Therapeutic options after first line treatment failure

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1 Therapeutic options after first line treatment failure Orlando ASH 215 Guillermo Garcia-Manero MD Professor of Medicine Chief Section of MDS Deputy Chair, Translational Research Department of Leukemia MD Anderson Cancer Center University of Texas Houston, TX

2 DISCLOSURE I have no relevant financial relationships to disclose.

3 What are the major needs in MDS? (problems that limit significant cure rate) Identification of poor prognosis lower risk patients By default sparing patients with no need of therapy Concept of early intervention Development of new targeted therapies for patients with lower risk MDS Development of new therapies for patients with higher risk MDS Understanding mechanisms of resistance to epigenetic modulators in MDS Understanding mechanisms of transformation to AML Incorporation of allosct in MDS Minimizing risk of relapse post allosct in MDS

4 Natural history of MDS after incorporation of HMAs Prodrome LR-MDS Untreated HMA? lenalidomide HMA failure? HR-MDS Untreated HMA AML-like SCT HMA failure AML-like?? AML HMA lower risk failure survival: months HMA higher risk failure survival: 4-6 months Jabbour. Cancer 215; Jabbour. Cancer 21

5 H3K4me3 Chip-seq Strategy in MDS MDS patient s BM Control BM CD34+ CD34+ CD34- CD34- Ch-IP with H3K4-3Me Antibody Solexa Sequencing of Specific H3K4-3Me Rich Chromatin Fragments Bio-info analysis MDS specific biomarkers (Potential Specific Epigenetic Change in MDS) Wei. Leukemia 213.

6 relative level of RNA relative level of RNA relative level of RNA H3K4m3 CHIP-Seq: Data Analysis & Validation criteria for MDS specific H3K4me3 peak selection +/- 2kb to TSS of a known gene MDS vs control > 3 fold p value < 1-6 C5AR1 MDS control promoter H3K4me3 enrichment relative level of RNA RNA expression C5AR1 N=94 N=8 MDS control PTAFR MDS control promoter H3K4me3 enrichment relative level of RNA RNA expression PTAFR N=1 N=9 MDS control FPR1 & FPR2 MDS control FPR1 N=65 N=4 MDS control FPR2 N=89 N=8 AQP9 MDS control TYROBP MDS relative level of RNA AQP9 N=87 N=4 MDS control TYROBP N=1 N= control 1 Wei. Leukemia MDS control 5 MDS control

7 H3K4me3 Associated Gene Activation in CD34+ Cells of MDS MDS BM CD34- MDS BM CD genes 156 genes CFD SLC11A1 Wei. Leukemia. 213

8 H3K4me3-associated Gene Activation in MDS CD34+ Cells targets an Innate Immunity Like Pathway Ingenuity Pathway Analysis predicted NFkB-centered signal activation = with reported involvement in innate immune signaling activation Wei. Leukemia. 213

9 Overexpression of Other Innate Immunity Like Signaling Components in MDS BM CD34+ (non-chip-seq identified) CHIP-Seq gene products Toll like receptors (TLR) TLR2/ TLR1 TLR2/ TLR6 Genes examined in MDS BM CD34+ cells TLR1, 2, 3, 4, 6, 7, 8, 9, MYD88, IL-8 expression level in primary MDS BM CD34+ cells MYD fold NF-kB I-kB p5 p65 IL8 receptor IL fold 5.5 fold 2 fold 138 fold IL8 TLR1 TLR2 TLR6 MYD88 IL-8 MDS bone marrow CD34+ Genes showing potential prognostic value TLR1 and MYD88 expression levels negatively associate with overall survival (OS) in MDS patients Wei. Leukemia. 213

10 TLR2 Stimulation Activates Histone Demethylase JMJD3 De Santa F et al Cell 27 JMJD3 is Overexpressed in MDS CD34+ Cells Wei. Leukemia. 213

11 Relative Expression Innate Immunity Genes & Patient Response to Epigenetic Targeting Drugs SAHA/ AZA 2 15 TLR C5AR FPR D D5 D21 D28 Resistance Sensitive N=11 N=7 FPR2 D D5 D21 D D D5 D21 D28 Resistance Sensitive TYROBP D D5 D21 D28 D D5 D21 D28 Resistance Sensitive Yang H et al Resistance Sensitive Resistance Sensitive

12 Cellular Immune Dyregulation in MDS MDS Immunosuppression CTL Th17 Tregs DC Macrophage Adaptive Immune Responses B Cells NK Selective Leukemic Clone Growth Tumor Immune Evasion Mechanisms: 1. Inhibitory B7 expression by tumor, APC and stroma cells. 2. APC 3. Treg.

