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 Innovative
Leukemia and
Lymphoma
Therapy

Kaspers_978-0849350832_TP.indd 1 4/23/08 10:13:13 AM

 Innovative
Leukemia and
Lymphoma
Therapy
Edited by
Gertjan J. L. Kaspers
VU University Medical Center
Amsterdam, The Netherlands
Bertrand Coiffier
Hospices Civils de Lyon and Claude Bernard University
Pierre-Benite, France
Michael C. Heinrich
Oregon Health & Science University Cancer Institute
Portland VA Medical Center
Portland, Oregon, USA
Elihu Estey
University of Washington Medical Center
Seattle, Washington, USA

Kaspers_978-0849350832_TP.indd 2 4/23/08 10:13:15 AM

CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742

© 2008 by Taylor & Francis Group, LLC

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No claim to original U.S. Government works

Version Date: 20130315

International Standard Book Number-13: 978-1-4200-1408-2 (eBook - PDF)

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accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to
make clear that any views or opinions expressed in this book by individual editors, authors or contributors are
personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guid-
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[pradeepr][D:/informa_Publishing/DK0832_Kaspers_112039/z_production/z_3B2_3D_files/978-0-
8493-5083-2_CH0000_O.3d] [24/4/08/11:1:35] [1–14]

Foreword

The outcome of therapy for leukemia and malignant lymphoma has improved
over the years, mainly in younger patients. Yet, there is no question that the
challenges in the area of developmental therapeutics have remained formidable.
These challenges relate to the patients who, from the start of treatment, fail to
respond to the currently available therapies or combinations of drugs. The
outlook of these primarily refractory patients is invariably dismal. Many of
the responder patients attaining an initial complete remission, unfortunately, will
finally present with relapse of disease. The relapses among the leukemias and
high-grade lymphomas usually occur early on, i.e., within the first two years.
Both groups, initial nonresponders and secondary failures, pose the notorious
difficulty of resistance to conventional therapy. These facts provide an overall
notion. Acquired somatic genetic abnormalities of the neoplasms provide keys to
the nature of the disease and offer important predictors of treatment failure. They
allow to pinpoint individual disease-specific features and distinguish variable
disease risks as well as identify those patients with the highest probability of
failure. The unmet therapeutic need is, by all standards, greatest among the large
population of older patients with hematological cancer in whom response rates
are comparatively low, relapse rates are high, and comorbidities prohibit the use
of classical chemotherapeutic agents at effective dose levels.
Scientists are on the way to discovering new drugs with different modes of
action that can overcome the limitations of today’s selection of drugs. Numerous
new drugs are currently in early clinical development with the aim of circum-
venting the clinical bottleneck of chemotherapy resistance. In the coming years,
several of these compounds are expected to settle as members of the standard
armamentarium of drugs available to the patient with a hematological tumor.
New drugs may be designed with the deliberate objective of affecting a known
molecular lesion or signaling pathway in the cancer cell, thus critically inhibiting

iii
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iv Foreword

tumor cell survival. These therapeutic compounds may tackle distinct, molecu-
larly defined subtypes of leukemia or lymphoma, and one would anticipate that
their greater specificity will allow for application with enhanced efficacy and
reduced toxicity.
Currently, we are witnessing the development of diagnostic technologies
that directly impact decision making in the clinical management of patients with
hematological malignancies. These technologies relate, on the one hand, to more
precise tissue diagnosis and involve innovative genomic, proteomic, and immu-
nological techniques. On the other hand, they involve improved in vivo imaging
methods, enabling a better and more sensitive visualization of neoplastic
deposits in the body. These techniques, when appropriately validated for clinical
use, will enable the distinction of prognostic disease subcategories and allow for
a specific diagnosis according quantitative, sensitive, and objective parameters.
This type of information will guide therapeutic decisions at the outset of
treatment. It will also provide substantial insights that will be useful in
monitoring treatment effects throughout the therapeutic management of patients
and redirect treatment choice. An ambitious diagnostic approach makes sense if
there is a choice for the physician among a broader scale of available therapeutic
options. One of the major objectives of today’s molecular diagnostics relates to
the identification of new druggable targets for pharma developments.
Innovative Leukemia and Lymphoma Therapy appropriately and critically
deals with each of the issues and challenges as regards developmental thera-
peutics. The book highlights current, clinically relevant diagnostic strategies for
high-throughput diagnosis and disease response monitoring. The book covers, in
a series of individual chapters, a collection of overviews that highlight clinically
relevant novel therapeutic strategies in concise reviews. It also provides updates
on therapeutic compounds with new mechanisms of action that currently raise
intense interest and are in active development. This book comes as a timely
resource of information that furnishes a state-of-the-art and comprehensive
compendium, which will be of value to the interested clinician, researcher,
and student.
Bob Löwenberg
Erasmus University Medical Center
Rotterdam, The Netherlands
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Preface

