New Agents for the Treatment of Acute Lymphoblastic Leukemia

349 Pages·2011·3.54 MB·English

by  Tim Eden (auth.)

New Agents for the Treatment
of Acute Lymphoblastic Leukemia

Vaskar Saha Pamela Kearns
●
Editors
New Agents for the
Treatment of Acute
Lymphoblastic Leukemia
Editors
Vaskar Saha Pamela Kearns
Paediatric and Adolescent Oncology School of Cancer Sciences
School of Cancer and Enabling Sciences University of Birmingham
Manchester Academic Health Science Edgbaston, Birmingham B15 2TT
Centre [email protected]
The University of Manchester
Manchester M20 4BX
[email protected]
ISBN 978-1-4419-8458-6 e-ISBN 978-1-4419-8459-3
DOI 10.1007/978-1-4419-8459-3
Springer New York Dordrecht Heidelberg London
Library of Congress Control Number: 2011925850
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Brief Overview
Over 80% of children with acute lymphoblastic leukemia (ALL) are cured by
modern chemotherapeutic regimens. These are the results of carefully conducted
randomised clinical trials. Mainly, current protocols have progressively intensified
therapy for all children and now use risk stratification to intensify treatment for
high-risk subgroups. As a result, therapy-related toxicity now outweighs disease
recurrence as a determinant of outcome. The prognosis for those who relapse or do
not respond to therapy remains poor. Further intensification is unlikely to benefit
those who fail therapy and may increase toxicity for those who do. Perhaps, the
most intense of therapies is allogeneic bone marrow transplantation. However, dis-
ease recurrence is the most common cause of transplantation failure in these
patients. The drugs that we use for ALL are now over 30 years old. To improve
outcome further and to decrease toxicity, we need new drugs.
These are exciting times. At long last, new agents that can potentially be used in
the ALL armamentarium are increasing rapidly. These include both conventional
cytotoxics and targeted therapy. However, there are a number of problems that need
to be solved. How does one evaluate the effect of a new drug in a disease where
over 80% of patients are cured from what is otherwise a fatal disease? What are
acce ptable surrogate markers of response to treatment given that therapeutic failure
can occur over a number of years? With shrinking number of patients suitable for
phase I and II trials, what new models of trial design are required to obtain answers
in the quickest possible time? What cellular and animal models will we accept as
most predictive for the clinical effect of the drug in question? These are some of the
questions that need to be answered before we can incorporate new agents into
frontline therapy for patients with ALL.
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Acknowledgements
This work was funded in part by a programme grant from Cancer Research UK
to Vaskar Saha. The editors thank Ms Charlotte O’Horo for editorial assistance.
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Contents
1 The Need for New Agents ....................................................................... 1
Tim Eden
2 Identifying Targets for New Therapies in Children
with Acute Lymphoblastic Leukemia .................................................... 25
Shekhar Krishnan, Ashish Masurekar, and Vaskar Saha
3 Preclinical Evaluation ............................................................................. 39
Barbara Szymanska, Hernan Carol, and Richard B. Lock
4 Design of Early-Phase Trials .................................................................. 61
James A. Whitlock and Terzah M. Horton
5 Strategies for Trial Design and Analyses .............................................. 83
Maria Grazia Valsecchi and Paola De Lorenzo
6 An Overview on Animal Models of ALL .............................................. 105
Michael A. Batey and Josef H. Vormoor
7 Targeting Bcl-2 Family Proteins in Childhood Leukemia ................... 117
Guy Makin and Caroline Dive
8 Targeting Leukemia Stem Cells and Stem Cell
Pathways in ALL ..................................................................................... 143
Clare Pridans and Brian J.P. Huntly
9 Nucleoside Analogues ............................................................................. 167
Pamela Kearns and Vaskar Saha
10 FLT3 Inhibitors as Therapeutic Agents in MLL
Rearranged Acute Lymphoblastic Leukemia ....................................... 189
Ronald W. Stam and Rob Pieters
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