Contemporary Management of Acute Lymphoblastic Leukemia Vinod Pullarkat
Page numbers followed by f refer to figure
lymphoblastic leukemia 1, 1f, 10, 12f16f, 22, 23f, 36, 49, 64, 67, 88, 90, 97, 135, 153, 160, 173, 200, 207, 210, 218, 219, 231f, 230f, 233, 235, 237, 246, 262, 276, 277f, 278, 279f, 285, 295, 318
chemotherapy 246
therapy 295
myeloid leukemia 23, 36, 55, 112, 306, 320
non-lymphocytic leukemia 32
Adrenocorticotropic hormone 298
Adult acute lymphoblastic leukemia 159, 165, 320
Allergy 30
hematopoietic stem cell transplantation 6, 283, 295
transplantation therapy 277f
American Academy of Pediatrics 30
Array comparative genomic hybridization 100
Asparaginase 177, 180
blues 179
enzymatic activity 188
use in induction 132
depletion 188
synthetase 264
Aspergillus niger 173
Ataxia telangiectasia 17
Bacillus Calmette-Guérin 7
B-acute lymphoblastic leukemia/lymphoma 49
acute lymphoblastic leukemia 88
precursor 67
Benzene 33
group 129
model 319
Blinatumomab 319, 320
Bloom syndrome 17
B-lymphoblastic leukemia/lymphoma 49
Bone marrow 49
core biopsy 50
Bordetella pertussis 63
Breastfeeding 30
Central nervous system 2, 129, 177, 218220, 223, 233, 237, 253, 295
Cerebrospinal fluid 218220, 223, 237
Chemotherapy of
adult acute lymphoblastic leukemia 149
childhood acute lymphoblastic leukemia 129
Childhood acute lymphoblastic leukemia 129
Chimeric antigen receptor 7, 321
modified T cells 321
graft-versus-host disease 287
lymphocytic leukemia 33, 322
myclogenous leukemia 36
myeloid leukemia 207
Cohort study 39
Common acute lymphoblastic leukemia 23
Cooperative group studies in adult ALL 150
Copy neutral loss of heterozygosity 97
Correlations with treatment outcome 203, 205
Corticosteroids 3, 254
radiation 229
therapy 135
radiotherapy 295, 298
Craniospinal radiation 298
Creb-binding protein 73
Cross resistance 266
Cyclophosphamide 130
Cytochemistry 52, 58
methods 98
of acute lymphoblastic leukemia 88
Deoxyribonucleic acid 176, 207, 246
Deoxythymidine monophosphate 250
Deoxyuridine monophosphate 250
Dexamethasone 234
Dihydrofolate 250
reductase 250, 252, 262
Donor lymphocyte infusion 288
Double strand breaks 19
Down syndrome 17, 50, 112
Endocrine dysfunction 295
Epratuzumab 320
Erwinia chrysanthemi 177
Escherichia coli 175, 223, 225
European Group for Blood and Marrow Transplantation 285
Extremely low-frequency 35
Fanconi anemia 17
Fluorescence in situ hybridization 97, 99
Follicle-stimulating hormone 300
Fresh frozen plasma 179
Gamma-secretase inhibitors 324
Genetics and molecular characteristics 61
association 17
studies 20, 98, 247
expression profiling 263
microarray approaches 100
mechanism of action 255
response element 255
Glutathione-S-transferases 255
Graft-versus-host disease 295
delayed infection hypotheses 25
hypothesized 25
Growth hormone 295
Haemophilus influenza 29
Heat-shock proteins 68
cell transplantation 318
stem cell 68
transplantation 133, 276
Hepatic veno-occlusive disease 323
High-resolution oligonucleotide 98
Human leukocyte antigen 6, 20, 276
Hygiene hypothesis 30
Hyperdiploidy 69
Hypoxanthine phosphoribosyltransferase 247
Induction therapy 130
Infertility 300
Inhibition of ribonucleic acid 176
monophosphate 248
triphosphate 248
pyrophosphatase 248, 262
Inotuzumab ozogamicin 320
Intrathecal chemotherapy 224, 232
cytarabine 237
methotrexate 235
Ionizing radiation 34
Adult Leukemia Study Group 157, 280
Marrow Donor Program 285
Society for Hematopoietic Cell Transplantation 285
hypothesis 38
population mixing 25
hypothesis 24
Klinefelter syndrome 17
Lactate dehydrogenase 219
Landmark pediatric trials 180
L-asparaginase 264
Late ophthalmic and dental effects 308
Leukemia-free survival 160
Leukemic phase of Burkitt lymphoma 63
Li-Fraumeni syndrome 17
Lower socioeconomic status 16
Lumbar puncture 220
Luteinizing hormone 300
Maintenance therapy 138
Management of acute lymphoblastic leukemia 149
