What are the appropriate molecular targets for therapy of MDS?
       - How should new agents be studied?
       - Which standard treatments should be used for comparison?

 Are there true differences between the subtypes of MDS?

 How should response to new targeted therapies be assessed in clinical trials?

Outcomes and Discussion Points

 Develop targets based on biology of hematopoiesis and apoptosis
       - Target areas: (1) proliferation and differentiation; (2) apoptosis vs. survival;
         (3) ligand-receptor interactions; and (4) homing or migration of cell
       - Targets based on disease etiology theory
              - Initiating genetic event (either somatically acquired or inherited)
              - Genetic progression with immune phenomenon
              - Secondary epiphenomenon (e.g., apoptosis, cytokines)
              - Target treatment at epiphenomenon until genetic pathways are understood

 Epidemiology and molecular genetics
       - Include epidemiologic studies in the design of future MDS trials
       - Apply comprehensive molecular/protein-based strategies to develop patterns to          study MDS
       - Broader identification of single target genes for MDS are necessary, especially a          target gene for the phenomenon of haplo-insufficiency for clonal disease

 Disease classification and response criteria
       - RAEB-t is separate from de novo AML and may represent end-stage MDS          evolving into AML
       - Refractory anemia class, as now defined, may incorporate potential non-MDS          cases (refractory cytopenias, sideroblastic disorders)
       - Evaluate targeted response criteria for specific therapies, including biological          agents and intensive chemotherapy, where the goal of treatment is not CR, or          where expected responses include refractory dysplastic features or cytogenetic          abnormalities

 Therapeutic options
       - No current treatment shows clear mortality improvement over palliative care
       - Gentler outpatient therapy options (low intensity treatments, growth factors, etc.)          may provide improved quality of life
       - Trials in transplantation must compare transplant results to intensive          chemotherapy and palliative care

 New treatments and agents
       - Immunosuppressive therapy shows promise in MDS based on similarity to          aplastic anemia and other bone marrow failure syndromes
       - Studies of growth factors and anti-cytokine agents show therapeutic value for          improvement in hematologic conditions and disease palliation but not cure
       - Testing of new agents should target: (1) untreated patients; (2) patients who fail          first best therapy; (3) patients in complete hematologic remission; and (4)          patients in relapse after complete remission

Key Recommendations

 Define durability of response to all new treatments - minimum of two-month duration   was presented generally, but a minimum response time across trials for all new   agents is needed as opposed to agent-dependent durations

 Develop clinical trials sensitive to analysis of MDS subtypes

 Validate the proposed response criteria and classification system by prospective   clinical trials

 Develop animal/in vitro models for preclinical testing to facilitate development of new   agents

 A "master" Phase II protocol was proposed for Cooperative Groups to use in a   randomized, rotating fashion.

 Dual endpoints were suggested for clinical trials - for low risk patients, comparison to   supportive care with analysis of complete response, survival, and quality of life; for   high risk patients, comparison of relevant endpoints (e.g. early mortality, quality of   life, survival) to AML type chemotherapy