MDS an overview. Andrew McDonald Alberts Cellular Therapy

Size: px

Start display at page:

Download "MDS an overview. Andrew McDonald Alberts Cellular Therapy"

Amber Lindsey
7 years ago
Views:

1 MDS an overview Andrew McDonald Alberts Cellular Therapy

2 CASES 75 year old woman with Hypertension, Type 2 DM, IHD previous CABG Renal dysfunction egfr 25ml/min Tiredness FBC Hb 10.6g/dl, MCV 97, WCC 4.1 Platelets 162 B12, folate and TSH normal Multifactorial anaemia Renal failure Anaemia of chronic disease Blood loss MDS

3 CASES 63 year old man with History of brachytherapy for prostate carcinoma 5 years prior Tiredness, episodes of phayryngitis FBC: Hb 7.3g/dl, MCV 102, WCC 1.9 (neut 0.7) Platelets 55 Blasts seen on blood 3% Unlikely any other differential except tmds taml

4 Spectrum of chronic myeloid malignancies CYTOPENIA INCREASED COUNTS MDS RCUD RARS RCMD 5q-syndrome RAEB MDS unclassifiable MDS/MPN CMML JMML acml MDS/MPN unclassifiable MULTIPLE MUTATIONS PV ET PMF CEL MPN Mastocytosis CNL [CML] JAK2 MPL CALR PDGFRA /B FGFR ckit BCR-ABL

5 INEFFECTIVE HAEMOPOEISIS

6 CLINICAL Age elderly predominate Cytopenias: Anaemia: tiredness, malaise, increasing angina, dyspnoea Neutropenia: increased infections NB RACIAL RANGE lower limit normal in African populations Thrombocytopenia: muco-cutaneous bleeding Constitutional symptoms LOW, malaise, (fever) Auto-immune symptoms Organomegaly Previous cancer / chemotherapy / radiotherapy

7 MDS: minimal diagnostic criteria Blood cytopenias marked and constant Exclusion of reactive causes of cytopenia MDS specific features at least one of: >10% dysplasia in at least one lineage Blasts >5% [>20% defines AML] Ringed sideroblasts 15% Evidence of clonality (MDS karyotype) Unbalanced NS Unbalanced sig Balanced +8 -Y 20q- -7/7q- -5/5qi(17q) or t(17p) -13/13q- 11q- 12p- or t(12p) 9qidic (X)(q13) t(11;16) t(3;21) t(1;3) t(2;11) inv 3 t(6;9) WHO 2008

8 MDS: minimal diagnostic criteria Blood cytopenias marked and constant : Hb <11g/dl OR Neutrophils (absolute) < 1.0 x 10 9 /l OR Platelets < 100 x 10 9 /l FOR [> 6 months]

9 MDS: minimal diagnostic criteria Blood cytopenias marked and constant Exclusion of reactive causes of cytopenia MDS specific features at least one of: >10% dysplasia in at least one lineage Blasts >5% [>20% defines AML] Ringed sideroblasts 15% Evidence of clonality (MDS karyotype) Unbalanced NS Unbalanced sig Balanced +8 -Y 20q- -7/7q- -5/5qi(17q) or t(17p) -13/13q- 11q- 12p- or t(12p) 9qidic (X)(q13) t(11;16) t(3;21) t(1;3) t(2;11) inv 3 t(6;9) WHO 2008

10 MDS: minimal diagnostic criteria Blood cytopenias marked and constant Exclusion of reactive causes of cytopenia: Haematinic deficiency Copper deficiency Hypothyroidism Significant organ dysfunction: Kidney Liver Ongoing inflammation HIV Hypersplenism (portal hypertension) DRUGS Auto-immune disease RA, SLE

11 MDS: minimal diagnostic criteria Blood cytopenias marked and constant Exclusion of reactive causes of cytopenia MDS specific features at least one of: >10% dysplasia in at least one lineage Blasts >5% [>20% defines AML] Ringed sideroblasts 15% Evidence of clonality (MDS karyotype) Unbalanced NS Unbalanced sig Balanced +8 -Y 20q- -7/7q- -5/5qi(17q) or t(17p) -13/13q- 11q- 12p- or t(12p) 9qidic (X)(q13) t(11;16) t(3;21) t(1;3) t(2;11) inv 3 t(6;9) WHO 2008

12 DYSPLASIA

13 MDS: minimal diagnostic criteria Blood cytopenias marked and constant Exclusion of reactive causes of cytopenia MDS specific features at least one of: >10% dysplasia in at least one lineage Blasts >5% [>20% defines AML] Ringed sideroblasts 15% Evidence of clonality (MDS karyotype) Unbalanced NS Unbalanced sig Balanced +8 -Y 20q- -7/7q- -5/5qi(17q) or t(17p) -13/13q- 11q- 12p- or t(12p) 9qidic (X)(q13) t(11;16) t(3;21) t(1;3) t(2;11) inv 3 t(6;9) WHO 2008

