mechanism of Action;151
14.11.2;Clinical Pharmacology and Pharmacokinetics;152
14.11.3;Adverse Effects;152
14.11.4;Drug Interactions;152
14.12;References;153
15;Chapter 11: Assessment of Response to Treatment;158
15.1;Introduction;158
15.1.1;Clinical Response Assessment;159
15.1.2;Hematologic/Morphologic;159
15.1.2.1;Central Nervous System Involvement;160
15.1.3;Minimal Residual Disease;160
15.1.3.1;Definitions of Response;161
15.1.3.2;Clinical Significance of MRD;162
15.1.3.3;MRD: Redefining Remission?;164
15.1.3.4;Cautions of MRD Interpretation;164
15.1.3.5;How to Respond to MRD Data – Therapeutic Decisions;164
15.1.3.5.1;MRD-Based Early Treatment Response;164
15.1.3.5.2;MRD Monitoring During Follow-Up to Detect Early Relapse;165
15.1.3.5.3;MRD-Based Post-Consolidation Therapy and SCT;165
15.1.4;Emerging Indicators for Response Assessment;166
15.1.4.1;Pharmacological;166
15.1.4.2;Epigenetics;166
15.2;Conclusions;166
15.3;References;167
16;Chapter 12: T-Cell Acute Lymphoblastic Leukemia;170
16.1;Introduction;170
16.2;T-ALL Classification;170
16.3;Molecular Genetics and Pathogenesis;171
16.4;Factors Predicting Clinical Outcomes in T-ALL;175
16.5;Treatment Outcomes in T-ALL;177
16.6;Novel and Investigational Therapies;180
16.7;T-ALL: Future Directions;181
16.8;References;182
17;Chapter 13: Burkitt Lymphoma and Leukemia;188
17.1;Introduction;188
17.2;Epidemiology;188
17.3;Pathogenesis;189
17.3.1;Role of c-myc;189
17.3.2;Role of Epstein-Barr Virus (EBV);190
17.3.3;The Germinal Center;191
17.4;Diagnosis of Burkitt Lymphoma and Burkitt Leukemia;191
17.4.1;B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma;197
17.5;Clinical Presentation of Burkitt Lymphoma and Leukemia;198
17.5.1;Burkitt Lymphoma;198
17.5.2;Burkitt Leukemia;199
17.6;Staging Systems;199
17.7;Treatment: Newly-Diagnosed Disease;200
17.7.1;Pediatric Studies;201
17.7.2;Adult Trials;203
17.7.3;Role of Rituximab;211
17.7.4;Therapy of HIV-Related Burkitt Lymphoma/Leukemia;212
17.8;Tumor Lysis Syndrome;215
17.9;Relapsed/Refractory Disease and the Role of Stem Cell Transplant;216
17.10;Novel Therapies;217
17.11;Conclusion;217
17.12;References;217
18;Chapter 14: Treatment of Acute Lymphoblastic Leukemia in Young Adults;224
18.1;Introduction;224
18.2;Adolescents with ALL : Young Adults or Old Children?;226
18.2.1;Adolescent ALL Characteristics;226
18.2.2;Dose Intensity;226
18.2.3;Allogeneic Transplantation (ASCT);230
18.2.4;Adherence to Treatment;230
18.3;Outcome of AYA in Adult Protocols;231
18.3.1;Prognostic Factors and Risk Assessment;231
18.3.2;Remission Induction;235
18.3.3;Post-remission Therapy;235
18.3.4;Allogeneic Stem Cell Transplantation (ASCT);236
18.3.5;Autologous Stem Cell Transplantation (autoSCT);236
18.4;Current Therapeutic Options for ALL in AYA;237
18.4.1;Treating AYA in “Hybrid” Protocols;237
18.4.2;Treating AYA According to Pediatric Trials;237
18.4.3;Long-Term Toxicity;238
18.5;Conclusion;239
18.6;References;239
19;Chapter 15: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia;245
19.1;Biology of Philadelphia Positive ALL;245
19.2;Historical Outcomes with Chemotherapy for Ph-Positive ALL;246