The treatment of leukemia and lymphoma is rapidly developing from conven-

tional chemotherapy toward a more tailored and targeted, innovative therapy.
However, conventional therapy is making progress as well. Targeted treatment
with increased efficacy and less side effects is becoming more and more a
reality, facilitated by fascinating developments such as oncogenomic studies and
sophisticated drug engineering. Knowledge on determinants of chemosensitivity
is also rapidly increasing. Together with pretreatment individualized tumor
response testing and with improved monitoring of treatment response by min-
imal residual disease measurements, treatment will indeed become more tailored
and individualized.
This book gives a complete and up-to-date overview of exciting new
treatment modalities in leukemia and lymphoma that have been introduced in the
clinic or will be introduced in the near future. Well-known international experts
summarize clinical studies on drugs such as tyrosine kinase inhibitors, mono-
clonal antibodies, proteasome inhibitors, farnesyl transferase inhibitors, hypo-
methylating agents, histone deacetylase inhibitors, mTOR targeting agents,
Notch pathway inhibitors, and inhibitors of cyclin-dependent kinases. The first
few chapters deal with methodological issues such as gene expression profiling
to detect new drug targets, individualized tumor response testing aiming at
selecting effective drugs, minimal residual monitoring to adapt treatment based
on actual treatment response, and statistical issues concerning clinical studies in
small subgroups of patients, while some discuss modulation of drug resistance
and improvements in allogeneic bone marrow transplantation. Other chapters
summarize targeting regulators of apoptosis, radioimmunotherapy, immunotherapy
by vaccination, gene-directed therapy, and anti-angiogenesis approaches. The
chapters provide a concise summary of the treatment rationale, of the pathways
that are involved, and of relevant preclinical research, whenever relevant.

v
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vi Preface

We recommend this well-illustrated, comprehensive book to students,

scientists, and clinicians with a special interest in innovative therapy who are
involved not only in research and/or treatment of leukemia and lymphoma in
particular, but in other malignancies as well.
Gertjan J. L. Kaspers
Bertrand Coiffier
Michael C. Heinrich
Elihu Estey
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Contents

Foreword Bob Löwenberg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

1. Gene Expression Profiling to Detect New Treatment Targets

in Leukemia and Lymphoma: A Future Perspective . . . . . . . . . 1
Torsten Haferlach, Wolfgang Kern, and Alexander Kohlmann

2. Individualized Tumor Response Testing in Leukemia

and Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Andrew G. Bosanquet, Peter Nygren, and Larry M. Weisenthal

3. Minimal Residual Disease ........................... 45

nski,
Jacques J. M. van Dongen, Tomasz Szczepa

and Vincent H. J. van der Velden

4. New Methods for Clinical Trials: AML as an Example ...... 85

Elihu Estey

5. Monoclonal Antibody Mediated Treatment in Acute Myeloid

Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Ch. Michel Zwaan and Marry M. van den Heuvel-Eibrink

6. Monoclonal Antibodies in the Treatment of Malignant

Lymphomas and Chronic Lymphocytic Leukemia ........ 125
Bertrand Coiffier

vii
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viii Contents

7. Radioimmunotherapy of Hematological Malignancies ...... 149

Tim Illidge and James Hainsworth

8. Differentiation Induction in Acute Promyelocytic Leukemia . . . . 185

Adi Gidron and Martin S. Tallman

9. DNA Methylation and Epigenetics: New Developments

in Biology and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
ubbert, and Mark Kirschbaum
Jesus Duque, Michael L€

10. The Emerging Role of Histone Deacetylase Inhibitors

in the Treatment of Lymphoma . . . . . . . . . . . . . . . . . . . . . . 233
Matko Kalac and Owen A. O’Connor

11. Antileukemic Treatment Targeted at Apoptosis Regulators . . . 257

Simone Fulda and Klaus-Michael Debatin

12. Angiogenesis in Hematological Malignancies . . . . . . . . . . . . . 283

Alida C. Weidenaar, Hendrik J. M. de Jonge, Arja ter Elst,
and Evelina S. J. M. de Bont

13. Nucleic Acid-Based, mRNA-Targeted Therapeutics

for Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . 311
Alan M. Gewirtz

14. Active Specific Immunization by the Use of Leukemic Dendritic

Cell Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Ilse Houtenbos, Gert J. Ossenkoppele,
and Arjan A. van de Loosdrecht

15. CDK Inhibitors in Leukemia and Lymphoma ............ 353

Yun Dai and Steven Grant

16. FLT3: A Receptor Tyrosine Kinase Target in Adult

and Pediatric AML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Mark Levis, Patrick Brown, and Donald Small

