Wednesday, November 30, 2011 University of Michigan

Wednesday, November 30, 2011 University of Michigan Presenter Gary J. Schiller, MD, FACP Professor, Department of Medicine, Hematology/Oncology Director, Hematological Malignancies/Stem Cell Transplantation Unit David Geffen UCLA School of Medicine Los Angeles, California Disclosure Information Dr Schiller has declared the following relevant financial relationships: Presenter Gary J. Schiller, MD, FACP Nature of Financial Relationships Grants / Research Support Commercial Interests Ambit Biosciences Inc. Celator Pharmaceuticals Cyclacel Pharmaceuticals, Inc. Genzyme Corporation Lilly USA, LLC Ref 1 2

AML Most common acute leukemia in adults Median age at diagnosis = 67 Median age = 72 (Swedish Acute Leukemia Registry) Male to female ratio = 5:3 Cases / year 12,000 Associated with environmental factors, genetic abnormalities, and other benign and malignant hematologic diseases Available at: http://seer.cancer.gov/statfacts/html/amyl.html. Accessed August 5, 2010; Yamamoto JF, et al. Cancer Causes Control. 2008;19:379-390; Juliusson G, et al. Blood. 2009;113:4179-4187. 3

AML With Recurrent Genetic Abnormalities (WHO) AML with t(8;21) (q22;q22) RUNX1-RUNX1T1 APL with t(15;17) (q22;q12); PML-RARA AML with inv(16) (p13.1q22) or AML with t(16;16) (p13.1;q22) CBFB MYH11 AML with t(9;11) (p22;q23); MLLT3 MLL AML with t(6;9) (p23,q34); DEK NUP214 AML with inv(3) (q21q26.2) or AML with t(3;3) (q21;q26.2) RPN1 EVI1 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15 MKL1 Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008; Vardiman JW, et al. Blood. 2009;114(5):937-951. 5

Prognostic Factors in AML Patient-specific factors Age Performance status Comorbid illnesses Leukemia-specific factors Cytogenetics Single gene mutations Antecedent hematologic disorder Secondary AML Cheson BD, et al. J Clin Oncol. 2003;21:4642-4649. 6

Risk Stratification Risk Status Cytogenetics Molecular Mutations Better-risk Intermediate Poor-risk MK, monosomal karyotype. t(8;21)(q22;q22) inv(16)(p13;q22) t(16;16)(p13;q22) t(15;17) Normal cytogenetics +8 only t(3;5) t(9;11)(p22;q23) Other non-defined Complex karyotype (> 3 abnormalities) MK+ -5 / 5q- -7 / 7q- Other 11q23 abnormalities, excluding t(9;11) inv(3)(q21;q26.2) t(3;3)(q21;q26.2) t(6;9) t(9;22) 17p abnormalities Normal cytogenetics with NPM1 mutation or CEBPA mutation in absence of FLT3-ITD c-kit mutation with: t(8;21)(q22;q22) or inv(16)(p13;q22), t(16;16)(p13;q22) Normal cytogenetics with FLT3-ITD in absence of NPM1 mutation Foran JM. ASH Education Program Book. 2010;47-55. 7

Overall Survival According to Revised Cytogenetic Risk Overall Survival (%) 1.0 0.8 0.6 Favorable, n = 153 Intermediate, n = 627 Unknown, n = 120 Unfavorable without MK, n = 264 Unfavorable with MK, n = 176 Log rank P < 0.01 0.4 0.2 0.0 0 5 10 15 T ime ( Y ears) Medeiros BC, et al. Blood. 2010;116:2224-2228. 5

Gene Mutation Incidence in Normal Karyotype (NK) AML Gene Mutation Incidence, N = 872 NPM1 53% FLT3-ITD 31% FLT3-TKD 11% CEBPA 14% MLL-PTD 8% NRAS 13% Gene Mutation Incidence, N = 358 IDHI 14% IDH2 19% Schlenk RF, et al. N Engl J Med. 2008;358(18):1909-1918; Marcucci G, et al. J Clin Oncol. 2010;28(14):2348-2355. 6

Modified Risk Schema Based on Cytogenetic and Molecular Risk Factors Risk Status Cytogenetics Molecular Mutations Better-Risk inv(16), t(16;16) t(8;21) Normal cytogenetics with isolated NPM1 mutation Intermediate- Risk Normal +8 only t(9;11) inv(16) with KIT mutation* Other abnormalities not listed elsewhere c-kit in patients with t(8;21) Poor-Risk Complex (> 3 abnormalities) -5-7 5q- 7q- Abnormalites of 11q23, excluding t(9;11) inv(3) t(3;3) t(6;9) Normal cytogenetics with isolated FLT3 mutation *Paschka P, et al. J Clin Oncol. 2006;24:3904-3911. 20

Workup of Newly Diagnosed AML Morphology gold standard Flow cytometry identify phenotype Cytogenetics risk classification Molecular FLT3, NPM, (CEBPA) risk assessment HLA typing 16

Proportion Surviving 1.0 0.8 0.6 0.4 0.2 0.0 AML Survival by Decade Patients < 60 0 1 2 3 4 5 6 7 8 Years ERA N Deaths 1960s 65 64 1970s 364 328 1980s 389 327 1990s 512 388 2000s 423 210 P < 0.001 Kantarjian H, O Brien S. Cancer. 2010;116(21):4896-4901. 24

