Jorge Cortes Cml University Hospital Of Texas

Chronic myeloid leukemia (CML) is a rare disease and yet it has had a profound impact on the development of modern, evidence-based medicine. Some 160 years ago the term leukemia was coined when Bennet, and almost simultaneously Virchov, described the striking white appearance of the blood of two patients with, presumably, CML. The discovery of the Philadelphia chromosome (Ph), first described as a minute chromosome 22 by Nowel and Hungerford in 1960, marks the first consistent association between a chromosomal abnormality and a specific malignancy, proving that alterations of DNA are causal to cancer. Thirteen years later it was Janet Rowley who recognized that Ph is in fact the result of a chromosomal translocation involving chromosomes 9 and 22. A decade later Bartram and Groffen identified the genes juxtaposed by the t(9;22) as ABL and BCR. Shortly thereafter the central role of tyrosine kinase activity for Bcr-Abl's ability to induce malignant transformation was recognized and murine models developed by Daley and colleagues generated experimental evidence that Bcr-Abl is necessary and probably sufficient to induce the chronic phase of CML. This provided a rationale for using pharmacological inhibitors of Bcr-Abl for the treatment of CML and ultimately led to the clinical development of imatinib by Druker and colleagues.

Imatinib has completely changed the CML landscape. Ten years ago there were few therapeutic choices. Allogeneic stem cell transplant was recommended to patients with a suitable donor and deemed fit to undergo the procedure. All other patients were treated with an interferon-alpha-based regimen, realizing that only a minority would achieve durable responses and become long-term survivors. This is history: the rate of complete cytogenetic response in newly diagnosed patients treated with imatinib approaches 90%, with many patients attaining more than 1000-fold reductions of their leukemia burden as measured by polymer-ase chain reaction (PCR). With the revolution of therapy came fundamental changes in monitoring. Quantitative PCR to measure the level of BCR-ABL transcripts, previously relevant only in the setting of allogeneic transplant, has become key to monitoring the majority of patients once they have achieved a complete cytogenetic response. For many CML patients the perception of their disease has evolved from being a deadly illness worth accepting the risks of an allogeneic transplant to becoming a chronic ailment that can be controlled for long periods of time with an oral medication that causes little if any discomfort. Despite the impressive responses achieved with imatinib in most patients, resistance develops in some patients with early disease and is frequent in those who start treatment in accelerated phase or blast crisis. Point mutations in the kinase domain of Bcr-Abl have been identified as the leading known mechanism of resistance to imatinib, again generating a novel paradigm in oncology. The problem of clinical resistance has led to the development of novel, more potent Bcr-Abl inhibitors that maintain activity against mutant Bcr-Abl and may eventually prove superior to imatinib as first-line therapy.

With all this, the management of CML has become a complex undertaking. While prescribing the pills is seemingly easy, exploiting the full potential of the novel therapies requires considerable knowledge and skills. The rapid accumulation of new data makes it ever harder to stay on top of this rapidly evolving field, even for CML experts. This defines the purpose of this book: to provide rapid, easy access to the most recent information. A panel of leaders in the field has been assembled to provide a comprehensive and yet condensed overview of CML in the year 2006, covering the most topical aspects of CML biology, diagnostics, therapy and monitoring. To do this we aimed at a very short lag period between conception of the book, writing of the chapters and publication of the final product to keep the information as current as possible. In a field as rapidly evolving as this, it is inevitable that new information will be available by the time this book reaches the reader. But we are confident that this formidable effort will still provide very current and valid information. We hope that the reader will find this book a useful guide to stay current in a complex field.

Jorge Cortes Michael Deininger

Contents

1. BCR-ABL as a Molecular Target 1

Michael Deininger

2. Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia 13

Mukta Arora and Mary M. Horowitz

3. Where Are We Today with Imatinib Therapy? 27

John M. Goldman

4. Monitoring Chronic Myeloid Leukemia in 2006 45

Nicola Hurst, Timothy P. Hughes, and Susan Branford

5. Dasatinib: A Dual ABL and SRC Inhibitor 59

Alfonso Quintas-Cardama, Hagop Kantarjian, and Jorge Cortes

6. Nilotinib (AMN107) for the Treatment of Chronic Myelogenous Leukemia 69

Elias Jabbour, Francis Giles, Jorge Cortes, Susan O'Brien, and Hagop Kantarjian

7. Resistance to Imatinib 79

Justus Duyster and Nikolas von Bubnoff

8. Immunotherapy of Chronic Myeloid Leukemia 95

Monica Bocchia and Francesco Lauria

9. Molecular Targets Other than Bcr-Abl: How to Incorporate Them into the CML Therapy? 109

Junia V. Melo and David J. Barnes

10. Blastic Transformation of Chronic Myelogenous Leukemia: Does BCR-ABL Orchestrate Disease Progression? 125

Bruno Calabretta and Danilo Perrotti

11. Early Intensification of Therapy: The Role of High-Dose Imatinib and Imatinib-Based Combinations 149

Francois Guilhot, Géraldine Martineau, Frederic Millot, and Lydia Roy Index . . . . 157

Contributors

Mukta Arora Department of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, U.S.A.

David J. Barnes Department of Haematology, Imperial College London, Hammersmith Hospital, London, U.K.

Monica Bocchia Department of Hematology, Siena University, Siena, Italy

Susan Branford Institute of Medical and Veterinary Science, Adelaide, South Australia

Bruno Calabretta Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, Pennsylvania, U.S.A.

Jorge Cortes Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Michael Deininger Oregon Health & Science University, Portland, Oregon, U.S.A.

Justus Duyster Department of Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

Francis Giles Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

John M. Goldman Hematology Branch, National Institutes of Health, Bethesda, Maryland, U.S.A.

Francois Guilhot Department of Oncology-Hematology and Cell Therapy, Clinical Research Centre, Poitiers, France

Mary M. Horowitz Department of Medicine, Centre for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.

Timothy P. Hughes Institute of Medical and Veterinary Science, Adelaide, South Australia

Nicola Hurst Institute of Medical and Veterinary Science, Adelaide, South Australia

Elias Jabbour Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Hagop Kantarjian Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Francesco Lauria Department of Hematology, Siena University, Siena, Italy

Géraldine Martineau Department of Oncology-Hematology and Cell Therapy, Clinical Research Centre, Poitiers, France

Junia V. Melo Department of Haematology, Imperial College London, Hammersmith Hospital, London, U.K.

Frédéric Millot Department of Oncology-Hematology and Cell Therapy, Clinical Research Centre, Poitiers, France

Susan O'Brien Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Danilo Perrotti Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, U.S.A.

Alfonso Quintas-Cardama Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Lydia Roy Department of Oncology-Hematology and Cell Therapy, Clinical Research Centre, Poitiers, France

Nikolas von Bubnoff Department of Internal Medicine III, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

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