17. Treatment of Chronic Myeloid Leukemia with Bcr-Abl

Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Michael J. Mauro and Michael C. Heinrich

18. Tyrosine Kinase Inhibitors: Targets Other Than FLT3,

BCR-ABL, and c-KIT ............................. 429
Suzanne R. Hayman and Judith E. Karp
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Contents ix

19. Tyrosine Phosphatases as New Treatment Targets

in Acute Myeloid Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . 449
I. Hubeek, K. Hoorweg, J. Cloos, and Gertjan J. L. Kaspers

20. Proteasome and Protease Inhibitors . . . . . . . . . . . . . . . . . . . 469

N. E. Franke, J. Vink, J. Cloos, and Gertjan J. L. Kaspers

21. Farnesyltransferase Inhibitors: Current and Prospective

Development for Hematologic Malignancies ............. 491
Judith E. Karp

22. Targeting Notch Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . 513

Jennifer O’Neil and A. Thomas Look

23. mTOR Targeting Agents for the Treatment of Lymphoma

and Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525
Andrea E. Wahner Hendrickson, Thomas E. Witzig,
and Scott H. Kaufmann

24. Allogeneic Hematopoietic Cell Transplantation After

Nonmyeloablative Conditioning ...................... 539
Frédéric Baron, Frederick R. Appelbaum, and Brenda M. Sandmaier

25. Modulation of Classical Multidrug Resistance and

Drug Resistance in General . . . . . . . . . . . . . . . . . . . . . . . . . 563
Branimir I. Sikic

Index .............................................. 581

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Contributors

Frederick R. Appelbaum Fred Hutchinson Cancer Research Center and The

University of Washington, Seattle, Washington, U.S.A.
Frédéric Baron Fred Hutchinson Cancer Research Center, Seattle, Washington,
U.S.A.
Andrew G. Bosanquet Bath Cancer Research, Royal United Hospital, Bath, U.K.
Patrick Brown Sidney Kimmel Comprehensive Cancer Center at Johns
Hopkins, Baltimore, Maryland, U.S.A.
J. Cloos Department of Pediatric Oncology/Hematology, VU University
Medical Center, Amsterdam, The Netherlands
Bertrand Coiffier Hematology Department, Hospices Civils de Lyon and
Claude Bernard University, Pierre-Benite, France
Yun Dai Department of Medicine, Virginia Commonwealth University and
Massey Cancer Center, Richmond, Virginia, U.S.A.
Evelina S. J. M. de Bont Department of Pediatric Oncology/Hematology,
University Medical Center Groningen, University of Groningen, Groningen,
The Netherlands
Hendrik J. M. de Jonge Department of Pediatric Oncology/Hematology,
University Medical Center Groningen, University of Groningen, Groningen,
The Netherlands
Klaus-Michael Debatin University Children’s Hospital, Ulm, Germany
Jesus Duque Department of Hematology/Oncology, University Medical
Center Freiburg, Freiburg, Germany

xi
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xii Contributors

Elihu Estey Division of Hematology, University of Washington Medical

Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A.
N. E. Franke Department of Pediatric Oncology/Hematology, VU University
Medical Center, Amsterdam, The Netherlands
Simone Fulda University Children’s Hospital, Ulm, Germany
Alan M. Gewirtz Division of Hematology/Oncology, Department of Medicine
& Abramson Family Cancer Research Institute, University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania, U.S.A.
Adi Gidron Division of Hematology/Oncology, Department of Medicine,
Northwestern University Feinberg School of Medicine and The Robert H. Lurie
Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, U.S.A.
Steven Grant Department of Medicine, Biochemistry, and Pharmacology,
Virginia Commonwealth University and Massey Cancer Center, Richmond,
Virginia, U.S.A.
Torsten Haferlach Munich Leukemia Laboratory, Munich, Germany
James Hainsworth Paterson Institute of Cancer Research, School of
Medicine, University of Manchester, Manchester, U.K.
Suzanne R. Hayman Division of Hematology, Department of Medicine,
Mayo Clinic, Rochester, Minnesota, U.S.A.
Michael C. Heinrich Center for Hematologic Malignancies and Departments
of Medicine and Cell and Developmental Biology, Oregon Cancer Institute,
Oregon Health & Science University and Portland VA Medical Center, Oregon
Health & Science University, Portland, Oregon, U.S.A.
K. Hoorweg Department of Pediatric Oncology/Hematology, VU University
Medical Center, Amsterdam, The Netherlands
Ilse Houtenbos Department of Hematology, VU University Medical Center,
Amsterdam, The Netherlands
I. Hubeek Department of Pediatric Oncology/Hematology, VU University
Medical Center, Amsterdam, The Netherlands
Tim Illidge Paterson Institute of Cancer Research, School of Medicine,
University of Manchester, Manchester, U.K.
Matko Kalac Herbert Irving Comprehensive Cancer Center, The New York
Presbyterian Hospital, Columbia University, New York, New York, U.S.A.
Judith E. Karp Division of Hematologic Malignancies, Johns Hopkins Sidney
Kimmel Comprehensive Cancer Center, Baltimore, Maryland, U.S.A.
[pradeepr][D:/informa_Publishing/DK0832_Kaspers_112039/z_production/z_3B2_3D_files/978-0-
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Contributors xiii

