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MDS Therapeutics – Beyond Erythropoietic Stimulating Agents

MDS Therapeutics – Beyond Erythropoietic Stimulating Agents. Alan List, MD Deputy Physician-in-Chief Chief, Malignant Hematology Division H. Lee Moffitt Cancer Center & Research Institute Tampa, FL, USA. Genetic Del(5q) - RPS14 > 90% by SNP. Normal MDS.

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MDS Therapeutics – Beyond Erythropoietic Stimulating Agents

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  1. MDS Therapeutics – Beyond Erythropoietic Stimulating Agents Alan List, MD Deputy Physician-in-Chief Chief, Malignant Hematology Division H. Lee Moffitt Cancer Center & Research Institute Tampa, FL, USA

  2. Genetic • Del(5q) - RPS14 • >90% by SNP Normal MDS Epigenetic • Environment • Immune suppression • Aptogenic cytokines • Receptor Signal • EPO-R/STAT5 Ineffective Erythropoiesis in MDSPathogenetic Features Figure adopted from Curry P. Cure:5 (4),2006

  3. Predictive Model for Response to rEPO + G-CSF Nordic MDS Group [N=98] • Serum EPO mU/mL • <100: Score +2 • 100–500: Score +1 • >500: Score -3 Score Patients (n) Response ≥2 29 74% ±1 31 23% <-1 34 7% • RBC transfusion • <2 units/mo.: Score +2 • >2 units/mo.: Score -2 Hellstrom-Lindberg et al, Br J Haematol 1997; 99: 344.

  4. Influence of Transfusion Intensity on Overall Survival in MDS without Excess Blasts Overall survival (HR = 1.36; p < 0.001) Leukaemia-free survival (HR = 1.40; p < 0.001) 1.0 1.0 0 U PRBC/4 week 1 U PRBC/4 week 2 U PRBC/4 week 3 U PRBC/4 week 4 U PRBC/4 week 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Cumulative survival Cumulative survival 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180 Time (months) Time (months) Malcovati L, et al. Haematologica 2006:91:1588.

  5. Phase III and Case Matching Studies Evaluating Effect of ESA Treatment on Disease Outcome Abbrevations: ESA, erythropoiesis-stimulating agent; NA, not available; SC, supportive care; mos, months; HR, Hazard ratio. *denotes comparison of overall survival in ESA responders vs. non-responders and controls. Melchart and List. Hematology 2007.

  6. Modulators of Ligand-Dependent Signals Thalidomide Phthaloyl ring Lenalidomide VEGF = vascular endothelial growth factor. bFGF = basic fibroblast growth factor. Rhu-EPO = recombinant human EPO. TNF = tumour necrosis factor. COX = cyclooxygenase. Bartlett JB. Nat Rev Cancer. 2004;4:314-22.

  7. MDS-002/003: Phase II Studies of Lenalidomide in Transfusion-Dependent Low/Int-1 MDS R E G I S T E R R E S P O N S E Yes Continue Lenalidomide 10 mg qd x 21 days • Eligibility •  2 U PRBC/8 weeks • Platelets > 50,000/μL • ANC > 500/μL Lenalidomide 10 mg qd daily MDS-003: del 5q31.1 MDS-002: other No Off study Dose reduction 5 mg every day 5 mg every other day Week 0 4 8 12 16 20 24 Primary end-point: transfusion independence (Hgb 1 g/dL) Secondary end-points: cytogenetic response, pathological response List AF, et al. NEJM 2006; 355: 1456

  8. MDS-003 Erythroid Response (ITT)Modified IWG 2000 ITT = intention to treat. TI = transfusion independent. List AF, et al. NEJM 2006; 355: 1456

  9. MDS-003: Mean Non-Transfused Hemoglobin by Treatment Cycle 14 Median timeto response Maximum Hb, g/dL [range] Baseline 7.8 [5.3–10.4] Lenalidomide 13.4 [9.2–18.6] Median Hb 5.4 [1.1–11.4] 12 Normalized, perNCCN guideline Hb (g/dL) 10 8 Responders Non-responders 6 0 2 4 6 8 10 12 14 16 18 Cycle (28 days) 95% CI is provided when n > 3Hb values in the 30 days following transfusion were excluded, unless the values were on or  3 days preceding a transfusion date. List AF, et al. NEJM 2006; 355: 1456

  10. MDS-003: TI rate by Cytogenetic Pattern * Excludes 1 patient defined by FISH only. FISH = fluorescence in situ hybridization. List AF, et al. NEJM 2006; 355: 1456

  11. Duration of Major Erythroid ResponseDeletion 5q Data as of 07May07 (N=113) Median duration TI =2.2 years Median F/U: 3.2 yr (Min 0.3 – Max 4.8 yr) §Symbols are censored patients who remain TI at time of data cut-off or at time of study discontinuation.

