2/7/2017. Updates in MDS: Overview

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1 Updates in Myelodysplastic Syndromes Mikkael A. Sekeres, MD, MS Professor of Medicine Vice-chair for Clinical Research Director, Leukemia Updates in MDS: Overview GENOMICS: Mutational profiling and its utility at each level of diagnosis and therapy Optimization of Lower-risk MDS treatment using currently available and novel therapeutics Targeted therapies Improving upon hypothmethylating agents and options at the time of MDS Basics: Definition A heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell Characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis MDS is a 1

2 MDS: Epidemiology Incidence Rate = 4.9/100,000 per year Howlader et al. SEER Cancer Statistics Review, , Siegel et al. CA Cancer J Clin 2014;64:9. Cross-sectional analysis of 4514 MDS patients in the U.S. in Age (Median) Newly diagnosed 71 years Sex (Mean) Duration of MDS (Median) Established Male (Newly diagnosed) (Established) years 55% 51-57% months MDS Status Primary 88 93% Secondary 7 12% Secondary Chemotherapy 55 80% Cause Radiation 6 21% MDS: Epidemiology Chemical exposure 2 9% Sekeres et al. J National Cancer Inst 2008;100:1542 MDS Basics: WHO Classification 2008 Name Abbrev Name Abbrev. Refractory cytopenia with unilineage dysplasia Refractory anemia with ring sideroblasts MDS w/ isolated del(5q) Refractory cytopenia with multilineage dysplasia Refractory anemia with excess blasts, type 1 RCUD (includes RA, RN and RT) MDS with single lineage dysplasia MDS-SLD RARS MDS with ring sideroblasts MDS-RS Del(5q) unchanged unchanged RCMD MDS with multilineage dysplasia (with ring sideroblasts) MDS-MLD MDS-RS- MLD RAEB-1 MDS with excess blasts, type 1 MDS-EB-1 Refractory anemia with excess blasts, RAEB-2 MDS with excess blasts, type 2 MDS-EB-2 type 2 Adapted MDS, Unclassifiable from Arber et al. Blood MDS-U2016 unchanged Higher Risk unchanged 2

3 percent 2/7/2017 MDS: WHO Survival Malcovati et al. JCO 2005;23:7594. N=467, Untreated Calculation of prognostic score Score BM Blast % < Cytogenetics Good Intermediate Poor Cytopenias 0/1 2/3 Estimation of prognosis MDS Basics: IPSS Higher Overall IPSS Subgroup Median Survival Risk Score (Years) 0 Low Intermediate Intermediate >2.5 High 0.4 Cytopenias: ANC < 1.5, HGB < 10.0, PLT < 100,000 Good Risk: [-Y,del(5q), del(20q),nl]; Intermediate Risk: [8+,other]; Poor Risk: [Chr. 7 abn, >3 abn] Greenberg P, et. al. Blood 1997:89: MDS Staging: IPSS Survival A MDS Survival years Low 267 pts B Int pts Int pts High 56 pts NSCLC Survival Greenberg P, et. al. Blood 1997:89: Greenberg P, et. al. Blood 1997:89: Detterbeck et al. Chest 2009;136:260. 3

4 MDS Basics: IPSS-R Cytogenetics Score Schanz et al. JCO 2012;30: VARIABLE Cytogenetics V. Good Good Intermediate Poor V. Poor BM Blast % 2 >2-<5% 5-10% >10% Hemoglobin 10 8-<10 <8 Platelets <100 <50 ANC 0.8 <0.8 IPSS-R Prognostic Risk Categories/Scores RISK GROUP Risk Score Median Survival (Yrs) Very Low Low > Intermediate > High > Very High >6 0.8 Greenberg et al. Blood 2012;120: MDS Staging: IPSS-R Prognostic Score Variables MDS Staging: IPSS-R Prognostic Score Variables < 3.5 > 3.5 Pfeilstocker et al. Blood 2016;128:902. 4

