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Abnormal blood test

Abnormal blood test. 3 YEARS. Diagnosis of MDS. Demographics of Germany [1910 – 2050] and Europe. Statistisches Bundesamt, 2002. Eurostat 2004-Percentage of people over age of 60 years in 2031. The Bone Marrow Failure Syndromes. PNH. AA. MDS. Low Risk. High Risk. AML. 5q-.

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Abnormal blood test

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  1. Abnormal blood test 3 YEARS Diagnosis of MDS

  2. Demographics of Germany[1910 – 2050] and Europe Statistisches Bundesamt, 2002 Eurostat 2004-Percentage of people over age of 60 years in 2031

  3. The Bone Marrow Failure Syndromes PNH AA MDS Low Risk High Risk AML 5q- AA – Aplastic Anaemia PNH – Paroxysmal Nocturnal Haemaglobinuria Adapted from N. Young

  4. Low Risk MDS 5-9% blasts 10-19% blasts AML >20% blasts

  5. MDS Classification – The Ultimate Simplification • Lower Risk (Survival 3-10 years, low rate of AML) • RA, RARS • RCUD, RCMD • MDS-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) • IPSSInt-2, High (Score > 1.5)

  6. CMML ( chromic myelomonocytic leukaemia) • Not CML!!

  7. Therapeutic goals Low risk MDS infection, bleeding anaemia High risk MDS delay/stop progression Ineffective haematopoiesis AML evolution MDS survival Quality of life

  8. Supportive care

  9. Red Cell Transfusion…The good • Improves the oxygen carrying ability and improves symptoms • Many patients will develop symptoms due to anaemia • Red cell transfusion is the commonest way anaemia is treated • The number and frequency may vary, but generally needs increase over time • Sense of Altruism for donors-all voluntary

  10. …….…The bad • Costly and decreasing donor pool • Impacts on QOL, hospital attendances • Transfusion reaction, infections and alloimmunisation • Each unit has 250 mg of elemental iron I might need a transfusion..

  11. Platelet transfusion-Liquid Gold • Platelet transfusion should be reserved for patients with bruising or bleeding symptoms • Planned surgery, dental extraction may also need to be covered by platelet transfusion

  12. Therapy in low risk MDS • Squeeze every ounce of production out of the remaining functional bone marrow cells by ERYTHROPOIETIN(EPO) and GROWTH FACTORS(eg GCSF)injections

  13. Therapy in low risk MDS • Blocks 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)

  14. High risk MDS • Replace the bone marrow (and immune system) Bone marrow transplant Chemotherapy Azacitidine/Decitabine Clinical trials/ novel agents

  15. Azacitidine in high-risk MDS It 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, karyotype Administered as injection into skin For high risk patients ineligible for transplantation

  16. Treatment algorithm for patients with MDS* 5q- Asymptomatic Symptomatic BM function Transfusion Low risk Survival Lenalidomide Azacitidine Thalidomide Decitabine Investigational Observation EPO/G-CSF SCT ablative RIC Blasts 7q Complex Azacitidine Decitabine Investigational Intensive chemotherapy RIC SCT – full ablative High risk Silverman LR in Cancer Medicine 7th ed. 2006.

  17. MyelodysplasiaIntensive treatment Bone 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 control Appropriate counselling regarding outcomes, risks, and intensive long- term follow-up

  18. Newer developments • Genes, genes and more genes • New risk scoring system-IPSS-R • Oral azacitdine • Newer targeted therapy/personalised medicine • Lenalidomide approved for 5q- syndrome (cancer drug fund and also NICE approved) • CMML- what is it??

  19. Gene Mutations in MDS Tyrosine Kinase Pathway Transcription Factors Others NPM1 RUNX1 KRAS BRAF TP53 JAK2 GATA2 Cohesins GNAS/GNB1 RNA helicases ETV6 NRAS RTK’s BCOR PTPN11 PHF6 EP300 WT1 CBL Epigenetic Dysregulation Splicing Factors U2AF1 ZRSF2 DNMT3A EZH2 SF3B1 IDH1 & 2 SETBP1 PRPF40B TET2 U2AF2 SRSF2 ASXL1 UTX PRPF8 SF1 SF3A1 ATRX

  20. Agents in clinical development for AML/MDS Imatinib Belinostat Quizartinib Agents Directly Targeting Tumors Agents Targeting Tumor Microenvironment Dasatinib (c-Kit +ve) Ganetespib Gataparsen Brentuximab$ GRNVAC1 INNO-305 Perifosine LY-2090314$ SC AML vaccine-Inovio HSC-835 Rigosertib$ SC Tosedostat StemEx C CLT-008 Rigosertib (Trisomy8) Plerixafor Brentuximab (CD30+ve) Sorafenib Oncohist Alisertib Lenalidomide (5q [31] Del) Lenalidomide (5q [31] Del) Volasertib Pacritinib AS-1411 BI 811283^ Lenalidomide Gemtuzumab ozogamycin Imatinib(post induction-consolidation in c-Kit +ve pts) KX2 391 TMZ Panobinostat* C Treosulfan MSC 1936369B Decitabine Clofarabine* (Non-FLT3 mut; Non-NPM1 mut) Sorafenib$ Sorafenib(post ASCT) Clofarabine Allostim C Nilotinib Clofarabine Clofarabine Vosaroxin Ruxolitinib Elacytarabine (2nd course remission) Lenalidomide (5q Del)$ Dasatinib Dasatinib LOR 2040 Everolimus$ Bortezomib$ TMZ Sorafenib Sorafenib Elacytarabine Midostaurin$ (FLT-3 mut) 4`thio-cytarabine Midostaurin (FLT-3 mut) Midostaurin (FLT-3 mut) SGI-110 Vorinostat(FLT-3 mut) GSK-1120212 Vorinostat^^ Midostaurin (FLT-3 mut) PR-104 Vorinostat (Int/Poor risk) SC FT-1050 Midostaurin CT-011 C Bylantra ALT-801 OVI-123 (TDT +ve) PLX 3397 (FLT3-mut) Lenalidomide Panobinostat* (post ASCT) CNDO-109 (CR1) Bortezomib$ Pazopanib Panobinostat Erlotinib(Refractory only) Crenolanib (FLT3-D835 mut) Vorinostat^^ *In AML with Intermediate or Unfavorable cytogenetics ^In untreated AML ineligible for intensive chemotherapy ^^Bortezomib + Sorafenib $ Also in patients ineligible for standard chemotherapy Source: 1. ADIS Insight; 2.TrialTrove; 3.Company Website 32

  21. Conclusion • MDS 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 risk • Optimistic future-novel drugs in early phase clinical trials • Personalised gene sequencing and individualised therapy-THE FUTURE !!

  22. Prof Ghulam Mufti Staff and patients at Kings College Hospital

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