3 YEARS Demographics of Germany 1910 2050 and Europe Statistisches Bundesamt 2002 Eurostat 2004Percentage of people over age of 60 years in 2031 The Bone Marrow Failure Syndromes AA ID: 1048060
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1. Abnormal blood testDiagnosis of MDS3 YEARS
2. Demographics of Germany [1910 – 2050] and EuropeStatistisches Bundesamt, 2002Eurostat 2004-Percentage of people over age of 60 years in 2031
3. The Bone Marrow Failure SyndromesAAPNHAMLLow RiskHighRiskAA – Aplastic AnaemiaPNH – Paroxysmal Nocturnal HaemaglobinuriaMDSAdapted from N. Young5q-
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5. Low Risk MDS5-9% blasts10-19% blastsAML >20% blasts
6. MDS Classification – The Ultimate SimplificationLower Risk (Survival 3-10 years, low rate of AML) RA, RARS RCUD, RCMDMDS-U, MDS del (5q)IPSS Low, Int-1 (Score 0-1.0)Higher Risk (Survival <1.5 years, high rate of AML) RAEB (-1, -2)IPSS Int-2, High (Score > 1.5)
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9. CMML ( chromic myelomonocytic leukaemia)Not CML!!
10. Therapeutic goalsMDSIneffective haematopoiesisAML evolutionLow risk MDS infection, bleeding anaemiaHigh risk MDS delay/stop progressionQuality of lifesurvival
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13. Supportive careRed cell transfusionAnaemia causing symptomsPlatelet transfusionLow platelets-bleeding & bruisingPlanned surgical operationErythropoietinAnaemiaGranulocyte-colony stimulating factorInfections associated with low white countAntibioticInfectionsIron chelation therapyPatients with low-risk disease with high transfusion requirement
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15. Improves the oxygen carrying ability and improves symptomsMany patients will develop symptoms due to anaemiaRed cell transfusion is the commonest way anaemia is treatedThe number and frequency may vary, but generally needs increase over time Red Cell Transfusion…The goodSense of Altruism for donors-all voluntary
16. …….…The badI might need a transfusion..Costly and decreasing donor poolImpacts on QOL, hospital attendancesTransfusion reaction, infections and alloimmunisationEach unit has 250 mg of elemental iron
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19. Platelet transfusion should be reserved for patients with bruising or bleeding symptomsPlanned surgery, dental extraction may also need to be covered by platelet transfusionPlatelet transfusion-Liquid Gold
20. Therapy in low risk MDSSqueeze every ounce of production out of the remaining functional bone marrow cells by ERYTHROPOIETIN(EPO) and GROWTH FACTORS(eg GCSF)injections
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22. Therapy in low risk MDSBlocks the effects of nasty cytokines (chemicals produced in excess by abnormal bone marrow cells which can kill the normal cells) eg. Lenalidomide ATG( horse or rabbit)
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24. High risk MDSReplace the bone marrow (and immune system) Bone marrow transplant Chemotherapy Azacitidine/Decitabine Clinical trials/ novel agents
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26. Azacitidine in high-risk MDSIt has been suggested that azacitidine may switch on important anti-cancer genes Reduced red cell transfusion Improvement in survival Less chance of MDS deteriorating Results not influenced by patient age, blast cells, karyotypeAdministered as injection into skin For high risk patients ineligible for transplantation
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28. Low riskAsymptomaticSymptomaticObservationEPO/G-CSFLenalidomide Azacitidine Thalidomide Decitabine InvestigationalSCT ablative RICAzacitidine Decitabine Investigational Intensive chemotherapy RIC SCT – full ablative TransfusionBM functionHigh riskSurvivalBlasts5q- Silverman LR in Cancer Medicine 7th ed. 2006.Treatment algorithm for patients with MDS*7qComplex
29. MyelodysplasiaIntensive treatmentBone marrow transplant should be considered when ‘curative’ therapy is thought to be appropriate.Key issues for patients:Motivated, and deemed fit for BMT ‘High-risk’ MDS, with disease under controlAppropriate counselling regarding outcomes, risks, and intensive long- term follow-up
30. Newer developmentsGenes, genes and more genesNew risk scoring system-IPSS-ROral azacitdineNewer targeted therapy/personalised medicineLenalidomide approved for 5q- syndrome (cancer drug fund and also NICE approved)CMML- what is it??