5 MDS: Prognosis MDS Prognosis Made Easy!!! Lower Risk RA, RARS RCMD, RCUD MDS-U, MDS del (5q) IPSS Low, Int-1 (0-1.0); IPSS-R V. Low, Low, Int (<3.5) Higher Risk RAEB (-1, -2) IPSS Int-2, High (> 1.5); IPSS-R Int (>3.5), High, V. High MDS mutation landscape 2016 IPSS independent good prognosis BRAF(<1%) GNAS(<1%) EZH2 6% TET2 21% Proliferation JAK2 3% KRAS 1% NRAS 4% Epigenetic regulation DNMT3A (8%) UTX 1% CBL 2% CDKN2A (<1%) IDH1/2 2% PTPN11(<1%) PTEN(<1%) ASXL1 14% ATR X <1% Impaired Differentiation RUNX1 9% NPM1(2%) SF1 1% SF3B1 22% Other ETV6 3% ZRSR2 5% No clear independent effect IPSS independent poor prognosis TP53 8% Pre-mRNA splicing U2AF1 8% SETBP1 7% PRPF40 B 1% SRSF2 11% STAG2 and other cohesins 5-10% SF3A1 1% U2AF65 <1% Genetic Testing Added to IPSS-R?? Better Differentiation for Overall Survival Overall Survival by IPSS-R Overall Survival by New Model With Gene Mutations Nahza et al Leukemia 2016 Jun 17 5

6 Learning cohort Validation cohort TET2, ASXL1, DNMT3A 2/7/2017 Study Population Unexplained Cytopenia N=683 Myeloid Neoplasm N=409 MDS N=233 MDS/MP N N=86 MPN N=35 MPN N=55 ICUS N=154 Other Cytopenia N=120 Second opinion for suspected myelodi neoplasm with myelodysplasia N=190 Myeloid Neoplasm N=138 ICUS N=14 Other Cytopenia N=38 Malcovati et al. ASH 2016; abstract 298 Diagnostic value of mutation status in patients with cytopenia of undetermined significance HR=13.93 (P<.001) Clonal Cytopenia of Undetermined Significance (CCUS) Unmutated Idiopathic Cytopenia of Undetermined Significance (ICUS) Malcovati et al. ASH 2016; abstract 298 Implications of mutation status for the diagnosis of myeloid neoplasms Specificity for myeloid Gene neoplasm with myelodysplasia SF3B (0.91-1) SRSF ( ) ZRSR2 1 (0.95-1) U2AF ( ) RUNX 0.90 ( ) 1 EZH ( ) CUX ( ) CBL 0.94 ( ) BCOR 1.0 ( ) TP ( ) Negative predictive value IDH2 1.0 ( ) Unmutated status: 0.84 Positive predictive value 2 mutation: 0.99 Mutation patterns: Unexplained Cytopenia Myeloid Neoplasm ICUS CCUS with False positive Myeloid CCUS with no highly specific myeloid neoplasm Neoplasm specific pattern pattern Mild dysplasia, no evidence of clonality, no evidence Candidate of disease mutation patterns progression providing presumptive evidence of MDS ICUS Malcovati et al. ASH 2016; abstract 298 6

7 MDS: Lower-risk, Treatment Algorithm Sekeres and Gerds Hematology (ASH Educ Program) MDS: Lower-risk, Treatment Algorithm Sekeres and Gerds Hematology (ASH Educ Program) MDS: ESA Response Rate ESAs RR ~40% Golshayan et al. Br J Haem 2007;137:125. 7