  12. MDS-003: Cytogenetic Response by Karyotype Complexity List AF, et al. NEJM 2006; 355: 1456

  13. Survival Co-VariatesMultivariate Analysis

  14. 100 PR, N=35, Median OS=unestimable 90 80 70 CR, N=55, 60 Median OS=unestimable 50 50 Cumulative Survival 40 30 20 10 NR/NE, N=78, OS=28 mnth 0 0 24 48 72 96 120 144 168 192 216 240 Months Survival from MDS Diagnosis by Cytogenetic Response [N=168] P<0.0001 [a] Product-Limit survival estimates adjusted for left-truncation. Note: CR=Complete Cytogenetic Response, PR=Partial Cytogenetic Response, NR=No Cytogenetic Response, NE=Not evaluable

  15. 100 N=168 90 80 67% 70 NR/NE (9/77) 60 50 Cum Risk of AMLEvolution P=0.010 40 30 15% 20 CCR/PCR (7/89) 10 0 0 24 48 72 96 120 144 168 192 216 240 Months AML Evolution from Diagnosis by Cytogenetic ResponseLeft Truncation Kaplan-Meier Analysis

  16. Demographics n (%) [range] No. patients 214 Median age, years 72 [27–94] Male 138 (64) >2 PRBC U/month 139 (65) IPSS Low/Int-1 168 (78) Int-2/High 8 (4) Unclassified 38 (18) FAB RA/RARS 127 (62) Abnl karyotype 47 (22) TI TI + minor 43 26 MDS-002 Erythroid Response (ITT)Modified IWG 2000 Erythroid response 80 Median TI duration: 41 wks (8-136 wks) Median Time to Response: 5 wks Median Hgb  :3.2 g/dL (range:1-9.8) 70 60 50 Erythroid response (%) 40 30 20 [n=56; 92] 10 0 ITT BLOOD 2008; 11: 86-93

  17. MDS-002/003: Drug-Related Adverse Events (NCI CTC 2.0) List AF, et al. NEJM 2006; 355: 1456 BLOOD 2008; 11: 86-93

  18. Independent Co-Variates for TI Response Del(5q) MDS-003 Multivariate Analysis* *Logistic regression analysis using categorized variables ^Continuous variable. Sekeres M, et al. ASH 2007; Abstr 821.

  19. Independent Co-variates for TI ResponseMDS-002 Multivariate Analysis* Sekeres M, et al. Florence MDS Symp. 2007. *Logistic regression analysis categorical variables.

  20. Gene Expression Signature for LEN Response  STAT5 & GATA-1 Gene Target Expression[N=16 Non-del5q] Ebert BL, et al. PLoS Med 2008; 5(2):e35.

  21. Gene Set Enrichment Score Z-Score Discrimination of Response Potential [N=16] Ebert BL, et al. PLoS Med 2008; 5(2):e35.

  22. * * * C Validation of LEN Response SignatureResponse Score in Non-Del(5q) & Del(5q) MDS [N=26] * Prediction accuracy = 85%. Ebert BL, et al. PLoS Med 2008; 5(2):e35.

  23. Lenalidomide Response Signature in MDSSummary • LEN responsive MDS share a common molecular profile characterized by profound impairment in erythroid differentiation • STAT5A & GATA-1 transcriptional targets are markedly decreased in LEN responsive patients • LEN exerts direct effects on erythroid progenitors to restore differentiation potential • These findings suggest that LEN may modify key regulators of the EPO-R/STAT5 transcriptional response Ebert BL, et al. PLoS Med 2008; 5(2):e35.

  24. Lenalidomide STAT5 Phosphorylation X STAT5 STAT5 STAT5 Lenalidomide Relieves Epo-R Signal Repression in non-Del(5q) Epo-Progenitors Modulation of Epo-R Jak/STAT5 Signal CD45 List A,F et al. ASH 2006. Adopted from: Pennington JM. Nature Immunol 2001.

  25. IgG isotype control 120 120 EPO 3 U/mL Lenalidomide + EPO 100 100 80 80 60 60 40 40 20 20 0 0 Lenalidomide Enhances EPO/STAT5 Signal in MDS CD117+/CD71Hi Erythroid Precursors MDS Normal IgG isotype control EPO 3 U/mL Lenalidomide + EPO Counts 100 101 102 103 104 100 101 102 103 104 p-STAT5 p-STAT5 List A,F et al. ASH 2006. MFI = mean fluorescence intensity.

  26. Thalidomide Lenalidomide Lenalidomide Inhibits rHu-CD45 PTP Activity [IC50 = 10nM] CD45-specific PTP activity assayed using the BIOMOL GreenTM CD45 Tyrosine Phosphatase Assay Kit. rhu-CD45 (Calbiochem) [75U] was incubated for 1H at 37o C with the indicated IMiD then pp60c-Src substrate [200 uM] was added and incubated for 1H and read on a plate reader at 620nm.

