Disclosures 1 Objectives Introduction Describe the clinical - PDF document

Winship Cancer Institute of Emory University Advances in the Management of MDS Martha L. Arellano, MD Associate Professor of Hematology/Oncology Winship Cancer Institute of Emory University Atlanta, GA Disclosures 1

Objectives • Introduction • Describe the clinical presentation and diagnostic evaluation of MDS • Discuss updates in the classification of MDS and tools to assess disease risk in MDS • Summarize data from key clinical trials in MDS • Apply current prognostic scoring system in the management of MDS Myelodysplastic Syndromes (MDS) • A group of malignant stem cell disorders characterized by ineffective hematopoiesis and variable risk of transformation to acute leukemia • Risk factors: – Age – Genetics – Environmental exposures – Prior therapy 2

Impact of MDS • Incidence in the US estimated at 3.3:100,000 • Median age at MDS diagnosis: 71 ‐ 76 • Annual incidence estimated at 75:100,000 among persons > 65 years of age • Estimated that 25% will progress to AML CR Cogle etal. Blood 2011; Ma et al. Cancer 2007 Age ‐ specific Incidence Williamson PJ, et al. Br J Haematol. 1994 3

Clinical Presentation Cytokine suppression Decreased Increased of hematopoiesis apoptosis apoptosis Dysplastic Ineffective hematopoiesis hematopoiesis Abnormal marrow Additional stromal cell ‐ cell mutations Interactions Life ‐ threatening complications of MDS Progression to AML Clinical Presentation • Asymptomatic • Cytopenia ‐ associated complications: – Anemia: fatigue, ischemic complications – Neutropenia: infection – Thrombocytopenia: hemorrhage • B ‐ symptoms: fever, weight loss • Auto ‐ immune manifestations: skin, neurological, other 4

2008 WHO Classification of MDS Disease Peripheral Blood findings Bone Marrow findings RCUD, RA, RN, RT uni or bicytopenia, blasts <1% *unilineage dysplasia, ≥ 10% of the cells , < 5% blasts, < 15% RS > 15% RS, <5% blasts, erythroid RARS anemia, no blasts dysplasia only dysplasia, > 10% cells of > 2 lineages, RCMD cytopenia(s), blasts < 1%, no auer <5% blasts, no auer rods, +/ ‐ 15% RS rods, monocytes <1 × 10 9 /L uni or multilineage dysplasia, RAEB ‐ 1 cytopenia(s), blasts < 5%, no auer 5 ‐ 9% blasts, no auer rods rods, monocytes <1 × 10 9 /L RAEB ‐ 2 cytopenia(s), blasts 5 ‐ 19%, auer uni or multilineage dysplasia, 10 ‐ 19% blasts, +/ ‐ auer rods rods ±, monocytes < 1 × 10 9 /L MDS ‐ U Cytopenias, < 1% blasts dysplasia in <10% cells, accompanied by cytogenetic evidence of MDS , < 5% blasts normal to ↑ megas with hypolobated MDS with Anemia, platelets normal or nuclei, <5% blasts, no Auer rods, isolated del (5q) increased, blasts < 1% Isolated del5q Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds): Lyon 2008. Recurring chromosomal abnormalities as presumptive evidence of MDS in the setting of persistent cytopenias without definitive dysplasia Unbalanced abnormalities Balanced abnormalities − 7 or del(7q) t(11;16)(q23;p13.3) − 5 or del(5q) t(3;21)(q26.2;q22.1) i(17q) or t(17p) t(1;3)(p36.3;q21.1) − 13 or del(13q) t(2;11)(p21;q23) del(11q) inv(3)(q21q26.2) del(12p) or t(12p) t(6;9)(p23;q34) del(9q) idic(X)(q13) 5