8 Proportion of patients with RBC-TI 8 weeks Patients (%) 2/7/2017 MDS-005: Study Design Pretreatment Double-blind (DB) treatment Off-treatment Continue DB phase until Key inclusion criteria Centrally reviewed IPSS Low or Int-1-risk MDS with karyotypes other than del(5q) RBC-TD Unresponsive or refractory to ESAs R A N D O M I Z E D 2:1 LEN 10 mg, orally, QD a Matching placebo W 24 RBC-TI 8 weeks or erythroid response No RBC-TI 8 weeks or erythroid response erythroid relapse or disease progression Discontinue DB phase Long-term followup ( 5 years from randomization) Overall survival AML progression Subsequent MDS treatments SPMs Santini et al. JCO 2016 MDS-005: RBC-TI 8 Weeks Significantly more LEN patients achieved RBC-TI 8 weeks versus placebo (P < 0.001) % LEN (n = 160) Placebo (n = 79) % RBC-TI 8 weeks Santini et al. JCO 2016 MDS-005: Duration of RBC-TI 8 Weeks The median duration of response was 32.9 weeks (95% CI ) among RBC-TI 8 weeks responders with LEN LEN Placebo Log-rank P = Censored No. of RBC-TI patients Duration of response (weeks) LEN Placebo Santini et al. ASH

9 E2905 Characteristic LEN (n = 81) LEN+Epo (n = 82) Age, median (range), years 75 (49-89) 73 (47-89) Male, n (%) 55 (68%) 61 (74%) Median years from diagnosis (range) 1.5 (0-17) 1.7 (0-18) Median RBC transfusion burden, units/28 days (range) 2 (0-7) 2 (0-8) Prior Azanucleoside therapy, n (%) 18 (22%) 9 (11%) Prior ESA treatment, n (%) 77 (95%) 74 (90%) IPSS risk, n (%) Low 28 (35%) 35 (43%) Int-1 51 (63%) 41 (50%) IPSS karyotype (central review) Good 64 (79%) 68 (83%) Intermediate 14 (18%) 11 (13%) Serum Epo [mu/ml] Median (range) 167 ( ) 143 ( ) < 500 mu/ml 60 (74%) 58 (71%) List et al. ASH 2016; abstract 223 E2905 Baseline Characteristics Characteristic LEN LEN+Epo (n = 81) (n = 82) WHO 2008 (central review) RA 6 (7%) 6 (7%) RARS 18 (22%) 22 (27%) RCMD/RCMD-RS 34 (42%) 33 (40%) RAEB1 9 (11%) 1 (1%) Missing or other 12 (15%) 20 (24%) Median BM blast % (range) 2 (0-15) 2 (0-54) Median ANC (range), /mm ( ) 2320 ( ) Median Platelet count (range), 191 (57-727) 226 (55-793) 10 3 mm 3 Serum Epo [mu/ml] Median (range) 167 ( ) 143 ( ) < 500 mu/ml 60 (74%) 58 (71%) List et al. ASH 2016; abstract 223 Week 16 Evaluable: Erythroid Response Arm A (%) Response & Cohort LEN Arm B (%) LEN+E po Week 16 Evaluable [n=117] N=56 N=60 MER 8 (14.3) 20 (32.8) Minor ER (23.1) (21.3) Overall ER (37.5) (54.1) P value P= P=0.83 P=0.09 List et al. ASH 2016; abstract 223 9

10 Duration of Major Erythroid Response List et al. ASH 2016; abstract 223 Trial Design HOVON89 Low and Int-1 myelodysplastic syndrome Age 18 Arm A Randomize Arm B 6 cycles 4 cycles 2 cycles No HI Off treatment No HI 2 cycles after HI 2 cycles 1 Epo 30,000 IU No HI 2 cycles 1 Epo 60,000 IU after HI Off treatment 2 cycles after HI 2 cycles 1 Epo 30,000 IU after HI No HI 2 cycles 2 cycles after HI 2 cycles 1 Epo IU after HI 2 cycles 1 Epo 60,000 IU after HI 2 cycles 1 Epo 60,000 IU G-CSF after HI Off treatment 2 cycles 2 cycles 1 Epo 30,000 IU 2 cycles 1 Epo 60,000 IU 2 cycles 1 Epo 60,000 IU G-CSF 2 cycles after HI after HI or no HI Off treatment after HI after HI or no HI or no HI Off treatment after HI Off treatment Maintenance cycles Maintenance cycles Epo 30,000 IU Maintenance cycles Epo 60,000 IU Maintenance cycles Epo 60,000 IU G-CSF Disease progression or baseline transfusion requirements After each cycle: Haematological evaluation of PB should be performed If disease progression or baseline transfusion requirements Off treatment Off treatment 1 For Epo and/or G-CSF reduction in case of HI, see protocol and Van DeLoosdrecht et al. ASH 2016; abstract 224 Results HOVON89: primary and secondary endpoints Hematological Improvement-Erythroid: 41% (according to IWG criteria) 39% and 42% of the patients for arm A and B, respectively (p = 0.45). Hematological Improvement-Erythroid: non-del5q versus del5q: 34% vs 79% Time-to-HI-E: 3.1 months (median; range ) for both arms Duration of HI-E: 10.6 months (range ) Van DeLoosdrecht et al. ASH 2016; abstract