  27. Summary Target of Lenalidomide Action in Non-Del 5q MDS • Lenalidomide is a PTP inhibitor that enhances EPO receptor signaling and CFC in non-del5q erythroid precursors. • Lenalidomide relieves CD45 repression of EPO ligand-dependent Jak2 and Lyn kinase mediated STAT5 activation. • Protein tyrosine phosphatase inhibition is selective without inhibition of SHP-1 or SHP-2 PTP activity • These findings suggest that combined treatment with LEN + ESA may improve erythroid response in non-Del(5q) MDS.

  28. MER Continue PK & Efficacy Study of LEN+EPO in rhuEPO FailuresLow/INT-1 IPSS [PK-002] M O N O T H E R A P Y R E S P O N S E LEN 10mg/d [N=25] • Eligibility • Low/Int-1 IPSS • Epo failure LEN 15mg/d [N=15] No LEN + EPO* *40,000 Units/wk Week: 0 4 8 12 16 20 24 Primary Objectives: LEN PK vs cytopenias,IWG 2000 MER List et al. . ASH 2007.

  29. Pilot Study LEN + rhu-EPO in Low/Int-1 MDSMajor Erythroid Response by Treatment Stage List et al. . ASH 2007.

  30. Phase III Intergroup Study of Lenalidomide (LEN)vs LEN + Epoetin Alpha in Low/Int-1 MDS [ECOG 2905] R A N D O M I Z E • Eligibility • IPSS Low/Int-1 • Hgb <9.5g/dL • Poor EPO Resp Profile or failed EPO S T R A T I F Y R E S P O N S E MER Continue A. LEN 10mg/d x 21d • Stratify • del(5)(q) • sEPO • Prior EPO/DA B. LEN + Epoetin No Combination [Arm A] Week: 0 4 8 12 16 Principal Objective: Modified IWG 2000 MER Secondary: CD45 isoform, LEN p-STAT5 

  31. Immunomodulatory Drugs (IMiDs™) Active Clinical Trials

  32. Randomized Phase II Study of Alternative AzaC (Vidaza™) Dose Schedules Study Design [N=151] A. 5-2-2: 75 mg/m2 N=50 • Eligibility • All FAB • cytopenia x6 IWG 2000 HI B. 5-2-5: 50 mg/m2 12 Cycles AZA x 5d Q4-6 wks N=51 C. 5: 75 mg/m2 N=50 Lyons et al. ASH 2007; Abstr 819.

  33. Alternate AzaC Dose Schedule Study Frequency of Major HI in Evaluable Patients [N=139] *IWG 2000 criteria. Lyons et al. ASH 2007; Abstr 819.

  34. Onset of IWG-Defined Hematologic Improvement Lyons et al. ASH 2007; Abstr 819.

  35. AZA-001 Phase III Survival Study Schema AZA-C 75 mg/m2 x 7 daysEvery 28 days [N=358] [N=179] Stratify (FAB, IPSS) • Eligibility • RAEB, RAEB-t, CMML • 10-29% blasts • IPSS-2/High risk [N=179] Conventional Care Regimen (CCR): 1. BSC only [n=105] 2. Low Dose Ara-C [n=49] 3. Induction/Consolidation [n=25] Primary Endpoint: Overall survival Fenaux P, et al. ASH 2007; Abstr 817.

  36. 1.0 0.9 0.8 0.7 50.8% 0.6 24.4 months 0.5 15 months 26.2% 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 30 35 40 Overall Survival: Azacitidine vs CCR ITT Analysis Log-Rank p=0.0001 HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Difference: 9.4 months Proportion Surviving AZA CCR Time (months) from Randomization

  37. AZA-001 Phase III Study vs CCRSurvival According to CCR and Cytogenetics Fenaux P, et al. ASH 2007; Abstr 817.

  38. Overall Survival: Azacitidine vs CCR Secondary Endpoints • Time to AML or death • 13 mos with AZA vs 7.6 mos with CCR, p=0.003 • Time to AML (During Treatment) • 26.1 mos with AZA vs 12.4 with CCR, p=0.004 • RBC Transfusion Independence • 45% with AZA vs 11% with CCR, p<0.0001 • Infections Requiring IV Antimicrobials: • Reduced by 33% with AZA vs CCR

  39. Epo<200mU/ml <2U RBC/mo Epo>200mU/ml RCMD >2U RBC/mo Del (5q) ESA Age Del5q Lenalidomide >60 <60 MTI +GCSF IST* *Consider trisomy 8. Anemia Management Algorithm - 2007Low/Int-1 Risk MDS Anemia • Decision Elements for Treatment Selection • EPO response profile • Karyotype • Age

  40. Acknowledgements Moffitt Collaborators Ann Williams Wayne Guida Myka Estes PK Burnette Yuki Ozawa Gary Reuther Ruth Heaton Julie Djeu Lubomir Sokol Sheng Wei E. Sotomayor

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