Gertjan J. L. Kaspers Department of Pediatric Oncology/Hematology, VU

University Medical Center, Amsterdam, The Netherlands
Scott H. Kaufmann Department of Molecular Pharmacology and
Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, U.S.A.
Wolfgang Kern Munich Leukemia Laboratory, Munich, Germany
Mark Kirschbaum Division of Hematology and Hematopoietic Cell
Transplantation, City of Hope Comprehensive Cancer Center, Duarte,
California, U.S.A.
Alexander Kohlmann Roche Molecular Systems, Pleasanton, California, U.S.A.
Michael L€ubbert Department of Hematology/Oncology, University Medical
Center Freiburg, Freiburg, Germany
Mark Levis Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,
Baltimore, Maryland, U.S.A.
A. Thomas Look Department of Pediatric Oncology, Dana-Farber Cancer
Institute, Boston, Massachusetts, U.S.A.
Michael J. Mauro Center for Hematologic Malignancies, Oregon Cancer
Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Peter Nygren Department of Oncology, Radiology, and Clinical Immunology,
University Hospital, Uppsala, Sweden
Owen A. O’Connor Herbert Irving Comprehensive Cancer Center, The
New York Presbyterian Hospital, Columbia University, New York, New York,
U.S.A.
Jennifer O’Neil Department of Pediatric Oncology, Dana-Farber Cancer
Institute, Boston, Massachusetts, U.S.A.
Gert J. Ossenkoppele Department of Hematology, VU University Medical
Center, Amsterdam, The Netherlands
Brenda M. Sandmaier Fred Hutchinson Cancer Research Center and The
University of Washington, Seattle, Washington, U.S.A.
Branimir I. Sikic Oncology Division, Department of Medicine, Stanford
University School of Medicine, Stanford, California, U.S.A.
Donald Small Sidney Kimmel Comprehensive Cancer Center at Johns
Hopkins, Baltimore, Maryland, U.S.A.
Tomasz Szczepa
nski Department of Immunology, Erasmus MC, University
Medical Center Rotterdam, Rotterdam, The Netherlands, and Department of
Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze,
Poland
[pradeepr][D:/informa_Publishing/DK0832_Kaspers_112039/z_production/z_3B2_3D_files/978-0-
8493-5083-2_CH0000_O.3d] [24/4/08/11:1:35] [1–14]

xiv Contributors

Martin S. Tallman Division of Hematology/Oncology, Department of

Medicine, Northwestern University Feinberg School of Medicine and The
Robert H. Lurie Comprehensive Cancer Center of Northwestern University,
Chicago, Illinois, U.S.A.
Arja ter Elst Department of Pediatric Oncology/Hematology,
University Medical Center Groningen, University of Groningen, Groningen,
The Netherlands
Marry M. van den Heuvel-Eibrink Department of Pediatric Oncology/
Hematology, Erasmus MC/Sophia Children’s Hospital, Rotterdam, The
Netherlands
Arjan A. van de Loosdrecht Department of Hematology, VU University
Medical Center, Amsterdam, The Netherlands
Vincent H. J. van der Velden Department of Immunology, Erasmus MC,
University Medical Center Rotterdam, Rotterdam, The Netherlands
Jacques J. M. van Dongen Department of Immunology, Erasmus MC,
University Medical Center Rotterdam, Rotterdam, The Netherlands
J. Vink Department of Pediatric Oncology/Hematology, VU University
Medical Center, Amsterdam, The Netherlands
Andrea E. Wahner Hendrickson Department of Medicine, Mayo Clinic,
Rochester, Minnesota, U.S.A.
Alida C. Weidenaar Department of Pediatric Oncology/Hematology,
University Medical Center Groningen, University of Groningen, Groningen,
The Netherlands
Larry M. Weisenthal Weisenthal Cancer Group, Huntington Beach,
California, U.S.A.
Thomas E. Witzig Department of Medicine, Mayo Clinic, Rochester,
Minnesota, U.S.A.
Ch. Michel Zwaan Department of Pediatric Oncology/Hematology, Erasmus
MC/Sophia Children’s Hospital, Rotterdam, The Netherlands
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