11 Progression Free Survival and Overall Survival HOVON89 by arm PFS: median 15.1 vs 15.0 months in arms A and B (p=0.364) OS: median 45.1 and 37.7 months for arm A and B (p=0.09) Van DeLoosdrecht et al. ASH 2016; abstract 224 Results: NGS and response to Presence of 2 or more mutations are inversely related to HI-E (p=0.004) Presence of 1 or more splicing factor mutations are inversely related to HI-E (p<0.0001) Of the 7 most frequently mutated genes i.e. TET2, ASXL1, DNMT3, ATRX, RUNX1, only SRSF2 (p=0.021) and SF3B1 (p=0.004) are significantly associated with lack of response to (HI-E) Van DeLoosdrecht et al. ASH 2016; abstract 224 AZA vs LEN in Lower Risk MDS Lenalidomide is widely used off-label in the non-del5q setting NCCN clinical guidelines list LEN as a 2 nd treatment option for TD anemia in lower-risk non-del 5q MDS after hypomethylating agents (HMAs) led to wide use of HMAs as frontline therapy after erythroid stimulating agents (ESA) failure in LR-MDS Response rate to LEN after HMA failure is not known, as MDS-002 and MDS-005 excluded patients previously treated with HMAs examined response rates to each drug when treatment order (LEN followed by HMA or HMA followed by LEN) differed. LEN 1 st line n= 80 Len 2 nd line n= 64 P value LEN ORR (HI+) 20% (n=16) 11% (n=7) AZA ORR (HI+) 30% (n=24) 39% (n=25) Komrojki et al. ASH 2016; abstract

12 MDS: Lower-risk, Treatment Algorithm Sekeres and Gerds Hematology (ASH Educ Program) Background and Clinical Hypothesis Intravenous (IV) Decitabine(DAC) is an approved therapy for MDS Oral bioavailability of DAC is low due to degradation in the gut by cytidine deaminase (CDA) O N N Decitabine O N HO NH 2 N O CDA N O HO HO NH O Inactive Metabolite HO MDS treatment requires continued treatment for long periods. An oral decitabine would provide significant benefit Development of a potent safe CDA inhibitor should enable decitabine oral bioavailability E7727, a novel potent CDA inhibitor (IC 50 is 0.28±0.06 µm) Garcia-Manero et al. ASH 2016; abstract 114 ASTX727 Phase 1 Results Clinical Activity N = 43 2 Clinical Response 1 N (%) Complete Response (CR) 4 (9%) Marrow Complete Response (mcr) Hematologic Improvement (HI) Transfusion Independence Response 2 (5%) 6 (14%) 7/23 (31%) Still On Treatment 10 (23%) Responses were observed in all cohorts and in patients previously treated with HMAs (56% of patients in Cohort 4-5 were previously treated with azacitidine) Five patients went on to Hematopoietic Stem Cell Transplant (HSCT) Median of 5 cycles was administered (Range 1-26) Garcia-Manero et al. ASH 2016; abstract