Case 70 year old female evaluated for yearly physical examination • PMH: HTN, coronary disease • Medications: beta blocker, aspirin • WBC 5 x 10 9 /L, 40% segs, no blasts, hgb 10 gm/dL, MCV 105, platelets 240 x 10 9 /L • Work ‐ up unrevealing for specific etiology • BM Bx: possible dysplasia in < 5% cells, no increase in blasts, chromosomes: deletion (7q) in 18 of 20 metaphases. • Dx: ??? 2008 WHO Classification of MDS Disease Peripheral Blood findings Bone Marrow findings uni or bicytopenia, blasts <1% *unilineage dysplasia, ≥ 10% of the RCUD, RA, RN, RT cells , < 5% blasts, < 15% RS RARS anemia, no blasts > 15% RS, <5% blasts erythroid dysplasia only RCMD cytopenia(s), blasts < 1%, no auer dysplasia, > 10% cells of > 2 lineages, <5% blasts, no auer rods, +/ ‐ 15% RS rods, monocytes <1 × 10 9 /L RAEB ‐ 1 cytopenia(s), blasts < 5%, no auer uni or multilineage dysplasia, 5 ‐ 9% blasts, no auer rods rods, monocytes <1 × 10 9 /L uni or multilineage dysplasia, RAEB ‐ 2 cytopenia(s), blasts 5 ‐ 19%, auer 10 ‐ 19% blasts, +/ ‐ auer rods rods ±, monocytes < 1 × 10 9 /L MDS ‐ U Cytopenias, < 1% blasts dysplasia in <10% cells, accompanied by cytogenetic evidence of MDS , < 5% blasts normal to ↑ megas with MDS with Anemia, platelets normal or hypolobated nuclei, <5% blasts, no isolated del (5q) increased, blasts < 1% Auer rods, Isolated del5q Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds): Lyon 2008. 6

MDS Prognosis The International Prognostic Scoring System (IPSS) and WHO PSS (WPSS) IPSS Score 0 0.5 1 1.5 2.0 % BM Blasts <5 5 ‐ 10 ‐‐ 11 ‐ 20 21 ‐ 30 Karyotype Good Intermediate Poor (other) (nl, 5q ‐ , 20q ‐ , ‐ Y) (complex, abn. chr. 7) # cytopenias 0 ‐ 1 2 ‐ 3 Total Score Risk Group Median Survival (yrs) 25% Progression to AML, y 0 Low 5.7 9.4 0.5 ‐ 1 Intermediate ‐ 1 3.5 3.3 1.5 ‐ 2 Intermediate ‐ 2 1.2 1.1 >2 High 0.4 0.2 WHO Score 0 1 2 3 category RA RARS, 5q ‐ RCMD, RCMD ‐ RS RAEB ‐ 1 RAEB ‐ 2 Karyotype good intermediate poor ‐ RBC Transfusion? No Yes ‐ ‐ Risk groups: Very low 0; low 1; int 2; high 3 ‐ 4; very high 5 ‐ 6; OS 1 ‐ 8.6 years, AML 0.06 ‐ 0.94 Greenberg, et al. Blood 89:2079 ‐ 88 (1997) Malcovati et al. JCO (2007) 25: 3503 ‐ 10 7

MD Anderson Lower ‐ Risk MDS Prognostic Scoring System G. Garcia ‐ Manero et al. Leukemia 22, 538–543 (2008) R. Bejar. Hematology 2013 The Revised International Prognostic Scoring System (IPSS ‐ R) Variable 0 0.5 1 1.5 2 3 4 CTG Very ‐ Good ‐ Interm. Poor Very good poor %BM < 2% ‐ > 2 ‐ < 5% ‐ 5 ‐ 10% > 10% ‐ blasts Hgb. > 10 ‐ 8 ‐ < 10 < 8 ‐ ‐ ‐ Platelets > 100 50 ‐ 99 < 50 ‐ ‐ ‐ ‐ ANC > 0.8 < 0.8 ‐ ‐ ‐ ‐ ‐ Cytogenetic (CTG) groupings: Very good : ‐ Y, del(11q) • Good : NL, del(5q), del(12p), del(20q), double including del (5q) • Intermediate : del(7q), +8, +19, i(17q), any other single or double clone • Poor : ‐ 7, inv(3)/t(3q)/del(3q), double incl. ‐ 7/del(7q) • Very poor : complex (> 3 abn) • Greenberg, et al. Blood 2012. 120: 2454 ‐ 2465 8