Metastatic small cell tumors 64
Methotrexate 2, 249, 295
Methylene tetrahydrofolate reductase 18, 262
Mimicking Burkitt lymphoma 58
Minimal residual disease 90, 133, 150, 200, 207, 210, 255, 276, 280, 320
Mixed lineage leukemia 22, 67, 69, 90, 140, 210, 320, 324
Monitoring of minimal residual disease 200
Moxetumomab 320
Multidrug resistance 265
associated-proteins 264
protein 264
Multiplex ligation-dependent probe amplification 100
Myeloperoxidase 52
National Comprehensive Cancer Network Guideline 276
Neurocognitive dysfunction 304
Non-Hodgkin's lymphoma 285
Nonsteroidal anti-inflammatory drugs 73
B-cell maturation 52
T-cell development 58
thymic tissue and thymoma 64
Obesity 36, 299
Periodic acid-schiff and non-specific esterase 52
Peripheral blood stem cells 286
Pesticide exposure 32
Pneumocystis jiroveci 308
Polymerase chain reaction 55, 133, 162, 200, 207
intensification 129, 138
therapy 133
Prenatal origin of leukemia 75
Presymptomatic central nervous system therapy 137
CNS prophylaxis 229
treatment of CNS leukemia 222
Radiation therapy 223
Reactive lymphocytosis 63
Recurrent cytogenetic and molecular aberrations in T-ALL 91, 95
Ribonucleic acid 207, 246
Rituximab 320
Role of asparaginase 187
CNS prophylaxis 238
malignancies 306
treatment of CNS leukemia 228
Single nucleotide polymorphism 17, 72, 98
Skeletal disorders 302
Southwest Oncology Group Protocols 156
Starry sky appearance 50, 58
Stem cell transplantation 105
Structural chromosomal B-all subgroups 103
Systemic chemotherapy 224
Taiwan's National Health Insurance Program 26
acute lymphoblastic leukemia/lymphoma 88
receptor 59, 207
gamma 115
gene rearrangements 114
Terminal deoxynucelotidyl transferase 52, 105
Testicular radiation 298
Tetrahydrofolate 250
Thioguanine nucleotides 247
Thiopurine 247
S-methyl transferase 247, 262
Thymidylate synthase 252, 262
leukemia/lymphoma 57
neoplasms 57
Total body irradiation 228, 298
Traumatic lumbar puncture 221
Treatment of
acute lymphoblastic leukemia 1
children with Down syndrome and ALL 142
infant ALL 141
newly diagnosed ALL 129
relapsed ALL 142
T-ALL 140
Tyrosine kinase inhibitors 97, 129, 149, 238, 276, 319
Umbilical cord blood 287
Use of
asparaginase in acute lymphoblastic leukemia therapy 173
prednisone prephase 130
Varicella zoster virus 308
Vinca alkaloids 4
blood cell 219, 220, 276
count 90, 210
cell count 90
Wiskott-Aldrich syndrome 17
Xanthine oxidase 248
Chapter Notes

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1Contemporary Management of Acute Lymphoblastic Leukemia2
3Contemporary Management of Acute Lymphoblastic Leukemia
Editor Vinod Pullarkat MD MRCP Associate Professor Department of Hematology and Hematopoietic Cell Transplantation City of Hope National Medical Center Los Angeles, California, USA Foreword Dan Douer MD
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Contemporary Management of Acute Lymphoblastic Leukemia
First Edition: 2014
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Contributing Authors
Dan Douer md
Attending Physician
Leukemia Service
Memorial Sloan Kettering Cancer Center
New York, USA
The classification of leukemias became technically possible once methods for staining blood films were developed, thus dividing the acute forms into acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). It is remarkable that such a simple technique was able to recognize two distinct entities, derived from two functionally different hematopoietic cell pathways, at a time when the hierarchy of the hematopoietic stem cell growth and differentiation was yet not experimentally established. The clinical and biological characteristics of ALL, as distinct from AML, were firmly confirmed with contemporary methods for studying patient populations and leukemia cell biology. This volume provides a timely and up-to-date detailed review of different aspects of ALL.