13 What about cellular immunity? Aberrant up-regulation of PD-L1, PD-L2, PD-1 and CTLA4 in CD34+ cells from MDS, CMML and AML. Yang et al Leukemia 214

14 Relative expression RelativeExpression Relative expression Relative Expression Dynamics of PD-L1, PD-L2, PD-1 and CTLA4 expression in patients treated with different forms of epigenetic therapy. PD-L1 CTLA Days on Therapy Days on Therapy PD-L2 2 P D Days on Therapy D a y s o n T h e r a p y Yang et al Leukemia 214

15 Epitargeting of immune pathways in MDS 2. Molecular Mechanisms: Searching endogenous PAMP/ DAMP that activates innate immune signaling and involves in MDS pathogenesis 3. Evaluate Therapeutic Potential of targeting innate immune signaling in MDS 1. Molecular Mechanisms: Interaction between innate immune signal and other genetic lesions in MDS pathogenesis Gomez-Ganan. Leukemia 215.

16 Adult murine hematopoiesis LT-HSC Lin - ckit + sca1 + CD34 - CD135 - HSC COMPARTMENT = KSL ST-HSC Lin - ckit + sca1 + CD34 + CD135 - Lin - ckit + sca1 + CD34 + CD135 + MYELOID PROGENITOR COMPARTMENT = KL Lin - ckit + sca1 - CD34 + CD16/32 - CMP Lin - ckit + sca1 - MEP Lin - ckit + sca1 - CD34 - CD16/32 - CD34 + CD16/32 + MPP GMP LMPP Lin - ckit + sca1 + CD34 + CD135 bright CLP LYMPHOID PROGENITOR COMPARTMENT ERYTHROCYTES PLATELETS GRANULOCYTES MONOCYTES PRO T-CELL PRO B-CELL Modified from Iwasaki H et al. Immunity 27

17 [H g b ] ( g / d L ) C e ll c o u n t s (1 3 / m m 3 ) C e ll c o u n t s (1 3 / m m 3 ) C e ll c o u n t s (1 3 / m m 3 ) Short-term in TERT-ER mice: effect Aza on CBC E ffe c t o f 7 -d a y A Z A tr e a tm e n t o n W B C c o u n ts in T E R T -E R m ic e E ffe c t o f 7 -d a y A Z A tr e a tm e n t o n n e u tro p h il c o u n ts in T E R T -E R m ic e **** B a s e lin e 1 w e e k ** **** B a s e lin e 1 w e e k * 5.5 V e h ic le A Z A V e h ic le A Z A G G 5 E ffe c t o f A Z A tre a tm e n t o n h e m o g lo b in le v e ls in T E R T -E R m ic e. V e h ic le A Z A V e h ic le A Z A G G 5 E ffe c t o f 7 -d a y A Z A tr e a tm e n t o n p la te le t c o u n ts in T E R T -E R m ic e *** ** B a s e lin e 1 w e e k **** *** B a s e lin e 1 w e e k V e h ic le A Z A V e h ic le A Z A V e h ic le A Z A V e h ic le A Z A G G 5 N=2 Colla. Cancer Cell 215; Gomez-Ganan poster 2852 Sunday G G 5

