Dismissed leukemia drug helps cll patients, studies show

December 08, 2008

COLUMBUS, Ohio - A drug once dismissed as ineffective in patients with chronic lymphocytic leukemia (CLL) has shown promising results in two phase I and II clinical trials, according to researchers at The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

Together, the trials involved 116 patients with advanced CLL who were treated with the drug flavopiridol (alvocidib). Responses were seen in approximately half of patients, many of whom had chromosomal abnormalities that made it unlikely they would be helped by standard therapies.

"Ohio State's success has reinvigorated interest in flavopiridol at the National Cancer Institute and other cancer centers," says Dr. Thomas Lin, a researcher and oncologist at Ohio State's Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

Lin, the study's first author and a member of the Experimental Therapeutics program at Ohio State's Comprehensive Cancer Center, will discuss the findings during the 50th Annual Meeting of the American Society of Hematology (ASH). Lin will explain the research during the ASH-ASCO Joint Symposium on Sunday morning (12/7), and later that day during an oral presentation on CLL therapy.

Earlier this year at the annual meeting of the American Society of Clinical Oncology, Ohio State investigators made an oral presentation on a phase II study of 64 patients treated with flavopiridol. The novel drug is effective in resistant CLL that does not respond to other therapies. Each year, ASH selects five ASCO abstracts to be featured during the Joint Symposium.

Chronic lymphocytic leukemia is the most common type of adult leukemia, with some 15,000 new cases this year. While therapy has improved, CLL remains incurable and patients often suffer significant infections as a consequence of the disease and treatment.

In the 1980s, animal tests showed flavopiridol to be a potent cancer-fighter. But when researchers gave it to humans in repeated trials using a continuous prolonged infusion, the drug proved ineffective and was essentially forgotten.

What wasn't known then - and what Ohio State researchers discovered later - is that flavopiridol binds to proteins in human blood, which ties up much of the available drug and leaves less free drug in the bloodstream to kill cancer cells. In essence, patients were not getting enough of the drug to be effective.

Researchers at Ohio State devised a new dosing schedule for the drug to increase its anti-tumor activity.

The new schedule increased the drug's blood level enough to kill cancer cells in humans, says Dr. Michael Grever, chairman of the department of internal medicine and co-leader of the Experimental Therapeutics program at Ohio State's Comprehensive Cancer Center.

"Flavopiridol has bridged the way for several CLL patients to receive a curative stem cell transplant," says Dr. John Byrd, associate director of translational research and principal investigator of the phase II trial. Ohio State is now participating in a multi-center flavopiridol trial to see if other cancer centers have similar results with flavopiridol.

Ohio State University Medical Center

Inhibitors of Cyclin-dependent Kinases as Anti-tumor Agents (Enzyme Inhibitors Series)
by Paul J. Smith (Editor), Eddy W. Yue (Editor)

One of the few books to cover all aspects of cyclin-dependent kinases (CDKs), Inhibitors of Cyclin-dependent Kinases as Anti-tumor Agents provides an overview of CDKs as molecular and functional entities, their involvement in different disease processes, and their potential for pharmacological modulation. With contributions from the top international researchers in the field, the book takes a contemporary approach to study the importance of rational drug design and knowledge-based therapeutics in relation to CDKs. The first two sections of the book discuss the integration of cell cycle control pathways, opportunities for targeting, targets of inhibitors, and the evaluation of CDK inhibitors, exploring topics such as the in vivo function of CDKs in normal homeostasisand tumor development...

Combination Cancer Therapy: Modulators and Potentiators (Cancer Drug Discovery and Development)
by Gary K. Schwartz (Editor)

Expert physician-scientists and clinicians review those combinations of novel target agents classic chemotherapies that hold the most promise for the future of medical oncology, and detail their optimal sequence, pharmacokinetic interactions, and interaction with downstream cellular signals. The combinations run the gamut of targeted therapies against cell surface receptors (EGF-R and HER2), the cell cycle (the CDKs), signal transduction events (PKC and NF-kB), apoptosis (bcl-2), as well as focused therapies in ovarian cancer, hematologic diseases, and breast cancer. The authors emphasize novel translational approaches that are rapidly moving from the laboratory bench top to the patient's bedside for the future treatments in cancer therapy.

Cell Cycle Inhibitors in Cancer Therapy (Cancer Drug Discovery and Development)
by Antonio Giordano (Editor), Kenneth J. Soprano (Editor)

Leading clinicians and investigators review in a comprehensible and user-friendly style all the latest information about the molecular biology of cell cycle control and demonstrate its clinical relevance to understanding neoplastic diseases. Topics range from Cdk inhibitors and cell cycle regulators to the prognostic value of p27 and tumor suppressor genes as diagnostic tools. Actual case studies show how the new molecular understanding has produced such drugs as Flavopiridol and Sulindac. The book brings all the recent critical research findings to bear on clinical practice, and clearly shows their powerful impact on the diagnostics, prognostics, and therapeutics of cancer, AIDS, and cardiovascular disease.