Acute lymphocytic leukemia is more common in children, in whom it is the most common cancer and the majority of ALL patients are treated by pediatricians; although 40% of the patients are older than age 21. The development of well-defined sets of cellular (surface or cytoplasmic) markers have provided pathologists practical tools to rapidly and reliably, establish the diagnosis and phenotype of ALL. However, recurring cytogenetic abnormalities better define the different prognostic subgroups of ALL that occur at different rates in different age groups and partially explain the significantly better outcome in children. The rapid development in molecular genetics has further defined the molecular heterogeneity of ALL whereby patients can be lumped into different subgroups with similar outcomes. This work was mostly done in children, adolescents, and young adults but the question whether older adults, for the most part, have different molecular abnormalities, remains open.
The treatment of pediatric ALL has developed over the past 40 years by a series of large clinical trials each designed with the results of earlier trials in mind and as a result, currently 80% of children are cured. More recently, molecular testing can define at diagnosis those children who will have a worse outcome with the same treatment, such as those with Philadelphia (Ph) negative ALL but with a molecular signature of Ph positive ALL, carrying mutations in the IKZF1, CRLF2, JAK2, and other genes. Treatment of adults, on the other hand evolved empirically and much less systematically 10into multiple regimens, all with the same unfavorable outcome of approximately 40% long term survival. Due to this lack of an established standard of care, new directions are needed to improve the outcome in adult ALL. One approach is from realizing that separating pediatric from adult regimens at age 16–21 is arbitrary; pediatric regimens can be tolerated in older adults (at least until age 40–50) and preliminary studies show promising results. The use of pediatric approach in adults is more complex than the regimen itself due to compliance and psychosocial differences between children and young adults. A second general treatment concept that is not well recognized but is well supported by the distinct epidemiological, molecular, and other proprieties of ALL is that the general treatment principles of AML may not apply to ALL. For example, the mandatory central nervous system prophylaxis in all ages (rarely used in AML) has resulted in the greatest increment in survival. Also, the concept of short periods of very intense myelosuppressive AML-like chemotherapy may not apply so well in ALL but rather longer less myelosuppressive regimens may be more effective as exemplified by the long-term, low intensity maintenance phase of therapy that is unique for ALL. This concept is also highlighted by the critical role of a longer duration of therapy with the nonmyelosuppressive agent, L-asparaginase, that is so far used almost exclusively in ALL. With these changes in our chemotherapy approaches and introduction of novel and effective drugs (e.g., tyrosine kinase inhibitors in Ph+ ALL), the role of hematopoietic stem cell transplantation, especially as consolidation therapy in adult ALL, is continuously being defined.
Several other evolving topics are discussed comprehensively. First, several prognostic factors at diagnosis are highlighted in the different chapters on pathology, molecular biology, and cytogenetics. However, after treatment has begun, faster response with early lower disease burden measured by minimal residual disease (MRD) is critical in determining response and deciding on treatment changes. MRD is routinely monitored in children, but its application needs better standardization in adults. Second, dosing of drugs based on pharmacogenomic principles should allow better tailoring treatments for individual patients in the future. Finally, novel targeted approaches use antibodies either in their “naked” forms or more recently as drug conjugates as well as antibodies that are genetically engineered into normal autologous T cells in attempt to harness the patient's own immune system against ALL cells offer much promise.
Today, most children with ALL are cured. We hope that with the introduction of molecular stratification and new treatment approaches, the cure rate of adults will also increase. We need to pay particular attention to long term complications like therapy-related AML, within the much broader spectrum of survivorship problems, including quality of life and psychosocial issues that will become more prevalent as we anticipate more ALL survivors.