18 C e ll n u m b e r (w e ig h t-n o r m a liz e d a n d r e la tiv e to C o n tr o l G ) C e ll n u m b e r (w e ig h t-n o r m a liz e d a n d r e la tiv e to C o n tr o l G ) C e ll n u m b e r (w e ig h t-n o r m a liz e d a n d r e la tiv e to C o n tr o l G ) C e ll n u m b e r (w e ig h -n o r m a liz e d a n d r e la tiv e to C o n tr o l G ) Short-term in TERT-ER mice: effect Aza on HSPC L T -H S C S T -H S C * V e h ic le A Z A V e h ic le A Z A V e h ic le A Z A V e h ic le A Z A G G 5 G G 5 C M P G M P 1 5 **** **** ** **** ** **** V e h ic le A Z A V e h ic le A Z A V e h ic le A Z A V e h ic le A Z A G G 5 N=2 Colla. Cancer Cell 215; Gomez-Ganan poster 2852 Sunday G G 5

19 Genomics of MDS Papaemmanuil et al Blood 213;122:

20 Clonal Progression from Myelodysplastic Syndrome (MDS) to Secondary Acute Myeloid Leukemia (saml). Walter MJ et al. N Engl J Med 212;366:

21 Daver et al. AJH 213 Flt3 alterations in MDS

22 Effect of acquisition of Flt3 or Ras mutations in MDS Probability of Transformation-free Survival Non-FLT3/RAS FLT3/RAS Time (Months) Takahashi. Leukemia 214

23 Ravandi. Blood 213 5AZA + Sorafenib Outcomes and Survival 46%

24 Lower risk non-hma failure

25 Proportion of patients Proportion of patients Results: AML-Free Survival by CyR in Patients With Isolated del(5q) and del(5q) + 1 Additional Abnormality Isolated del(5q) (n = 13) del(5q) + 1 additional abnormality (n = 32) 1..8 CyR Responder Non-responder Log-rank P = CyR Responder Non-responder Log-rank P = Median AML-free survival, months (95% CI) Major + Minor 59.9 (43.2 NR) Non-responder 36.7 ( ) Time to AML or death (months).2 Median AML-free survival, months (95% CI) Major + Minor 58.1 (34.8 NR) Non-responder 3.7 ( ) Time to AML or death (months) For the risk of AML transformation or death, CyR was associated with a 41% reduction (95% CI.38.92; P =.19) in patients with isolated del(5q) and a 58% reduction (95% CI ; P =.56) in patients with del(5q) + 1 additional abnormality, compared with no CyR Sekeres MA, et al. ASH 213; abstract 39.

26 Low dose DAC in LR MDS: Transfusion Independence Rate Arm A (Daily) N(%) Arm B (Weekly) N (%) RBC Transfusion Independence 2 (62.5) 15 (68.2) Platelet Transfusion Independence 22 (68.8) 18 (81.8) RBC/PLT Transfusion Independence 2 (62.5) 13 (59.1) Garcia-Manero JCO 213

27 Disposition Phase 1 Oral Aza Study Response to Therapy (N=41) Garcia-Manero JCO 211 MDS (N=29) N (%) CMML (N=4) N (%) AML (N=8) N (%) Ongoing 8 (28) 2 (5) 2 (25) Terminated 21 (72) 2 (5) 6 (75) Median duration of oral therapy, # of cycles, (range) 6. (1 23+) 7. (3 17+) 4.5 (1 14+) Cycle 7 Response Assessment* 13 (45) 2 (5) 2 (25) CR / PR / HI 4 (31) 1 (5) () SD 8 (61) 1 (5) 2 (1) Progression 1 (8) () () * IWG 23 or 26 Subjects did not meet criteria for progression or response by IWG 23

28 Lower risk HMA failure

29 LR MDS post HMA Failure. Outcome n events mos Median follow-up: 16 (1-8) months Median TFS and OS: 15 and 17 months Jabbour et al Cancer 215

30 Dual Inhibition of p38 and Tie2 by ARRY-614 p38 MAPK in MDS Stress/Inflammatory Stimuli (Cytokines, Hypoxia, FasL) Tie2 in MDS Emerging Target Ang-1 Ang-2 TNF-α, IL-6, Chemokines Decreased RBC, WBC, platelets p38 Apoptosis Pleiotropic effects on Progenitors and AML blasts Major regulator of the cellular pathways which sense stress Over-activated, leading to inappropriate production of myelosuppressive cytokines Garcia-Manero et al. Clin Cancer Res 215 Dysregulated, may be a survival factor for AML blast Increased signaling associated with poor prognosis 3

