MYELODYSPLASTIC SYNDROME: prognosis & treatment options JILL Fulcher MD PhD FRCP(UK) 13th oct 2018

Normal blood smear 1. Red cells - Contain Hb Anemia when low 2. White cells - neutrophils - Infection when low 3. Platelets Clot formation Bleeding when low

Normal hematopoiesis Blood cells are made in the bone marrow Hematopoietic stem cell (HSC) Undergo a series of developmental steps resulting in mature red cells, neutrophils and platelets Released into bloodstream

Myelodysplastic syndrome Chung SS & Park YP. 2017. Blood Advances;1(26):2572-8

MDS: Abnormal haematopoiesis Myelodysplastic Syndrome Anemia, infection, bleeding

Prognostic Scoring System for MDS

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Symptomatic MDS bleeding Infections fatigue, SOB +/- Iron chelation Medications: Tranexamic acid Antibiotics Antiviral agent Anti-fungal agent (TPO receptor agonists) bleeding Infections fatigue, SOB +/- Iron chelation

Anemia – Trial of Erythropoietin Replacement Therapy (ERT) Response rate predicted from: Serum EPO level Transfusion requirements 74% chance of responding when EPO < 500 U/L, <2 units RBC/mth 7% if EPO > 500, >2 units RBC/mth Target Hb 100-120g/L Synergy with GCSF

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Other therapies for lower-risk mds Lenalidomide Immuno-modulating agent MDS with del(5q) with anemia 10mg/d for 21d out of 28d Response in 4-6 weeks Rise in Hb of 32 g/L 65 - 70% achieve transfusion independence, 30-40% cytogenetic remission Improves survival (2y OS 90%v74%) S/E: low neutrophils, low platelets, rash, GI, ? secondary malignancy Immunosuppressive therapy (IST) ATG + cyclosporine More likely to work in patients: 60y/o or younger Low-risk disease BM blasts < 5% Bone marrow hypoplasia Normal cytogenetics HLA-DR15 PNH clone

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The only cure for MDS is Hematopoietic Stem Cell Transplantation

Myelodysplastic Syndrome: a disease mostly of the elderly Mean age at diagnosis 70-75y Incidence : 4.9 per 100,000/year <40y 0.1 per 100,000/year 70-79y 30.2 per 100,000/year >80y 59.9 per 100,000/year Buckstein R. Leuk Res 2009;33:1313-8 Williamson PJ, et al. Br J Haematol. 1994;87:743

Co-morbidities affect transplant outcomes Sorror et al, 2005. Blood; 106(5):2912-2919

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Hypomethylating agents

Effect of Azacitidine in Higher-risk MDS (>/= IPSS-2) Fenaux et al, Lancet Oncol 2009 358 patients Median OS: 24.5 vs 15 mths Alive at 2 years: 51% vs. 26% Transformation to AML: 11.5 vs. 17.8%

Agents iN clinical trial Hypomethylating agents (HMAs) Decitabine iv Guadecitabine (SGI-110) Oral azacitidine (CC486) Oral decitabine (Cedurazine) Erythroid Stimulating Agents Luspatercept Thrombopoiesis Stimulating Agents TPO mimetics Romiplostin (intectable) Eltrombopag (oral)

Timing of Transplant in Lower-risk MDS De Witte et al. 2017. Blood;127(13):1753-1762

Thank you QUESTIONS?