In this volume, Dr Pullarkat, an experienced investigator in the field of acute leukemia has brought together a panel of world renowned experts specializing in various aspects of the biology and therapy of ALL. Each chapter is a concise, yet comprehensive and up-to-date review of the developments in that field. This book would be a valuable reference for anyone involved in caring for patients with ALL.
Acute lymphoblastic leukemia (ALL), the commonest childhood leukemia, is now an eminently curable disease in children, thanks to developments in chemotherapy over the last 6 decades. However, adult ALL still remains a therapeutic challenge, particularly in older patients who are not candidates for intensive chemotherapy or hematopoietic stem cell transplantation (HSCT). Much work, therefore, remains to be done in order to improve outcomes of adult patients as well as patients with relapsed disease. This book is an attempt to compile the latest advances in the understanding of the pathogenesis of ALL as well as various aspects of its treatment.
The history of ALL therapy is fascinating and has important lessons for basic as well as clinical oncology research. In chapter 1, I have tried to briefly depict the evolution of ALL therapy from the remarkable efforts of early pioneers of cancer chemotherapy to the origin and development of modern oncology cooperative groups.
ALL is a heterogeneous disease with interesting epidemiologic features that differentiate childhood and adult ALL. Large scale epidemiologic studies as well as recent advances in genomic technology have provided interesting insights into the etiology of ALL, which for the most part still remains unclear. These data are discussed comprehensively in chapter 2.
The recent years have seen an explosion in knowledge regarding the cytogenetics, genomics, and molecular pathogenesis of ALL. These developments have led to the better classification as well as risk stratification of the disease which is critical for successful therapy. These topics are covered extensively in chapters 3 to 5.
Much of the advances in ALL therapy have come from systematic performance of large clinical trials by cooperative groups. Treatment of childhood and adult ALL are discussed in chapters 6 and 7. Although many aspects of treatment remain unclear, particularly in adult ALL, we have attempted to provide evidence based recommendations whenever possible. Chapter 8 deals with the use of asparaginase, a key drug in pediatric ALL therapy and discusses in detail its increasing role in adult ALL therapy.
Minimal residual disease monitoring has become an integral part of modern ALL therapy. However, it is technically challenging and requires standardization. These aspects are covered in chapter 9. Chapter 10 is devoted to prophylaxis and treatment of CNS disease, a critical component of ALL therapy. Advances in pharmacogenomics have the potential to allow tailoring of ALL therapy based on patient and disease characteristics 12in order to maximize efficacy and minimize toxicity. Pharmacogenomics of ALL therapy is discussed in chapter 11.
Allogeneic HSCT remains the only curative therapy for many ALL patients particularly those with relapsed disease. However, the role of HSCT in ALL therapy is continually evolving. As we gather molecular prognostic data, one can hope that we will be able to better select the patients who would benefit most from allogeneic HSCT. Use of HSCT in ALL is discussed in chapter 12.
As an increasing number of childhood ALL survivors enter adulthood; awareness of the long-term sequelae of therapy is critical in order to ensure quality of life and longevity of survivors. Long-term complications of ALL therapy and their management are considered in chapter 13.
In recent years, there has been tremendous excitement generated by the success of two immunologic approaches to ALL therapy, namely bispecific T-cell engaging antibodies and autologous chimeric antigen receptor expressing T-cells. These and other novel approaches hold promise to further improve outcomes of ALL therapy and are discussed in chapter 14.
Vinod Pullarkat md mrcp
Associate Professor
Department of Hematology and Hematopoietic Cell Transplantation
City of Hope National Medical Center
Los Angeles, California, USA
I wish to thank Dr Madhu Choudhary and Jaypee Brothers Medical Publishers for approaching me with the concept for this volume. I thank her as well as her editorial staff for providing me and my fellow contributors prompt assistance and support throughout the publishing process.
I am deeply indebted to all the contributors who despite their busy schedules took the time and effort to write the comprehensive and up-to-date chapters without which this book would not have been possible. Finally, I would like to thank all our patients for their trust and selfless participation in our clinical trials.