Abnormal blood test Y E A R S. Diagnosis of MDS

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1 Abnormal blood test 3 Y E A R S Diagnosis of MDS

2 Demographics of Germany [ ] and Europe Italy Germany Spain Austria Greece eu5 Countrybyrankorder in203 Finland Portugal Belgium France UK Netherlands Denmark Sw eden 203 Luxembourg 2004 Ireland Percentage Statistisches Bundesamt, 2002 Eurostat 2004-Percentage of people over age of 60 years in 203

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

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5 5-9% blasts 0-9% blasts AML >20% blasts Low Risk MDS

6 MDS Classification The Ultimate Simplification Lower Risk (Survival 3-0 years, low rate of AML) RA, RARS RCUD, RCMD MDS-U, MDS del (5q) IPSS Low, Int- (Score 0-.0) Higher Risk (Survival <.5 years, high rate of AML) RAEB (-, -2) IPSS Int-2, High (Score >.5)

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9 CMML ( chromic myelomonocytic leukaemia) Not CML!!

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

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13 Supportive care Red cell transfusion Anaemia causing symptoms Platelet transfusion Low platelets-bleeding & bruising Planned surgical operation Erythropoietin Anaemia Granulocyte-colony stimulating factor Infections associated with low white count Antibiotic Infections Iron chelation therapy Patients with low-risk disease with high transfusion requirement

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15 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 Sense of Altruism for donorsall voluntary The number and frequency may vary, but generally needs increase over time

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

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19 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

20 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

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22 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)

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24 High risk MDS Replace 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 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

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28 Treatment algorithm for patients with MDS* Asymptomatic Symptomatic BM function Low risk High risk S u r v i v a l Transfusion Observation EPO/G-CSF 5qB l a s t s 7q Lenalidomide Azacitidine Thalidomide Decitabine Investigational SCT ablative RIC Complex Azacitidine Decitabine Investigational Intensive chemotherapy RIC SCT full ablative Silverman LR in Cancer Medicine 7th ed

29 Myelodysplasia Intensive 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

30 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??

31 Gene Mutations in MDS Tyrosine Kinase Pathway JAK2 JAK2 BRAF KRAS BRAF KRAS Transcription Factors RUNX RUNX NRAS NRAS PTPN PTPN RTK s RTK s CBL CBL Epigenetic Dysregulation IDH IDH &2 &2 TET2 TET2 DNMT3A DNMT3A UTX UTX ATRX ATRX Others GATA2 GATA2 ETV6 ETV6 WT WT EP300 EP300 PHF6 PHF6 Splicing Factors EZH2 EZH2 SF3B SF3B TP53 TP53 Cohesins Cohesins GNAS/GNB GNAS/GNB RNA helicases BCORRNA helicases BCOR U2AF U2AF SETBP SETBP ASXL ASXL SF SF NPM NPM SRSF2 SRSF2 ZRSF2 ZRSF2 PRPF40B PRPF40B U2AF2 U2AF2 PRPF8 PRPF8 SF3A SF3A

32 Agents in clinical development for AML/MDS Belinostat Agents Directly Targeting Tumors Ganetespib Brentuximab$ LY Tosedostat Oncohist Alisertib AS-4 GRNVAC $ SC INNO-305 Treosulfan Clofarabine* (Non-FLT3 mut; Non-NPM C mut) Decitabine Clofarabine Nilotinib Clofarabine Clofarabine Vosaroxin (2nd Elacytarabine course remission) LOR 2040 TMZ Dasatini b Sorafenib Elacytarabine PR-04 Bylantra Panobinostat* (post ASCT) Panobinostat *In AML with Intermediate or Unfavorable cytogenetics ^In untreated AML ineligible for intensive chemotherapy ^^Bortezomib + Sorafenib $ Also in patients ineligible for standard chemotherapy Sorafenib $ Vorinostat (FLT-3 Vorinostat^^ mut) Vorinostat (Int/Poor risk) OVI-23 (TDT +ve) Bortezomib$ Everolimus Midostaurin 4`thio-cytarabine SGI0 Ruxolitini b Lenalidomide Dasatinib (5q Del)$ $ Midostaurin Midostaurin (FLT-3 mut) (FLT-3 mut) (FLT-3 mut) GSKMidostaurin 2022 (FLT-3 mut) SC FT-050 Midostaurin C CT-0 ALT-80 PLX 3397 (FLT3-mut) Lenalidomide CNDO-09 (CR) Pazopanib Erlotinib (Refractory only) Vorinostat^^ Crenolanib (FLT3-D835 mut) Transplant Related Biomarker Status No Biomarker Biomarker Driven Mechanism of Action Sorafenib$ Sorafenib Allostim (post ASCT) Bortezomib$ No Line Defined Induction/Consolidation C Conditioning SC Stem Cells Maintenance Refractory/Relapse SC Imatinib KX2 (post induction- 39 consolidation in c-kit +ve pts) MSC B Panobinostat* C Gataparse n Perifosine Lenalidomide Gemtuzumab ozogamycin Line Of Therapy Agents Targeting Tumor Microenvironment AML vaccinerigosertib$ Inovio C StemEx CLT-008 Rigosertib Plerixafor Brentuxima Sorafeni (Trisomy8) b b Lenalidomide Lenalidomide Volasertib(CD30+ve) Pacritinib (5q [3] Del) (5q [3] Del) HSC-835 BI 8283^ TMZ Imatinib Quizartinib Dasatinib (c-kit +ve) 3 9 Aurora kinase inhibitor GSK 3 Beta inhibitor HSP 90 inhibitors CD33 linked immunoconjugate HDAC inhibitors PLK- antagonist Proteasome inhibitor Amino peptidase inhibitor DNA inhibitors KIF protein inhibitor Pyruvate dehydrogenase stimulant RNA synthesis inhibitor Tubulin polymerization inhibitors Guanosine-rich oligonucleotide aptamer Hypoxia and AKTC3 activated alkylator Akt-inhibitor Bcr-abl tyrosine kinase inhibitor BIRC5 protein inhibitor CXCR4 receptor antagonist Dual Src kinase and pre-tubulin inhibitor Dual TKI-FLT3 and KIT inhibitor EGFR inhibitor FLT-3 inhibitor Janus kinase inhibitor MEK inhibitor mtor inhibitor Multi TKI PDCD protein inhibitor PDGFR inhibitor PI3K inhibitor Immunomodulators Supportive Care Source:. ADIS Insight; 2.TrialTrove; 3.Company Website 3 2

33 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!!

34 Prof Ghulam Mufti Staff and patients at Kings College Hospital