14 MDS: diagnostic maneuvers Karyotype: PRO: Analyze all chromosomes CON: Live cells required Experienced techs FISH: PRO: Sensitive No living cells required CON: Specific genes only

15 MDS Molecular Mutations n

16 MDS Molecular Mutations n EPIGENETICS RNA SPLICING

17 MDS Molecular Mutations n Revolutionize MDS: More common than karyotype abnormalities DIAGNOSTIC PROGNOSTIC THERAPEUTIC TARGETS Bejar and Steensma Blood 2014

18 MDS Molecular Mutations n Bejar and Steensma Blood 2014

19 MDS: diagnostic maneuvers FBC and ancillary blood tests Radiology Ultrasound spleen Exclude lymph nodes Bone marrow biopsy Flow cytometry Karyotype (cytogenetics) / FISH Molecular studies

20 MDS: differential pitfalls Hypoplastic anemia versus hypoplastic MDS Inherited bone marrow failure syndromes Fanconi anaemia Dyskeratosis congenita LGL leukaemia / rheumatoid arthritis (Felty s syndrome) Auto-immune (SLE) Fibrosis with dysplasia

Spectrum of MDS related disorders Traditional ICUS MDS by WHO 2008 ICUS IDUS 2 CHIP CCUS Low risk MDS High risk MDS Clonality - - + + + + Dysplasia - + - - + + Cytopenias + - - + + + BM blast% <5%

21 Spectrum of MDS related disorders Traditional ICUS MDS by WHO 2008 ICUS IDUS 2 CHIP CCUS Low risk MDS High risk MDS Clonality Dysplasia Cytopenias BM blast% <5% <5% <5% <5% <5% <19% Risk Very low Very low Very low Low(?) Low High Therapy Obs/BSC / (?GF) Obs Obs Obs/BSC /GF Obs/BSC /GF/IMiD /IST HMA/HCS T ICUS: Idiopathic cytopenia of uncertain significance IDUS: Idiopathic dysplasia of uncertain significance CHIP: Clonal haemopoeisis of indeterminate potential CCUS: Clonal cytopenia of uncertain significance Clonal cytopenias 1) Steensma et al Blood epub 30 April ) Valent et al Am J Cancer Res 2011

22 IPSS-R Need a simple, widely available prognostic scoring system Cytopenias Hb, neutrophil, platelets Lower = worse Blast percentage Higher = worse Cytogenetics Predicts for 5 risk categories prior to therapy Peter L. Greenberg et al. Blood 2012;120:

23 IPSS-R Survival based on IPSS-R prognostic risk-based categories. AML evolution based on IPSS-R prognostic risk-based categories. Peter L. Greenberg et al. Blood 2012;120:

24 IPSS-R age adjusted Peter L. Greenberg et al. Blood 2012;120:

25 Other prognostic variables Raised LDH RBC transfusions more severe cytopenia Increased cardiovascular events Immune modulation Iron overload Inadequate response to therapy Peter L. Greenberg et al. Blood 2012;120:

26 MDS therapy MDS incurable outside of stem cell transplant Therapy generally lifelong if responding Especially for hypomethylating agents Treatment considerations: Overall survival Symptoms / QOL Event free survival

27 AGE / PS MDS RISK MDS therapy THERAPY BEST SUPPORTIVE CARE Watch and wait Transfusions Antibiotics GROWTH FACTORS Erythropoietin GCSF [Thrombopoeitin analogues] MISCELLANEOUS Immune suppression Iron chelation Lenolidamide DEMETHYLATING AGENTS 5-azacytidine (Vidaza ) Decitabine (Dacogen ) CONVENTIONAL CHEMOTHERAPY Intensive AML-like chemo STEM CELL TRANSPLANT Allogeneic

28 MDS therapy

29 MDS Transplant Bejar et al JCO Sep 2014

30 MDS therapy practical tips Frequent blood counts and check-up Transfusions pre-emptively Infection prophylaxis, investigation and management Erythropoeitin High dose (30/ /80 000iu weekly) Iron chelation - Exjade Food and dosing considerations increases creatinine (not renal failure) Vidaza Subcutaneous injection site inflammation - corticosteroids Anti-emetics serotonin antgonists Constipation Psycho-social support Patient support groups

Emerging New Prognostic Scoring Systems in Myelodysplastic Syndromes 2012

Emerging New Prognostic Scoring Systems in Myelodysplastic Syndromes 2012 Arjan A. van de Loosdrecht, MD, PhD Department of Hematology VU University Medical Center VU-Institute of Cancer and Immunology