LEUKEMIA LYMPHOMA MYELOMA Advances in Clinical Trials

Transcription

1 LEUKEMIA LYMPHOMA MYELOMA Advances in Clinical Trials OUR FOCUS ABOUT emerging treatments Presentation for: Judith E. Karp, MD Advancements for Acute Myelogenous Leukemia Supported by an unrestricted educational grant from:

2 Blood Cancers: A Large and Worthy Challenge Estimated Incidences 06-07: Lymphomas 67,000 Leukemias 35,000 Myeloma 17,000 There are now almost 800,000 people living with blood cancers right now in the US! Challenges to Curing Leukemias, Lymphomas and Myelomas Components of Cellular Survival and Drug Resistance Cell Cycle Regulation Apoptosis/Anti-Apoptosis Pathways Mitochondrial and Cytoplasmic Components Repair of DNA Damage Handling Cellular Stress Signal Transduction Pathways: Cytokines Receptors Intermediaries Transporter Molecules Tuesday, May 8,

3 Clinical Trials: The Road to Medical Advances Clinical trials are important because: At the present time, we don t have a reasonable standard of care because we are not curing nearly enough people Clinical trials with new ideas and new drugs offer a chance to do better What we have learned from clinical trials in years past is the basis for what we do today (and we are better than we were 2-3 decades ago!) What we learn from today s trials will help us to develop more effective approaches tomorrow Tuesday, May 8,

4 Translational-Clinical Research in Blood Cancers: LLS Support Translational Research Program Specialized Centers Of Research (SCOR) Career Development Awards: Scholar in Clinical Research Special Fellow in Clinical Research Hierarchy Model of Hematopoiesis and Leukemogenesis CD33 + CD33 - AML Leukemia Stem Cell CD33 + (Erythrocytes) HSC CD33 - Myeloid Stem Cell (Granulocytes) (Platelets) Tuesday, May 8,

5 Pathophysiology of Acute Leukemia: Determinants of Clinical Presentation CLINICAL FACTOR CONSEQUENCES CORRECTION Bone Marrow Failure Anemia Restore Normal Bleeding Hematopoiesis Infection Leukemia Leukostasis Cytoreduction Phenotype Endothelial Damage DIC Extramedullary Tissue Infiltration Tumor Lysis Syndrome Leukemia Biology: A Simplistic View Two Major Defects: Inability to differentiate Inability to die in response to stress Tuesday, May 8,

6 AML Demographics: 2006 New cases = 12,000; deaths = 9,000 Median age = 68 yrs Incidence = 3.8 per 100,000 <65 yrs = 2.1 per 100,000 >65 yrs = 18 per 100,000 Chance of developing AML For a 50-yr-old = 1 in 50,000 For a 70-yr-old = 1 in 5,000 Special Challenges in AML Biology of Disease Treatment-Related AML AML Evolving from MDS AML in Older Adults Biology of Treatment Addressing Minimal Residual Disease Augmenting Anti-Leukemic Immunity Tuesday, May 8,

7 Why is AML in the Older Adult so Difficult to Treat? Disease Biology DNA Damage/Toxin Exposure Increases with Age Detoxifying Enzyme Activity Decreases with Age Immune Surveillance Decreases with Age Host Biology Intolerance for Cytotoxic Chemotherapy New Treatment Concepts for Older Adults with AML Reasoning with the Malignant Clone Avoid Very Intensive Chemotherapy Modulate Leukemia Cell Gene Expression Coax Cells into Differentiating Combine Multiple Approaches (New Drugs and Old Drugs) Immunomodulation: Vaccines? New Approaches to Stem Cell-Based Therapies Tuesday, May 8,

8 Addressing Minimal Residual Disease Identifying Small Amounts of Leukemia Flow Cytometry Leukemia Surface Markers Isolating Leukemia Stem Cells Genetic Technologies Cytogenetics, FISH, RT-PCR Gene Expression Profiling Silencing of Selected Genes New Strategies to Target Minimal Residual Disease: Selected Possibilities Agents with unique mechanisms of action that may cause leukemic cells to differentiate (eg, ATRA in APL) Agents that might suppress the leukemic clone (eg, Signal transduction inhibitors FLT3, FT) Agents that might modulate leukemia gene expression (eg, demethylating agents, HDAC inhibitors) Agents that may enhance the patients immunity against leukemia (eg, bevacizumab, vaccines) Tuesday, May 8,

9 Translational-Clinical Research in AML: LLS Support Novel Molecular Targets for Therapy Cell cycle regulatory proteins Proteins involved in cell-cell interaction Drug resistance transporter proteins Anti-cell death proteins New Treatment Strategies Combining targeted agents with chemotherapy Epigenetics: modulating gene expression Immunomodulation: vaccines, donor lymphocytes, new approaches to stem cell transplants Exploiting Leukemia Cell Biology to Move Beyond Today s Horizon Overcoming Drug Resistance Continue to define survival pathways Identify the pathways upon which the leukemic cell is dependent (more so than the normal cell) Select agents that abrogate activity of key pathways Combine those agents to form a multi-directed attack to nullify the ability of the leukemic cell to survive direct or indirect cytotoxic drug-induced DNA damage Reinstate normal balance between growth, differentiation, and eventual cell death Tuesday, May 8,

10 Molecular Therapeutic Possibilities for Leukemias: Selected Drugs and Targets MECHANISM DRUG MOLECULAR TARGET Signal Transduction Tipifarnib Farnesyltransferase CEP-701 Flt-3 KW-2449 Flt-3, Aurora Kinase, VEGFR Sorafenib Raf kinase, VEGF Bevacizumab VEGF Cell Cycle Regulation/ Flavopiridol CDKs, Transcription Factors Apoptosis SNS-595 G2 arrest AEG35156 XIAP (anti-apoptosis protein) DNA Repair Triapine Ribonucleotide Reductase Clofarabine Adenine, RR 17-AAG Hsp 90 ABT-888 PARP Differentiation/ MS-275, SAHA Histone Deacetylase Gene Expression 5-azacytidine DNA Methyltransferase ATRA RAR- Merging Old and New Concepts Maximize Tumor Kill Reach MRD Manipulate cell growth kinetics and apoptosis Impede repair of DNA damage Minimize Normal Cellular Damage Modulate leukemia-selective factors MRD: The Stage is Set for CURE CR maintenance through clonal suppression with leukemia-selective agents Immunomodulation (eg, vaccines) Tuesday, May 8,

11 Clinical Trials: The Road to Medical Advances Clinical trials are important because: At the present time, we don t have a reasonable standard of care because we are not curing nearly enough people Clinical trials with new ideas and new drugs offer a chance to do better What we have learned from clinical trials in years past is the basis for what we do today (and we are better than we were 2-3 decades ago!) What we learn from today s trials will help us to develop more effective approaches tomorrow Tuesday, May 8,