**Meet the editor**

Stefan Faderl, M.D., Professor of Medicine came to M.D. Anderson in 1996. Dr. Faderl graduated from Ludwig Maximilian Medical School in Munich, Germany in 1990 and received his medical/academic degree (magna cum laude) from the same institution in 1994. Dr. Faderl is board certified in Internal Medicine and Medical Oncology. He specializes in acute and chronic leukemias.

His main areas of interest include acute lymphoblastic leukemias (ALL), acute myeloid leukemias (AML), chronic lymphocytic leukemia (CLL) and its variants, as well as chronic myeloid leukemias (CML). Dr. Faderl has authored and co-authored many abstracts, articles in peer-reviewed journals and book chapters. He serves on numerous editorial boards and is a member of several professional societies such as the American Society of Hematology (ASH), the American College of Physicians (ACP), and the American Society of Clinical Oncology.

Contents

**Preface IX** 

**Part 2 NK Cell Leukemia 33** 

Chapter 2 **Natural Killer Cell Leukemia:** 

Shoko Kobayashi

**Part 3 Clinical Manifestations of** 

Chapter 3 **Ophthalmological Manifestations** 

Chapter 4 **Acute Lymphoblastic Leukemia:** 

Chapter 1 **Childhood Acute Leukemias in Hispanic Population:** 

**Diagnosis, Pathogenesis and Treatment 35** 

**Acute Lymphoblastic Leukemia 51** 

**in Acute Lymphoblastic Leukemia 53**  Javier Mateo, Francisco J. Ascaso, Esther Núñez, Carlos Peiro, Gonzalo González and José A. Cristóbal

**What Have We Learned About the Effects of This Disease and Its Treatment on the Nervous System? 73** 

Van Huynh, Leonard Sender and Daniela A. Bota

**Part 4 Therapy of Acute Lymphoblastic Leukemia 99** 

Chapter 5 **Treatment of Pediatric Acute Lymphoblastic Leukemia and Recent Advances 101**  Tai-Tsung Chang and Pei-Chin Lin

**Differences by Age Peak and Immunophenotype 3**  Juan Manuel Mejía-Aranguré, María Luisa Pérez-Saldivar, Rosana Pelayo-Camacho, Ezequiel Fuentes-Pananá, Carolina Bekker-Mendez, Abigail Morales-Sánchez, David Aldebarán Duarte-Rodríguez and Arturo Fajardo-Gutiérrez

**Part 1 Epidemiology 1** 

## Contents

## **Preface XI**

#### **Part 1 Epidemiology 1**

Chapter 1 **Childhood Acute Leukemias in Hispanic Population: Differences by Age Peak and Immunophenotype 3**  Juan Manuel Mejía-Aranguré, María Luisa Pérez-Saldivar, Rosana Pelayo-Camacho, Ezequiel Fuentes-Pananá, Carolina Bekker-Mendez, Abigail Morales-Sánchez, David Aldebarán Duarte-Rodríguez and Arturo Fajardo-Gutiérrez

#### **Part 2 NK Cell Leukemia 33**

	- **Part 3 Clinical Manifestations of Acute Lymphoblastic Leukemia 51**
	- **Part 4 Therapy of Acute Lymphoblastic Leukemia 99**
	- **Part 5 Resistance to Therapy 145**

#### **Part 6 Pathophysiology and Novel Targets 163**


## Preface

Acute lymphoblastic leukemia (ALL) is one of the great success stories in cancer medicine. Its transformation from a universally fatal disease to one which nowadays is highly curable in children extends over more than four decades. This exemplary progress is founded on a combination of factors. Starting from the vision of a few bold men who dared to make the first steps of treating patients with chemotherapy regimens that many others at the time considered to be at best ineffective and at worst un-ethical, it soon became clear that the life of patients with ALL can indeed be prolonged with this approach. Since then, clinical research in trial after trial established better and more effective therapies. At the same time, the many contributions by laboratory and translational researchers have expanded our understanding about the biology of ALL with far-reaching ramifications into the development of new drugs, the design of therapies, and an appreciation of the differences among subtypes of ALL and those between ALL in children and adults.