19.3;Historical Outcomes with Stem Cell Transplant for Ph-Positive ALL;246
19.4;Imatinib Mesylate for Previously Treated Ph-Positive ALL;247
19.5;Imatinib-Based Chemotherapy Regimens for De Novo Ph-Positive ALL;248
19.5.1;Imatinib-Based Chemotherapy Regimens for Younger De Novo Ph Positive ALL;248
19.6;Perspectives on Allogeneic Stem Cell Transplant in the TKI-Era;252
19.6.1;Role of Imatinib Post Allogeneic Stem Cell Transplantation;253
19.7;Treatment of Elderly Patients with Ph-Positive ALL;253
19.8;Mechanisms of Resistance to Tyrosine Kinase Inhibitors;254
19.8.1;ABL Kinase Domain Mutations;254
19.8.2;Other Mechanisms of Resistance to Imatinib;256
19.9;Second Generation Tyrosine Kinase Inhibitors for Ph-Positive ALL;257
19.9.1;Dasatinib;257
19.9.2;Nilotinib;259
19.9.3;Later Generation ABL Tyrosine Kinase Inhibitors;259
19.10;Targeting the T315I ABL Kinase Domain Mutation;259
19.11;Role of Monoclonal Antibodies in Ph-Positive ALL;259
19.12;Future Directions;260
19.13;Conclusions;260
19.14;References;261
20;Chapter 16: Molecular Therapies;268
20.1;Introduction;268
20.2;Epigenetic Therapy;269
20.2.1;Methylation;269
20.2.2;Histone Acetylation;270
20.3;Molecular Targets;271
20.3.1;Mammalian Target of Rapamycin (mTOR);271
20.3.2;Angiogenesis;272
20.3.3;Hedgehog Signaling;273
20.3.4;Survivin;273
20.3.5;NOTCH1 Signaling;274
20.3.6;Toll-like Receptor Signaling;275
20.3.7;Other Pathways and Targets;275
20.4;Monoclonal Antibodies;276
20.5;Conclusions;278
20.6;References;278
21;Chapter 17: Treatment of Relapsed Acute Lymphoblastic Leukemia;287
21.1;Introduction;287
21.2;Strategies for the Treatment of Patients with Relapsed ALL;288
21.3;Salvage Chemotherapy;289
21.4;Stem-Cell Transplantation;291
21.5;Prognostic Factors;292
21.6;Biologic Features;293
21.7;Clonal Evolution of Relapsed Leukemia;293
21.8;CNS Relapse;293
21.9;Testicular Relapse;294
21.10;Nucleoside Analogues;294
21.10.1;Clofarabine;294
21.10.2;Nelarabine;295
21.10.3;Asparaginase Preparations;296
21.10.4;Methotrexate Analogues;296
21.10.5;Monoclonal Antibodies;297
21.10.6;Liposomal Conjugates;297
21.10.7;Targeted Therapy;298
21.10.8;Other Agents;299
21.11;Conclusion;300
21.12;References;301
22;Chapter 18: Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia in Adults;307
22.1;Introduction;307
22.2;Rationale and the Graft Versus Leukaemia Effect;307
22.3;Conditioning Regimens;308
22.4;Sibling Allografting in First Remission;308
22.5;Unrelated Donor (UD) SCT in First Remission;309
22.6;The Role of RIC Allografting;310
22.7;Allografting for Relapsed Disease;310
22.8;Donor Lymphocyte Infusions;311
22.9;Allografting for Refractory Disease;311
22.10;Haploidentical and Cord Blood Transplantation for High-Risk ALL;311
22.11;Other Issues and Supportive Care;312
22.11.1;Central Nervous System (CNS) Disease;312
22.11.2;Palifermin;312
22.11.3;The Future;312
22.12;References;313
23;Chapter 19: Hematopoietic Stem Cell Transplantation in Philadelphia-Positive Acute Lymphoblastic Leukemia;315
23.1;Introduction;315
23.2;Historical Perspective;315
23.3;Allogeneic Stem Cell Transplant;316
