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Evolving Treatments for Acute Leukemia and Myelodysplastic Syndromes Mark B Juckett MD University of Wisconsin
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Leukemia Mortality by State
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Incidence of Leukemia in Older Adults Incidence of 55-64 age group, data from 1994-98, SEER database
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AML/MDS - definition Clonal neoplastic disorder of a myeloid stem cell –Problems with blood production Anemia, thrombocytopenia, neutropenia –Problems with neoplastic cell growth Constitutional symptoms, leukostasis, organ dysfunction, bone pain
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AML 1994-1998 Incidence by age In United States BMT Candidates
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Pathogenesis - “the usual” Complex interaction between agents, environment, genetics. Accumulation of genetic events (mutations, deletions, etc), multistep process Faulty genetic program impedes differentiation, favors growth Process continues until organ dysfunction, cell growth causes symptoms
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Genetic Events alter Differentiation
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Environmental Factors Associated with AML/MDS Environment –Arsenic –Benzene Smoking Ionizing radiation –Medical radiation –Nuclear accidents –Radon ? Chemotherapy –Alkylating agents Cyclophosphamide –Topoisomerase II etoposide Other drugs –Immunosuppressives –Chloramphenicol
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Genetic Factors Down Syndrome Fanconi Syndrome Bloom Syndrome Klinefelter Syndrome Ataxia-telangiectasia Dyskeratosis Congentia Congenital aneuploidy Identical Sib with AML Combined Immunodeficiency Li-Fraumeni syndrome
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Environmental Risk Factors for MDS Nisse BJH 112;927, 2001 204 MDS patients and controls Interviewed at home –demographic data, lifetime residence, medical history, proximity to nuclear, chemical, industrial plants, carcinogen exposure. Occupational history with exposure to list of compounds. Reviewed validity with occupational experts (reviewers blinded)
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Environmental Risk Factors Results Nisse BJH 112;927, 2001
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AML Classification WHO Classification 1997 Rely on morphology, immunophenotype, genetic & clinical features Most important - Cytogenetics Most morphological distinctions difficult Increasingly merge with myelodysplastic syndromes JCO 17:3835, 1999
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WHO Classification - AML AML with recurrent cytogenetics –t(8;21), t(15;17), t(16;16), 11q23 AML with multilineage dysplasia AML with MDS, therapy related AML –subtype by morphology (M0, M1, etc.) JCO 17:3835, 1999
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WHO Classification - MDS Refractory anemia –with ringed sideroblasts –without ringed sideroblasts Refractory cytopenia with multilineage dysplasia Refractory anemia with excess blasts 5q- syndrome Myelodysplastic syndrome, NOS JCO 17:3835, 1999
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Cytogenetic abnormalities AML Best Prognosis Intermediate Prognosis Worst Prognosis t(8;21) t(16;16) t(15;17) Normal cytogenetics Trisomy 8 Chromosome 5, 7 11q23 abnl 3q21,26 abnl Complex
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Myelodysplasia - International Prognostic Index Blasts Cytogenetics –Y-, 5q-, 20q- good –chr 7 or multiple bad Cytopenia –0 or 1 good –2 or 3 bad Median Survival –Low Risk 5.7 years –Low Intermediate 3.5 –High Intermediate 1.2 –High 6 months
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Initial Treatment Strategy for AML Rapidly control metabolic imbalances Transfuse (Hgb > 8, Plt > 10 - 20k) Control WBC if needed –Hydroxyurea –Leukapheresis Evaluate cardiorespiratory function Given chemotherapy when “tuned”
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Presentation - Emergencies Coagulopathy - Acute promyelocytic Tumor lysis syndromes Hypercalcemia Neutropenic sepsis Leukostasis Pulmonary Failure Severe cytopenia
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Initial Diagnosis Usually made by CBC and manual differential Bone Marrow Biopsy –Biopsy and Aspiration –Marrow samples sent for: Flow cytometry Cytogenetics FISH (as indicated)
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Proposed treatment schema for AML Induction FavorableUnfavorableIntermediate Standard anthracycline + cytarabine (3 + 7) CR Rates *Not APL
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Next step - “Consolidation” No further therapy –100% relapse, median 4.1 mo (Cassileth, JCO 6:583) Chemotherapy alone –Standard high dose cytarabine 2 or 3 times Autologous Bone Marrow Transplantation Allogeneic Bone Marrow Transplantation
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Consolidation Favorable Cytogenetics Standard –3 or 4 cycles of high dose cytarabine Possible Benefit –Myeloablative chemo/radiotherapy with autologous peripheral blood stem cell rescue Unclear Benefit –Allogeneic BMT (studies inconclusive) Results - long-term survival 50-60%
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Standard (under 65) –Matched sibling donor available Allogeneic BMT in first CR –No donor High dose cytarabine followed by autologous BMT Results –Allogeneic BMT - 55-65% 3-year survival –Autologous BMT - 40-50% 3-year survival Consolidation Intermediate Cytogenetics
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Standard –Matched sibling donor Allogeneic BMT in first CR (under 65) –No donor Alternative donor (under 55) maybe Autologous BMT ? Results –Allogeneic BMT - 30-50% 3-year survival –Other - less than 15% Consolidation Unfavorable Cytogenetics
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Bone Marrow Transplantation Best - Matched Sibling (1/4 change/sib) Matched Unrelated, Partial matched family an option - even more risky Best case - Non-relapse Mortality 20-30% Autologous - Less risk, more relapse Prolonged recovery - disability 1 year Long term problems ?
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Survival after AML (< 55 years) AML Pts on ECOG protocols since 1973
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Survival after AML (> 55 years) AML Pts on ECOG protocols since 1973
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Novel Approaches Immunoconjugates Signal Transduction modifiers Non-myeloablative transplantation Multidrug resistance modulation
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AML/MDS Activation Pathways Tyrosine Kinases Ras Signaling
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Gemtuzumab Ozogamicin (Mylotarg®) FDA Approved Indication –“Mylotarg is indicated for the treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy.” IgG4 chimeric murine/human monoclonal antibody against CD33 conjugated with calicheamicin
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Gemtuzumab Ozogamicin Structure Murine Variable Region Human Constant Region IgG4 Linker Calicheamicin
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Mylotarg in relapsed AML NR CR CRp
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Cooperative Group Trial - ECOG E4999 Patients with relapsed/refractory AML AML CD33 positive
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Myeloablative SCT High dose radiation High dose chemo Stem cells Supportive Care Watch and Wait
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Non-myeloablative SCT Immuno suppression Stem cells Manipulate the Immune response to maximize Graft vs. Disease
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Multidrug Resistance Chemotherapy IN MDRMDR Chemotherapy OUT
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Multidrug Resistance Chemotherapy IN MDRMDR MDR Block
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MDR modulation in poor-risk AML List, Blood, 98:3212, 2001
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Treatment of MDS “Standard Care” - supportive BMT - only curative option Under investigation –Immunomodulation - ATG, thalidomide, Ontak –Differentiation - Doxercalciferol, arsenic, amifostine, decitabine –Signaling Pathway inhibitors –Novel BMT regimens
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Conclusions AML/MDS are diseases of older people Prognosis is best predicted by cytogenetics Outcome has improved for patients under 55 Outcome has not improved for older people HSC transplantation is indicated for most younger patients New agents really do look promising
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