ANCO 2006 ASH UPDATE MDS Joseph M. Tuscano, M.D. UC Davis Cancer Center

MDS-001 N=43 Phase I/II initiated Feb 2002 Del(5q) MDS-003 N=148 Phase II initiated July 2003 MDS-002 N=214 Phase II initiated July 2003 Non-del(5q) Clinical Development of Lenalidomide in MDS: Completed Trials Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; Orlando, FL

Primary endpoints: Transfusion independence (TI); Hgb response Secondary endpoints: Cytogenetic response; safety MDS-002 Study Design RESPONSERESPONSE R E G I S T E R Lenalidomide 10 mg po × 21 days Eligibility IPSS diagnosed Low/Int-1 MDS w/o del(5q) abnormality  2 U RBC/8 wk Platelets >50,000/μL ANC >500/μL Yes Continue No Off study Week Lenalidomide 10 mg po daily Dose reduction 5 mg every day 5 mg every other day Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

MDS-002: Patient Characteristics Parameter Daily Dose n= Day Dose n=114 All Patients N=214 Median PRBCs/8 wk 3.0 (1.0–12.5) 4.0 (1.0–12.0) 4.0 (1.0–12.5) Median age, yr 74 (27–94) 70 (38–86) 72 (27–94) Median duration MDS, yr 2.6 (0.1–11.5) 1.8 (0–12.9) 2.2 (0–12.9) Sex, n (%) Male Male 68 (68) 70 (61) 138 (64) IPSS score, n (%) Low/Int-1 Low/Int-1 77 (77) 91 (80) 168 (78) Int-2/High Int-2/High 2 (2) 6 (5) 8 (4) Missing Missing 21 (21) 17 (15) 38 (18) Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

MDS-002: Erythroid Response Parameter Daily Dose n= Day Dose n=114 All Patients N=214 Erythroid response, n (%) 41 (41) 51 (45) 92 (43) TI TI 26 (26) 30 (26) 56 (26) Minor (>50% decrease) Minor (>50% decrease) 15 (15) 21 (18) 36 (17) Time to initial response, wk Median Median Range Range 4.1– – –9.0 Lenalidomide eliminated or reduced transfusion requirements in 43% of MDS patients without del(5q) cytogenetic abnormalities Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

MDS-002: Hemoglobin Response Hgb, g/dL Daily Dose n=26 21-Day Dose n=30 All Patients N=56 Baseline Median Median Range Range (6.2–9.7) 6.1–10.6) (6.2–10.6) Maximum Median Median Range Range (9.1–16.8) (7.3–18.0) Change Median Median Range Range (1.5–9.2) (1.0–9.8) Patients who responded to lenalidomide had a median Hgb increase of 3.2 g/dL Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

*Censored patients who remain TI at time of data cut-off or at time of study discontinuation MDS-002: Duration of Transfusion Independence Data cut-off: July Time (wk) Transfusion Independent (%) Median duration TI: 41 wk Range: 8.0– wk 35 patients TI ≥24 wk 20 patients TI ≥52 wk 19 patients ongoing Censored* n=56 Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

ErythroidResponse Erythroid Response (%) MDS-002: Erythroid Response by FAB Diagnosis Erythroid response is similar in RA, RARS, RAEB, and CMML RA n=47 RARS n=86 RAEB n=24 CMML n=20 Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

MDS-002: Cytogenetic Response Variablen/N (%)95% CI Evaluable* 47/214 (22) Cytogenetic response Complete Complete 4/47 (9) 1.1%–10.1% Minor (≥50% ↓) Minor (≥50% ↓) 5/47 (11) 2.3%–12.9% *Chromosome marker present at baseline Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

MDS-002: Most Frequent Drug-Related AEs AE All Grades N (%) Grade ≥3 n (%) Neutropenia 60 (28) 53 (25) Thrombocytopenia 56 (26) 43 (20) Rash 47 (22) 9 (4) Pruritus 45 (21) 2 (1) Fatigue 33 (15) 8 (4) Diarrhea 32 (15) 3 (1) NCI CTC Similar to baselineSimilar to baseline Manageable with dose reduction or interruptionManageable with dose reduction or interruption Neutropenia and thrombocytopenia Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