23.3.1;“Donor” Versus “No Donor”;316
23.3.2;Umbilical Cord Blood Transplants;317
23.3.3;Graft Versus Leukemia Effect;317
23.3.4;Reduced-Intensity Conditioning Regimens;317
23.4;Autologous Stem Cell Transplant;318
23.5;Myeloablative Preparative Regimens;318
23.6;Tyrosine Kinase Inhibitors (TKIs);319
23.7;Conclusion;320
23.8;References;321
24;Chapter 20: Special Challenges: Genetic Polymorphisms and Therapy;324
24.1;Thiopurines;324
24.2;Methotrexate;327
24.3;Methylene Tetrahydrofolate Reductase;328
24.4;Thymidylate Synthase;328
24.5;Cyclin D1 (CCND1);329
24.6;Reduced Folate Carrier;329
24.7;Multidrug-Resistance Protein and Multidrug-Resistance-Associated Proteins;330
24.8;Corticosteroids;330
24.9;Genes of CS Action Pathways;330
24.10;Genes Coding for Xenobiotic Metabolizing Enzymes;331
24.11;Disease-Associated Genes;331
24.12;Other Genes Modulating the Therapeutic Response in Acute Lymphoblastic Leukemia;333
24.13;Hematopoietic Stem Cell Transplantation;333
24.14;Conclusion;334
24.15;References;334
25;Chapter 21: Late Consequences of Therapy of Acute Lymphoblastic Leukemia;340
25.1;Introduction;340
25.2;Cohort Studies;340
25.3;Neurologic;343
25.4;Endocrine;343
25.4.1;Height and Weight;343
25.4.2;Thyroid;344
25.4.3;Fertility and Sterility;344
25.4.4;Bone;345
25.5;Cardiac;346
25.6;Respiratory;347
25.7;Hepatic;347
25.8;Genitourinary;347
25.9;Ophthalmologic;348
25.10;Dental;348
25.11;Second Malignancies;348
25.12;Psychosocial;349
25.13;Blood and Marrow Transplantation;350
25.14;Follow-up Care;352
25.15;Conclusion;353
25.16;References;353
26;Chapter 22: Immunotherapy for Acute Lymphocytic Leukemia;359
26.1;Introduction;359
26.2;Allogeneic Transplantation as Cellular Immunotherapy;359
26.3;Reduced Intensity Conditioning;361
26.4;Donor Lymphocyte Infusion;361
26.5;Augmenting Alloreactive Immunity;362
26.6;Role of NK Cells;362
26.7;Generation of Leukemia Specific Immunity;363
26.8;Leukemia-Associated Targets for Antibody-Mediated Immunotherapy;363
26.9;T Cells Expressing Chimeric Antigen Receptors: Combined Humoral and Adoptive Immunotherapy;364
26.10;Targeting Known Tumor-Associated Antigens;365
26.11;Enhancement of Antigen Presentation Using Dendritic Cells;365
26.12;Conversion of ALL Cells into Antigen Presenting Cells;366
26.13;Cytokine Therapy as Immune Adjuvants;367
26.14;Summary;367
26.15;References;367
27;Chapter 23: Unique Subtypes in Acute Lymphoblastic Leukemia;372
27.1;Myeloid Antigen Expression in ALL;373
27.2;My Agpos Genetic Subtypes;375
27.2.1;BCR/ABLpos ALL;376
27.2.2;CD117pos ALL with or Without FLT3 Gene Mutations;376
27.2.3;NOTCH1-Mutated T-ALL with Myeloid Features;379
27.2.4;T-ALL with HOX11/TLX1 Overexpression;379
27.2.5;TEL/AML1pos ALL;380
27.2.6;MLL/AF4pos ALL;380
27.3;Genotypes with Unique Antigenic Features Other Than My Ags;381
27.3.1;CALM/AF10pos T-ALL and Gd-T-Cell Receptor Expression;381
27.3.2;E2A/PBX1pos B-Lineage ALL;381
27.3.3;TCRb-HOXA Rearranged T-ALL;382
27.4;Unique ALL Subtypes without Invariably Apparent Genetic Correlates;382
27.4.1;CD56pos ALL;382
27.4.2;CD2pos B-Lineage ALL;383
27.5;Comments for the Future;383
27.6;References;384
28;Index;389