31 ARRY-614 Prior Therapies N = 71 Median prior therapies: 3 (range -6; 5 pts with no prior MDS therapies) % of Patients Azacitidine Only Decitabine Only Aza and Decitabine HMA ESA Lenalidomide G/GM-CSF Immunosuppression Other Investigational* ATG and/or prednisone includes cyclosporine, cytarabine, valproic acid, cladribine, mitoxantrone, rituximab, dexamethasone *includes siltuximab, HDAC inhibitors, hedgehog inhibitor, TXA127, Garcia-Manero et al. Clin Cancer Res 215

32 Epitargeting of immune pathways in MDS 2. Molecular Mechanisms: Searching endogenous PAMP/ DAMP that activates innate immune signaling and involves in MDS pathogenesis 3. Evaluate Therapeutic Potential of targeting innate immune signaling in MDS 1. Molecular Mechanisms: Interaction between innate immune signal and other genetic lesions in MDS pathogenesis Gomez-Ganan. Leukemia 215.

33 Higher risk HMA failure

34 Outcome in MDS post hypomethylating failure Jabbour. Cancer 21

35 Overall Survival and Subgroup Analysis from a Randomized Phase III Study of Intravenous Rigosertib vs Best Supportive Care in Patients with Higher-risk Myelodysplastic Syndrome After Failure of Hypomethylating Agents (ONTIME Trial of ON 191) G. Garcia-Manero, P. Fenaux, A. Al-Kali, M. R. Baer, M. Sekeres, G. Roboz, G. Gaidano, B. Scott, P. Greenberg, U. Platzbecker, D. P. Steensma, S. Kambhampati, L. Godley, R. Collins, E. Atallah, F. Wilhelm, I. Darnis-Wilhelm, N. Azarnia, M. Maniar, L. R. Silverman, for the ONTIME Investigators ASH

36 ONTIME Trial: Primary Efficacy Results ITT ASH

37 ONTIME Trial: Median Overall Survival for Pts with Primary HMA Failure - Blinded, Centralized Assessment ASH 214 Per Prebet 211, Primary HMA Failure was defined as either no response to or progression during HMA therapy 37

38 Clofarabine Plus Low-Dose Cytarabine For The Treatment Of Patients With higher-risk Myelodysplastic Syndrome Who Have Relapsed Or Are Refractory To Hypomethylating Agent Jabbour E, Sasaki K, Daver N, Pemmaraju N, Jain N, Kadia T, DiNardo C, Ravandi F, Miller D, Maduike R, Borthakur G, Konopleva M, Faderl S, O Brien S, Cortes J, Kantarjian H, Garcia-Manero G Department of Leukemia at MD Anderson Cancer Center Houston, Texas ASH 214

39 CLO and LDAC in HR MDS post HMA. Response (N=61) Best Response N (%); Median [range] Complete response 1 (15) Marrow CR 9 (14) CRp 3 (5) Partial response 1 (2) Hematologic improvement 4 (6) Overall response rate 27 (44) # Cycles to best response 1 [1-7] Early death 1 (2) ASH 214

40 CLO and LDAC in HR MDS post HMA. MVA for Response and Survival Multivariate analysis Response Survival Parameter OR P HR P Cyto Complex vs. No Plt 3 vs. >3 NA NS PS 2 vs. <2 NA NS 5.5 <.1 Response vs. Non-Response NA NS 7.1 <.1 Prior response to HMA NA NS NA NS ASH 214

41 CLO and LDAC in HR MDS post HMA. Survival by Response Status ASH 214

42 Aberrant up-regulation of PD-L1, PD-L2, PD-1 and CTLA4 in CD34+ cells from MDS, CMML and AML. Yang et al Leukemia 214

43 Examples of clinical trial options Genomic annotation: IDH1, IDH2, RAS, Flt-3 PD1/PDL1 combinations Toll-like receptor inhibitors (OPN-35) Oral azacitidine (CC-486) Bortezomib Omacetaxine FF-51

44 Guillermo Garcia-Manero