31. RUNX1ETV6WT1PHF6GATA2DNMT3AEZH2ASXL1IDH1 & 2UTXTP53Transcription FactorsTyrosine Kinase PathwayEpigenetic DysregulationSF3B1Splicing FactorsJAK2NRAS BRAF KRAS RTK’s PTPN11CohesinsGNAS/GNB1RNA helicasesCBLNPM1ATRXOthersSRSF2U2AF1ZRSF2SETBP1SF1SF3A1PRPF40BU2AF2PRPF8BCORTET2Gene Mutations in MDSEP300
32. Agents in clinical development for AML/MDS32Source: 1. ADIS Insight; 2.TrialTrove; 3.Company WebsiteLine Of TherapyBiomarker StatusNo Line Defined No BiomarkerInduction/ConsolidationTransplant RelatedCConditioning Biomarker DrivenSCStem CellsMaintenanceRefractory/RelapseAgents Directly Targeting Tumors*In AML with Intermediate or Unfavorable cytogenetics^In untreated AML ineligible for intensive chemotherapy^^Bortezomib + Sorafenib$ Also in patients ineligible for standard chemotherapyVosaroxinLOR 2040ElacytarabineClofarabineDecitabineSGI-110PR-104CClofarabineTreosulfanCElacytarabine(2nd course remission)ClofarabineClofarabine*(Non-FLT3 mut; Non-NPM1 mut)BylantraTMZTMZAS-1411TosedostatOVI-123 (TDT +ve)4`thio-cytarabinePanobinostatVorinostat^^Vorinostat(Int/Poor risk)Vorinostat^^LY-2090314$Bortezomib$Brentuximab$GanetespibPanobinostat* (post ASCT)Panobinostat* BelinostatBI 811283^VolasertibMidostaurin(FLT-3 mut)ImatinibImatinib(post induction-consolidation in c-Kit +ve pts)KX2 391Midostaurin(FLT-3 mut)Midostaurin(FLT-3 mut)QuizartinibSorafenib(post ASCT)SorafenibSorafenibDasatinib (c-Kit +ve)SorafenibGataparsenPerifosineCrenolanib(FLT3-D835 mut)Erlotinib(Refractory only)PazopanibPLX 3397 (FLT3-mut)MidostaurinMidostaurin$(FLT-3 mut)Sorafenib$PlerixaforCEverolimus$RuxolitinibDasatinibDasatinibRigosertib$Rigosertib (Trisomy8)HSC-835SCPacritinibNilotinibAgents Targeting Tumor MicroenvironmentCT-011SCStemExOncohistAlisertibGSK-1120212Mechanism of Action1Aurora kinase inhibitor1GSK 3 Beta inhibitor1HSP 90 inhibitors1CD33 linked immunoconjugate3HDAC inhibitors1PLK-1 antagonist1Proteasome inhibitor 1Amino peptidase inhibitor9DNA inhibitors1KIF11 protein inhibitor1Pyruvate dehydrogenase stimulant1RNA synthesis inhibitor1Tubulin polymerization inhibitors1Guanosine-rich oligonucleotide aptamer 1Hypoxia and AKT1C3 activated alkylator1Akt-inhibitor1Bcr-abl tyrosine kinase inhibitor1BIRC5 protein inhibitor1CXCR4 receptor antagonist1Dual Src kinase and pre-tubulin inhibitor1Dual TKI-FLT3 and KIT inhibitor1EGFR inhibitor1FLT-3 inhibitor2Janus kinase inhibitor2MEK inhibitor1mTOR inhibitor5Multi TKI1PDCD 1 protein inhibitor1PDGFR inhibitor1PI3K inhibitor8Immunomodulators1Supportive CareBrentuximab(CD30+ve)MSC 1936369BLenalidomide(5q Del)$Lenalidomide(5q [31] Del)LenalidomideLenalidomide(5q [31] Del)LenalidomideALT-801CCNDO-109 (CR1)GRNVAC1INNO-305AML vaccine-InovioFT-1050SCAllostimCLT-008Vorinostat(FLT-3 mut)Bortezomib$Gemtuzumab ozogamycin
33. ConclusionMDS is more common than we think!Delay therapy until symptoms develop or needing transfusions Treatment based on the risk of disease- low risk versus high riskOptimistic future-novel drugs in early phase clinical trialsPersonalised gene sequencing and individualised therapy-THE FUTURE !!
34. Prof Ghulam MuftiStaff and patients at Kings College Hospital