13 Proportion Surviving 2/7/2017 MDS: Higher-risk, Treatment Algorithm Sekeres and Cutler Blood 2014;123: MDS: Higher-risk, Treatment Algorithm Sekeres and Cutler Blood 2014;123: months MDS: Higher-risk, Hypomethylating Therapy Log-Rank p= HR = 0.58 [95% CI: 0.43, 0.77] ORR=35% 50.8% 24.4 months 26.2% AZA CCR Time (months) from Randomization Fenaux P, et al. Lancet Oncology 2009;10:

14 MDS: Higher-risk, Hypomethylating Therapy Lubbert et al. JCO 2011;29:1987. Median OS 10.1 vs. 8.5 months Rationale for PD-1 Blockade in MDS PD-1 and its ligands PD-L1 and PD-L2 aid immune escape 1 HMAs upregulate PD-1, PD-L1 and PD-L2 on peripheral blood mononuclear cells of MDS patients 1 Pembrolizumab blocks interaction between PD-1 and its ligands PD-L1 and PD- L2, and restores anti-tumor responses KEYNOTE-013: phase 1b, multicohort study of pembrolizumab in patients with advanced hematologic malignancies ASH 2016: Data from chl 2 and PMBCL 3 cohorts will also be presented 1. Yang H. Leukemia. 2014;28: Armand P et al. ASH Abstract Zinzani PL et al. ASH Abstract 619. Garcia-Manero et al. ASH 2016; abstract 345 Baseline Characteristics Data cut-off: May 27, Characteristic, n (%) N = 28 Median age, years (range) 65 years 73 (38-84) 23 (82) Male 18 (64) Caucasian 27 (96) ECOG performance status 0 1 Prior lines of therapy (36) 18 (64) 21 (75) 5 (19) (7) Garcia-Manero et al. ASH 2016; abstract

15 Treatment-Related Adverse Events Data cut-off: May 27, Adverse Event, n N = 28 (%) All grade Grade 3-4 Hypothyroidism 4 (14) 0 Fatigue 3 (11) 0 Peripheral edema 2 (7) 0 Decreased appetite 2 (7) 0 Arthralgia 1 (4) 0 Gastroenteritis 1 (4) 1 (4) Groin pain 1 (4) 0 Increased blood creatinine 1 (4) 0 Maculopapular rash 1 (4) 0 Musculoskeletal stiffness 1 (4) 0 Pain in extremity 1 (4) 0 Pruritis 1 (4) 0 Pyrexia 1 (4) 0 Rash (generalized) 1 (4) 0 Skin pain 1 (4) 0 Tumor lysis syndrome 1 (4) 1 (4) All grade treatmentrelated AEs in 10 (36%) patients; grade 3-4 in 2 (7%) Discontinuation in 2 (7%) patients (grade 3-4 tumor lysis syndrome, grade 2 arthralgia) No treatment related deaths No immune mediated adverse events reported Garcia-Manero et al. ASH 2016; abstract 345 Clinical Activity of Pembrolizumab Best Overall Response a N = 27 n % (90% CI) Overall response rate 1 4 (0-16) Complete response 0 0 (0-10) Partial response 1 4 (0-16) Bone marrow complete response 3 11 (3-26) Stable disease (35-69) Progressive disease 9 33 (19-51) 3 (11%) patients experienced hematologic improvement Erythroid response in 2 (7%) patients Platelet response in 1 (4%) patient a Per IWG 2006 criteria. Data cut-off: May 27, Garcia-Manero et al. ASH 2016; abstract 345 AZA+Nivo in d/refractory AML: Characteristics (N=53) Characteristic Category N (%); Median [range] Age >60 years 68 [44-90] 41 (77) Diagnosis AML de 30 (57) novo 23 (43) 2 AML Median Prior Rx (include Rx for MDS) 2 [1-7] Prior therapy HMAbased HiDACbased Int-dose 13 AraC 27 Molecular Rx Prior Stem Cell Tx 9 Daver (17) et al. ASH 2016; abstract