MDS: IPSS ‐ R Risk Category Risk Score Very Low < 1.5 Low 2 ‐ 3 Intermediate 3.5 ‐ 4.5 High 5 ‐ 6 Very High > 6 N Very Low Low Interm. High Very High Patients, % 7012 19 38 20 13 10 Med. Survival, 8.8 5.3 3 1.6 0.8 years (95% CI) (7.8 ‐ 9.9) (5.1 ‐ 5.7) (2.7 ‐ 3.3) (1.5 ‐ 1.7) (0.7 ‐ 0.8) AML/25%, NR 10.8 3.2 1.4 0.73 years (14.5 ‐ NR) (9.2 ‐ NR) (2.8 ‐ 4.4) (1.1 ‐ 1.7) (0.7 ‐ 0.9) Greenberg, et al. Blood 2012. 120: 2454 ‐ 2465 Outcomes according to IPSS ‐ R Survival AML ‐ free Survival Greenberg, et al. Blood 2012. 120: 2454 ‐ 2465 9

Frequency of Point Mutations in MDS and Association with Survival R. Bejar et al. N Engl J Med 2011. Hazard Ratio for Death R. Bejar et al. N Engl J Med 2011. 10

Overall Survival according to IPSS category and mutational status R. Bejar et al. N Engl J Med 2011. Treatment Options REWARD RISK 11

Goals of Therapy for MDS • Treatment selection: factors to consider – Who is the patient (comorbidities, performance status) – Disease classification (risk, HLA ‐ DR type) • Lower risk disease – Reduce transfusion requirement – Decrease infection risk – Improve quality of life? • Higher risk disease – Prolong survival – Delay AML onset – Cure??? MDS: Treatment Options • Options: – Supportive: transfusion, antibiotics, cytokines – Immune suppression (hypoplastic MDS, HLA ‐ DR15) – Chemotherapy (cytotoxic, HMT, IMIDs, newer/targeted agents) – Transplantation 12

MDS Treatment: Cytokines and Imids Agent Responses Comments rHEPO 25 ‐ 40% • Predictive model for response (7 ‐ 74%) using baseline epo level (< 500) and RBC transfusion requirement (< 2 U) rHEPO + G ‐ CSF 40 ‐ 70% • Epo non ‐ responders may respond after addition of G ‐ CSF Thrombopoietin 40 ‐ 65% platelet • Caution advised due to concern for AML, DVT, marrow mimetics responses fibrosis Lenalidomide 43 ‐ 76% • Dose 10mg/day x 21 ‐ 28 days transfusion • Predictors of response (not consistently seen): 5q ‐ , independence younger age, shorter MDS duration, lower transfusion needs, therapy ‐ related thrombocytopenia Balleari et al. Ann Hematol 2005 Sekeres. Leukemia 2012 List et al. NEJM 2006 MDS Treatment: Immune suppression Agent N Response Comments ATG 129 39 (30%; 12/39 CR) • 3 years median follow ‐ up of patients treated at NIH, compared to 816 patients on BSC reported to 18/74 ATG, 20/42 the international myelodysplasia risk analysis ATG/CSP, 1/13 CSP workshop( IMRAW). • Younger age, int and low risk IPSS, HLA ‐ DR15+, ATG + CSP combination were associated with response. ATG/CSP 88 Hem response: • Ph III RCT of ATG/CSP vs. BSC • Crossover design (14 BSC subjects) (ATG 45 ATG: 13/45 (29%) • Therapy: ATG 15mg/kg/day x 5d; oral CSP x 180 BSC 43) BSC: 4/43 (9%) days • Hem response: ‐ P= 0.0156 for ATG/CSP; TFS/OS P= NS Alemtuzumab 32 21/31 (68% HI + CR) • Denovo MDS; selected based on probability of responding to IST (age, HLA ‐ DR15 status, # mos. of (31 eval) red cell transfusion dependence) • Alem dose: 10mg/day IV x 10 days Sloand et al. JCO 2008 Passweg et al. JCO 2011 13