Innovative Leukemia and Lymphoma Therapy (Basic and Clinical Oncology)
by Gertjan J.L. Kaspers (Editor), Bertrand Coiffer (Editor), Michael C. Heinrich (Editor), Elihu H. Estey (Editor)

Innovative Leukemia and Lymphoma Therapy provides a complete and up-to-date overview of the exciting new treatment modalities in leukemia and lymphoma that are being introduced in the clinic today. Written by international experts in the field, this volume examines clinical studies on topics such as: tyrosine kinase inhibitors, histon deacetylase inhibitors, and farnesyl transferase inhibitors radioimmunotherapy, gene-directed therapy, and immunotherapy by vaccination monoclonal antibodies anti-angiogenesis approaches Within each chapter, this well-illustrated, comprehensive source provides a summary of the rationale for treatment, the pathways that are involved, and the translational research to students, scientists, and clinicians. In addition, this book focuses on the...

Cancer Immunotherapy: Immune Suppression and Tumor Growth
by George C. Prendergast (Editor), Elizabeth M. Jaffee (Editor)

There has been major growth in understanding immune suppression mechanisms and its relationship to cancer progression and therapy. This book highlights emerging new principles of immune suppression that drive cancer and it offers radically new ideas about how therapy can be improved by attacking these principles. Following work that firmly establishes immune escape as an essential trait of cancer, recent studies have now defined specific mechanisms of tumoral immune suppression. It also demonstrates how attacking tumors with molecular targeted therapeutics or traditional chemotherapeutic drugs can produce potent anti-tumor effects in preclinical models. This book provides basic, translational, and clinical cancer researchers an indispensable overview of immune escape as a critical trait...

Advances in Targeted Cancer Therapy (Progress in Drug Research)
by Richard M. Schultz (Editor)

This volume is the first book to cover the general topic of targeted cancer therapy. It presents a range of targets such as tumor angiogenesis, cell cycle control and cell signalling, COX-2, apoptosis/cell survival, invasion and metastasis and approaches like kinase inhibitors, antisense, and antibody-based therapeutics. The emphasis is on preclinical development, including target validation, development of biomarkers, strategies for combination approaches, and development of resistance. The particular challenges involved in translating these data to clinical application are discussed. This volume should be of broad general interest to researchers and clinicians involved in cancer therapy as well as other scientists interested in current strategies for cancer treatment.

Checkpoint Responses in Cancer Therapy (Cancer Drug Discovery and Development)
by Wei Dai (Editor)

Extensive research has uncovered a set of molecular surveillance mechanisms – commonly called “checkpoints” – which tightly monitor cell-cycle processes. Today’s anticancer drug development has identified many of these cell-cycle checkpoint molecules as effective targets. Research now promises to uncover a new generation of anticancer drugs with improved therapeutic indices based on their ability to target emerging checkpoint components. Checkpoint Responses in Cancer Therapy summarizes the advances made over the past 20 years, identifying components of cell-cycle checkpoints and their molecular regulation during checkpoint activation and validating the use of checkpoint proteins as targets for the development of anticancer drugs. This book’s distinguished panel of authors...

Cell Cycle Deregulation in Cancer (Current Cancer Research)
by Greg H. Enders (Editor)

Cancer is fundamentally a disease of abnormal cell proliferation: Cancer cells multiply when and where they should not. This proliferation entails escape from normal bounds imposed by the tissue environment, the internal biology of the cell (DNA damage, chromosomal imbalances, disorganized mitotic spindles), and the proliferative history of the cell (normal generational times). Some of the key oncogenic events in cancer directly perturb proteins that regulate progression through the cell division cycle, others alter cell cycle progression indirectly, through effects on signaling pathway that impinge on the cell cycle. This biology is fundamentally important in cancer therapy. Many of the workhorse treatments for cancer rely on killing proliferating cells. Furthermore, there is growing...

Chronic Lymphocytic Leukemia
by Susan O'Brien (Editor), John G. Gribben (Editor)

Written by authors from the world’s most prominent cancer centers, Chronic Lymphocytic Leukemia supplies a comprehensive, up-to-date picture of CLL and how to better treat patients inflicted with the disease. New information on developments in the molecular pathogenesis of this disease impacts how physicians approach and treat patients with CLL. The various predisposing factors for the disease are addressed along with current and future treatment modalities and recommended standards of care. Key features include: introduction by Kanti Rai, MD who developed the Rai Classification and Staging system used in CLL diagnosis CLL in relationship to gene expression profiling and molecular abnormalities familial clustering and gene predisposition targeted therapy trials ...

Tumor Suppressing Viruses, Genes, and Drugs: Innovative Cancer Therapy Approaches
by Hiroshi Maruta (Editor)

Tumor Suppressing Viruses, Genes, and Drugs profiles the new generation of cancer treatments now in development. The book examines the innovative new approaches of viral, gene, and signal therapies that promise to replace or enhance conventional methods such as surgery, radiation, and chemotherapy. The timely information presented by this book should be of interest to anyone concerned with advancing cancer treatment beyond current medical practices.