State-of-the-art ALL therapy can be bewildering in its complexity, yet every regimen adheres to a few basic tenets: induction therapy followed by intensified consolidation and a prolonged maintenance phase. Central nervous system (CNS) prophylaxis is a mandatory component and part of the early treatment stages of all patients. Induction therapy is based on a core group of drugs (vincristine, steroids, anthracyclines) to which various others have been added over time (asparaginase, cyclophosphamide, methorexate, cytarabine). Consolidation therapy can consist of a repetition of the induction, further intensification with added drugs, or a stem cell transplant for select patients. Maintenance extends up to three years and consists of a standard combination of vincristine, steroids, mercaptopurine, and methotrexate. CNS prophylaxis includes intrathecal chemotherapy, high-dose systemic therapy with CNS penetration (eg, cytarabine and methotrexate), and cranial radiation. With this strategy, remission rates of up to 90% and long-term disease free survival of up to 85% in children and 45% in adults are achievable.

Much progress in adult patients with ALL stems from lessons adapted from successful strategies in children. Yet, the prognosis in children remains significantly better. Explanations for this discrepancy at the expense of adults are many: decreased tolerance to intensive therapies and drugs such as asparaginase more specifically, differences in the metabolism of drugs such as methotrexate, higher X Preface

expression of multi-drug resistance related proteins, and a higher likelihood to detect unfavorable cytogenetic abnormalities (eg, Ph chromosome, 11q23 translocations) whereas better prognosis karyotypes are found more rarely (eg, *ETV6-RUNX1* fusion, hyperdiploidy).

Preface XI

Department of Leukemia, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center,

**Stefan Faderl**

Houston, USA

more important. This book does not claim to be comprehensive but hopefully provides enough insight and information to serve as a source for knowledge and

inspiration.

Hence, the basic structure of ALL therapy has experienced many modifications. Some important aspects of this development relate to the following:


The chapters in this book have been written by a diverse group of investigators throughout the world. Each of them contributes their unique knowledge and interpretation of several aspects of the biology, manifestations, and therapy of ALL. The following chapters cover aspects of the epidemiology of ALL in Hispanic patients, describe some often overlooked ophthalmologic manifestations at diagnosis and in the course of the management of ALL, and provide overviews of current therapy. Throughout several chapters investigators will elaborate on drugresistance mechanisms, elucidate novel biological pathways and targets, and describe drugs in development. Last but not least, long-term consequences of CNS prophylaxis and therapy deal with some survivorship issues that are becoming ever Preface XI

more important. This book does not claim to be comprehensive but hopefully provides enough insight and information to serve as a source for knowledge and inspiration.

X Preface

trials.

ALL.

*ABL*-negative disease.

*ETV6-RUNX1* fusion, hyperdiploidy).

expression of multi-drug resistance related proteins, and a higher likelihood to detect unfavorable cytogenetic abnormalities (eg, Ph chromosome, 11q23 translocations) whereas better prognosis karyotypes are found more rarely (eg,

Hence, the basic structure of ALL therapy has experienced many modifications.

1. Intensification of therapy in adult patients. Pediatric studies have shown better outcome among adolescents and young adults when therapy is augmented by intensifying the exposure to a group of non-myelosuppressive drugs such as vincristine, steroids, and asparaginase. This approach is now carried over in the "younger" adults to an age of up to 40 to 50 years in many ongoing clinical

2. Risk-adaptation of therapy. To intensify therapy (including stem cell transplant) where necessary but avoid toxicities where possible is one of the main thrusts of clinical ALL research. Much experience has been gathered about different responses to therapy of various subtypes of ALL based on immunophenotyping and cytogenetic/molecular characteristics. An important post-treatment aspect is the measurement of minimal residual disease (MRD), the presence of which has a high positive predictive value for higher relapse likelihood in children on therapy and appears to have similar relevance in some groups of adults with