MDS-002: Conclusions Lenalidomide is effective in Low and Int-1 risk MDS patients without del(5q) 1 Lenalidomide is effective in Low and Int-1 risk MDS patients without del(5q) 1 –TI response in 26% (median duration: 41 wk) –Erythroid improvement in 43% Neutropenia and thrombocytopenia were similar to baseline and manageable with dose reduction or interruption Neutropenia and thrombocytopenia were similar to baseline and manageable with dose reduction or interruption – Lower occurrence than in del(5q) patients 2 Lenalidomide may offer an effective alternative to cytokine therapy Lenalidomide may offer an effective alternative to cytokine therapy Raza A et al. Presented at: ASH Annual Meeting; December 9–12, 2006; 108:Ab# 250

1. Borthakur G et al. Blood. 2006;108:157a [abstract 518]; 2. Cheson BD et al. Blood. 2006;108:419 Decitabine Responses in MDS Patients After Prior 5-Azacitidine 1

Decitabine 20 mg/m 2 IV/day × 5 q4 wk Decitabine 20 mg/m 2 IV/day × 5 q4 wk 14 patients treated to date; median 4 courses prior 5-azacitidine (range, 1–9) 14 patients treated to date; median 4 courses prior 5-azacitidine (range, 1–9) Median age of enrolled patients was 74 years (range, 58–85) Median age of enrolled patients was 74 years (range, 58–85) Chromosomal abnormalities in 6 pts (43%) Chromosomal abnormalities in 6 pts (43%) Patients had previously received a median of 4 courses of azacitidine (  3 courses in 12 [85%] patients) Patients had previously received a median of 4 courses of azacitidine (  3 courses in 12 [85%] patients) 1. Borthakur G et al. Blood. 2006;108:157a [abstract 518]; 2. Cheson BD et al. Blood. 2006;108:419

Patients (%) Modified IWG criteria 2 Decitabine Responses in MDS Patients After Prior 5-Azacitidine 1 Responses in 5 patients (35%) Responses in 5 patients (35%) Median remission duration 5.3 mo. Median remission duration 5.3 mo. Median survival 6.0 mo. Median survival 6.0 mo. 1. Borthakur G et al. Blood. 2006;108:157a [abstract 518]; 2. Cheson BD et al. Blood. 2006;108:419

Erythropoietin and G-CSF in MDS Patients With Low Transfusion Need Jadersten M et al. Blood. 2006;108:158a [abstract 521]

Erythropoietin and G-CSF in MDS Patients With Low Transfusion Need Jadersten M et al. Blood. 2006;108:158a [abstract 521] Retrospective analysis of Epo + G-CSF (n=123) vs untreated (n=240) patients Retrospective analysis of Epo + G-CSF (n=123) vs untreated (n=240) patients All were transfusion dependent (n=176) or had Hgb level <10 g/dL (n=187) All were transfusion dependent (n=176) or had Hgb level <10 g/dL (n=187) Erythroid response (TI) was observed in 41% of treated patients Erythroid response (TI) was observed in 41% of treated patients Median response duration was 23 mo (3-116+). Median response duration was 23 mo (3-116+).

Erythropoietin and G-CSF in MDS Patients With Low Transfusion Need Jadersten M et al. Blood. 2006;108:158a [abstract 521] Transfusion RequirementOS, PLeukemic Transformation, P <2 units of RBC/mo <2 units of RBC/mo (NS)  2 units of RBC/mo  2 units of RBC/mo <0.36 (NS) 0.21 (NS) Multivariate Cox regression analysis