16 AZA+Nivo in d/refractory AML: Response (N=53) Best response / Outcome N (%) Evaluable 53 CR/CRi 11 (21) HI + 50% blast reduction 3 (6) HI only (2 pts had 2 lineage) 4 (8) ORR 18 (34) 50% reduction in blast 14 (26) Progression/Stable dz 21 (18 / 3) 8-week mortality 4 (8) Median cycles to response 2 [1-11] Median follow-up 6.0 [ ] AZA+Nivo in d/refractory AML: OS AZA+Nivo versus historical HMA-combo Salvage 1 Daver et al. ASH 2016; abstract 344 MDS: Higher-risk, Treatment Algorithm Sekeres and Cutler Blood 2014;123:

17 MDS: Higher-risk Therapy - HSCT Test of Equality over Strata Test p Log-Rank <.0001 Wilcoxon < Log(LR) <.0001 Low/Int-1 MDS Koreth et al. JCO 2013;31:2662 MDS: Higher-risk Therapy - HSCT Test of Equality over Strata Test p Log-Rank <.0001 Wilcoxon < Log(LR) <.0001 Int-2/High MDS Koreth et al. JCO 2013;31:2662 Myelodysplastic Syndrome Allogeneic transplantation Survival Cause of death Pasquini MC, Zhu X. Lindsley et al. ASH 2016; abstract 69 17

18 Approach Cohort: 1514 MDS patients - Broadly representative: 130 transplant centers - Uniform diagnosis: MDS - No CMML or MDS/MPN - Blasts <20% - Year of transplant: Analysis - Samples: pre-sct whole blood (NMDP biorepository) - Targeted sequencing: 129 candidate genes - Myeloid malignancies - Inherited or acquired bone marrow failure - Clinical annotation: CIBMTR research database 3497 mutations in 65 genes, 1 mutation in 79% of patients Lindsley et al. ASH 2016; abstract 69 TP53 mutated MDS Poor prognosis due to early relapse Survival No TP53 mutation MDS TP53 mutation p < TP53 mutation Median OS = 8 months No TP53 mutation TP53 mutation No TP53 mutation p < Lindsley et al. ASH 2016; abstract 69 TP53 mutation Myeloablative conditioning does not improve outcome TP53 mutation Overall Survival TP53 mutation p = 0.20 MAC RIC Probability of relapse MAC RIC Years Lindsley et al. ASH 2016; abstract 69 18

19 RAS pathway mutation Myeloablative conditioning improves survival and reduces relapse RAS pathway Overall Survival RAS pathway p = 0.01 MAC RIC Probability of relapse MAC RIC Years Lindsley et al. ASH 2016; abstract 69 IDH Mutations as a Target in MDS IDH are critical enzymes of the citric acid cycle Mutant IDH2 (midh2) produces 2-HG, which alters DNA methylation, blocks cellular differentiation midh2 in ~5% of MDS 1 Enasidenib (AG-221/CC-90007) - selective, oral, potent inhibitor of midh2 enzyme Objective: safety and efficacy of enasidenib in midh2 MDS Tumor Cell AML, acute myeloid leukemia; IDH, isocitrate dehydrogenase; 2-HG, 2-hydroxyglutarate; midh2, mutated IDH2 1. DiNardo et al. Leukemia 2016;30(4):980-4 Stein et al. ASH 2016; abstract 343 Phase 1/2 Dose-escalation and Expansion Dose Escalation Expansion Phase 1 Any hematologic malignancy ineligible for other arms Advanced hematologic malignancies with IDH2 mutation R/R AML age <60, excluding patients relapsed post-bmt Continuous 28 day cycles Untreated AML patients age Cumulative daily doses 60 who decline standard of of mg care R/R AML age 60, or any age if relapsed post-bmt Phase 2 Accrual Completed Enasidenib 100 mg PO QD R/R AML (N=108) Completed (n=113) Completed (n=126) N=239 R/R AML: 176 Untreated AML: 37 MDS: 17 Other: 9 Stein et al. ASH 2016; abstract