3. Incorporation of new drugs. In this respect, the most notable progress in recent years has been the success of tyrosine kinase inhibitor (TKI) therapy in *BCR-ABL*-positive ALL where early and continuous use of TKI now achieves diseasefree survival rates akin to the responses of chemotherapy in patients with *BCR-*

4. CNS prophylaxis. There has been a trend away from cranial radiation to intrathecal and systemic chemotherapy appreciating the long-term adverse

The chapters in this book have been written by a diverse group of investigators throughout the world. Each of them contributes their unique knowledge and interpretation of several aspects of the biology, manifestations, and therapy of ALL. The following chapters cover aspects of the epidemiology of ALL in Hispanic patients, describe some often overlooked ophthalmologic manifestations at diagnosis and in the course of the management of ALL, and provide overviews of current therapy. Throughout several chapters investigators will elaborate on drugresistance mechanisms, elucidate novel biological pathways and targets, and describe drugs in development. Last but not least, long-term consequences of CNS prophylaxis and therapy deal with some survivorship issues that are becoming ever

events of therapeutic interventions in survivors.

Some important aspects of this development relate to the following:

**Stefan Faderl** Department of Leukemia, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, USA

**Part 1** 

**Epidemiology** 

**Part 1** 

**Epidemiology** 

**1** 

*México* 

**Childhood Acute Leukemias in Hispanic** 

*Unidad de Investigación en Epidemiología Clínica, Enfermedades Oncológicas,* 

*Enfermedades Infecciosas y Parasitarias/Hospital de Pediatria & División de Laboratorios de Vigilancia e Investigación Epidemiológica, Instituto Mexicano del Seguro Social* 

Childhood cancer represents 0.5–5.7% of all cancers (Birch & Blair, 1992; Smith & Gloecker, 2002). The most important kinds of cancer during childhood differ from those most frequently found in adulthood (Schellong, 1985). During infancy, the principal cancers are not epithelial, in contrast to those in the later stages of life (Miller, 1983). Therefore, it is possible that the risk factors for cancer are different during infancy than during adulthood; for children, risk factors may be present *in utero* or during the firsts months of the life

The age peak of cancer during infancy, especially those for leukemias and lymphomas, varies among countries. Although the peak age for leukemias worldwide is principally between 2–5 years of age, a peak as late as 7–13 years of age was reported for Niger (William, 1975). In developed countries such as Germany or the United States of America (USA), the age peak for lymphomas is between 10–14 years of age, whereas in less developed countries, Mexico for example, the age peak is between 5–9 years of age (Fajardo-Gutiérrez et al., 1995; Kaatsch et al., 1995; Nully-Brown et al., 1989; Young et al., 1986). Leukemia is the most common cancer in children under 15 years old, representing between 25–35% of all childhood cancers in most populations (Parkin et al., 1988, 1998). Leukemia is a heterogeneous group of hematopoietic malignancies, with several biologically distinct subgroups. The main subtypes of leukemia described by most cancer registries include acute lymphoblastic leukemia (ALL), representing about 80% of all leukemias; AML, with a frequency of 15%; and chronic myeloid leukemia (CML) with a frequency of 3–5% (Bathia, 2003). ALL is the most frequent leukemia in infancy (Mejía Arangure et al., 2005a). The age

 María Luisa Pérez-Saldivar, Rosana Pelayo-Camacho, Ezequiel Fuentes-Pananá, Carolina Bekker-Mendez, Abigail Morales-Sánchez, David Aldebarán Duarte-Rodríguez

*Unidad de Investigación en Epidemiología Clínica, Enfermedades Oncológicas, Enfermedades Infecciosas y Parasitarias/Hospital de Pediatria & División de Laboratorios de Vigilancia e Investigación Epidemiológica,* 

**1. Introduction** 

(Draper, 1994).

 \*

and Arturo Fajardo-Gutiérrez

*Instituto Mexicano del Seguro Social, México* 

**Population: Differences by Age Peak** 

**and Immunophenotype** 

Juan Manuel Mejía-Aranguré et al.\*