Comparative Meta-Analysis of Erythroid Response Rates for Epo and Darbepoetin (DARB) Mundle S et al. Blood. 2006;108:755a [abstract 2672] Identified 9 Epo (N=619) and 8 DARB (N=442) studies for comparison Baseline characteristics, age, gender, baseline Hgb, FAB subtype’s were comparable Baseline sEpo levels were significantly higher for the Epo group (376 vs 133, p=0.0026) Average dose of Epo 47,851 (30-80,000) vs DARB 176 ( ) Higher doses of EPO 60-80,000 or DARB (>150 mcg) showed higher ER rates (EPO 48% vs 63%, DARB 52 vs 71%)

Comparative Meta-Analysis of Erythroid Response Rates for Epo and Darbepoetin ParameterDarbepoetin Studies Darbepoetin vs Epo IWG Studies P Value Erythroid response, % (95% CI) 59.4 (49.0–69.9) 57.6 (45.1–70.0) Major erythroid response, % (95% CI) 46.8 (36.6–57.1) 36.5 (23.4–49.6) Mundle S et al. Blood. 2006;108:755a [abstract 2672] Erythroid response rates (IWG criteria) were comparable between epoetin alfa (Epo) and darbepoetin studies Erythroid response rates (IWG criteria) were comparable between epoetin alfa (Epo) and darbepoetin studies Higher initial dose and lower baseline serum Epo predicted for higher response for both therapies Higher initial dose and lower baseline serum Epo predicted for higher response for both therapies

Allogeneic SCT for MDS Patients ≥50 Years: Study Population Lim ZY et al. Blood. 2006;108:157a [abstract 520]

Allogeneic SCT for MDS Patients ≥50 Years: Study Population Retrospective analysis of factors influencing outcomes for 1000 matched sibling (72%) and 385 (28%) matched unrelated donor SCT Retrospective analysis of factors influencing outcomes for 1000 matched sibling (72%) and 385 (28%) matched unrelated donor SCT CharacteristicAll Patients (n=1385) Median age, yr (range) 56 (50–74) Standard myeloablative conditioning, n (%) 604 (44) Reduced intensity conditioning, n (%) 781 (56) RA or RARS/RAEB/RAEB-t/2 o AML/unknown, % 14/28/17/28/13 Patients treated with reduced intensity (30% RIC vs 14% SMC) conditioning were older (age >60 yr); p 60 yr); p<0.001 Those with standard myeloablative conditioning had more advanced disease Those with standard myeloablative conditioning had more advanced disease No difference in donor type for reduced vs standard intensity groups No difference in donor type for reduced vs standard intensity groups Lim ZY et al. Blood. 2006;108:157a [abstract 520]

Allogeneic SCT for MDS Patients ≥50 Years: Multivariate Analysis Lim ZY et al. Blood. 2006;108:157a [abstract 520] Variable4-yr OutcomeHazard Ratio [95% CI] P Value Age >60 yr Relapse rate 1.28 [1.0–1.6] 0.04 Reduced intensity conditioning Relapse rate 1.5 [1.2–1.9] <0.001 Advanced disease stage at SCT Relapse rate 1.51 [1.2–2.0] Donor type Relapse rate 1.12 [NA] >0.30 (NS) Reduced intensity conditioning TRM 0.71 [0.57–0.88] <0.01 Advanced disease stage at SCT TRM 1.4 [1.1–1.8] <0.01 Donor type TRM0.94 >0.30 (NS) Advanced disease stage at SCT OS 1.47 [1.2–1.8] <.001 TRM = treatment-related mortality

On multivariate analysis of 4-year outcome parameters, age >60 years, use of reduced intensity conditioning, and advanced disease stage at transplantation were associated with an increased relapse rate The use of reduced intensity conditioning was associated with lower treatment-related mortality, and advanced disease was associated with higher treatment-related mortality Advanced disease stage at transplantation was the only independent variable associated with an inferior 4-year OS Whereas patients aged >60 years had an increased relapse rate, there was no significant difference in OS compared with those aged 50–60 years Allogeneic SCT for MDS Patients ≥50 Years: Multivariate Analysis Lim ZY et al. Blood. 2006;108:157a [abstract 520]