20 Response and time on therapy Overall response rate (CR + PR + mcr + HI) Best Response MDS Patients (N=17) n (%) 10/17 (59) Complete remission* 1/11 (9) Partial remission* 1/11 (9) Marrow CR* 3/11 (27) Any hematologic improvement (HI) 5/17 (29) HI-E 3/15 (20) HI-P 4/12 (33) HI-N 4/10 (40) *Investigator-assessed; evaluable pts had 5% bone marrow blasts at baseline HI was programmatically adjudicated per IWG 2006 criteria for MDS; denominators reflect eligibility Of 13 patients who had received prior HMA therapy, 7 (54%) had a response with CR, complete remission; PR, partial remission; mcr, marrow CR; HI, hematologic enasidenib improvement Of patients who attained HI, 2 had trilineage and 2 had bilineage improvement Median time to response was 21 days (range 10-87) Stein et al. ASH 2016; abstract 343 Treatment Durations and Study Outcomes Median number of treatment cycles: 3.0 CR / mcr / PR HI NR Ongoing Proceeded to SCT/BMT Discontinued: Investigator Decision/Other Discontinued: Death or Progression Treatment duration (months) CR, complete remission; HI, hematologic improvement; mcr, marrow CR; NR, no response; PR, partial remission; SCT/BMT, stem cell transplant / bone marrow transplant Stein et al. ASH 2016; abstract 343 Grade 3-4 Treatment-emergent Adverse Events Grade 3-4 TEAEs (any cause), n=14 (82%) Grade 3-4 TEAEs occurring in 2 patients MDS Patients (n=17) Preferred Term n (%) Hyperbilirubinemia* 5 (30) Pneumonia 4 (24) Thrombocytopenia 4 (24) Anemia 3 (18) Hypokalemia 3 (18) grade 3-4 drug-related 6 patients Nine TEAEs reported for Dyspnea 2 (12) Enasidenib-related lysis syndrome serious TEAEs, n=4 (tumor [2], blood bilirubin Tumor increased, lysis transaminitis) syndrome 2 (12) No treatment-related *Unconjugated. Includes deaths hyperbilirubinemia and blood bilirubin increased Stein et al. ASH 2016; abstract

21 Conclusions Molecular profiling moving into standard of care Utility for diagnosis, prognosis and treatment planning at each phase of disease Serial evaluations likely have merit Always potential trial combinations of therapy in MDS arena Transplant remains curative but biology must be considered to optimize Patients with lower-risk disease with increased options post ESA therapy Add LEN Order LEN before AZA Options at the time of HMA failure Immunotherapy in myeloid diseases Targeted therapy of IDH2 Thanks! Cleveland Clinic Leukemia/MDS Program Jaroslaw Maciejewski, MD, PhD Sudipto Mukherjee, MD, PhD Camille Urban, RN, NP Yogen Saunthararajah, MD Nina D ambrosio, RN, NP Hetty Carraway, MD, MBA Barb Tripp, RN, NP Anjali Advani, MD Alicia Bitterice, RN, NP Matt Kalaycio, MD Meghan Scully, RN, NP Ronald Sobecks, MD Becky Habecker, BA Betty Hamilton, MD Chante Cavin, BA Aaron Gerds, MD, MS Sarah Kaufman, BA Aziz Nazha, MD Dennis Kramarz, BA John Desamito, MD Ben Pannell, BA Tracy Cinalli, RN Allison Unger, BA Kristen Colaluca, RN Jaime Fensterl, MS Christine Cooper, RN Abby Statler, MPH Mary Lynn Rush, RN Donna Abounader, BA Rachael Diligente, RN Abigail Snow, BA Andrea Smith, RN Justine DeAngelis, BA Eric Parsons, RN Ziad Chartouni, BA Samjhana Bogati, RN Brittani Demarest Barbara Paulic, RN, NP Caitlin Swann, PharmD Raychel Berardinelli, RN, NP Connie Cheng, PharmD And Our 21