Intensified Induction in AML Patients < 60 ECOG E1900 Induction Post -Remission DNR 45 mg/m 2 x 3 days + Cytarabine 100 mg/m 2 x 7 days 1-2 course to CR High-dose Cytarabine x 2 Observation Auto- HCT DNR 90 mg/m 2 x 3 days Sibling Allogeneic HCT Gemtuzumab Ozogamicin 6 mg/m 2 IV day 1 (DISCONTINUED) Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259. 26

Probability Probability Probability ECOG E1900: Overall Survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Log Rank P = 0.003 All Patients (N = 647) Month Induction Treatment DNR 45 mg/m 2 /day DNR 90 mg/m 2 /day N = 327 N = 330 0 10 20 30 40 50 60 70 80 DNR 45 DNR 90 P Induction Deaths 4.5% 5.5% 0.60 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Log Rank P = 0.004 Favorable and Intermediate Cytogenetics N = 178 N = 180 0 10 20 30 40 50 60 70 Month Log Rank P = 0.45 Unfavorable Cytogenetics N = 63 N = 59 0 10 20 30 40 50 60 Month Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259. 27

Intensified Induction in AML ECOG E1900 Overall CR and OS benefit for younger patients with favorable / intermediate prognostic factors Less, if any, benefit for patients with Adverse cytogenetics Age > 55 WBC > 10K Adverse genetics (FLT3- ITD+, MLL- PTD+) Fernandez H, et al. J Clin Oncol. 2009;27(15s). Abstract 7003. 28

Proportion Surviving AML Survival by Decade, Patients > 60 1.0 0.8 0.6 0.4 0.2 0.0 ERA N Deaths 1960s 39 39 1970s 166 164 1980s 263 259 1990s 495 461 2000s 486 350 0 1 2 3 4 5 6 7 8 Years Kantarjian H, O Brien S. Cancer. 2010;116(21):4896-4901. 32

Why Do Elderly AML Patients Fare Poorly? Patient-related Poor tolerance to intensive chemotherapy Increased mortality Poor PS Co-morbid conditions Disease-related AML biology for older patients appears to be different from younger patients MDR incidence of antecedent hematologic disorders incidence of adverse cytogenetic abnormalities incidence of other adverse molecular features 34

Sample CR, Early Death, and Survival Rates in Older ( 55 years) AML STUDY N Induction / Consolidation CR ED OS (3-5 year) CALGB 388 DA/A or MA 52% 25% 15% ECOG 348 D or I or M (each) + A/A 42% 17% 10% SWOG 328 DA or ME/DA 43% 7% 19% MRC 1,314 DAT or ADE or MAC/DAT Or COAP, DAT, COAP 55% 19% 10% Kantarjian H, et al.* 466 Various cytarabine-based intensive chemotherapy regimens 45% - 4 weeks = 26% 8 weeks = 36% 1 year = 28% *Age 70 years or older. Tallman MS, et al. Hematology. 2005;143-150; Kantarjian H, et al. Blood First Edition Paper, prepublished online July 28, 2010. 35

% Still alive % Still alive UK NCRI AML 14 Trial: Low Dose Cytarabine vs Hydroxyurea AML14 Non-Intensive - Overall Survival Favorable/Intermediate AML14 Non-Intensive - Overall Survival Adverse 100 LD Ara-C HU 100 LD Ara-C HU 75 50 LD Ara-C HU No. Patients 58 63 No. Events 57 53 Obs - EX P. -14.1 14.1 2 P = 0.004 75 50 LD Ara-C HU No. Patients 18 24 No. Events 18 24 Obs - EX P. 2.4-2.4 2 P = 0.4 25 25 0 0 1 2 0% 3 Y ears from entry 2% 0% 0% 0 1 2 3 Y ears from entry Burnett A, et al. Cancer. 2007;109:1114-1124.

Decitabine Monotherapy vs Treatment Choice in Elderly AML, Phase III Randomized Study Enrolled newly diagnosed or 2 o AML with intermediate or poor-risk cytogenetics > 65 years N = 485 Pre-select Supportive care Or Low-dose cytarabine R Stratification ECOG PS Age Cytogenetic risk Decitabine 20 mg/m 2 1 hr IV infusion for 5 days every 4 weeks n = 242 Treatment Choice Low-dose cytarabine 20 mg/m 2 SC for 10 days every 4 weeks, n = 215 or Supportive care, n = 28 Treatment choice Supportive care Cytarabine Total Decitabine Median age 75 years 73 years 73 73 ECOG PS2 32% 26% 27% 25% 2 o AML 39% 34% 35% 36% Poor-risk cytogenetics 29% 37% 36% 36% Thomas XG, et al. ASCO Meeting Abstracts. 2011;29(15S):6504. 42

Decitabine Monotherapy vs Low-Dose Cytarabine or Supportive Care in Elderly AML Phase III Randomized Study Toxicity was not different between the 2 arms Common decitabine toxicity Infection complications (febrile neutropenia [32%], pneumonia [21%]) Myelosuppression Is this the proper comparator? Decitabine n = 242 SC or LDcytarabine n = 243 CR + CRp 43% 19% 0.001 CRi 9.9% 2.9% NR Median OS 7.7 mo 5 mo 0.037 LD, low-dose; CR, complete remission; CRp, CR with incomplete platelet recovery; NR, not reported; OS, overall survival; mo, month. P Thomas XG, et al. ASCO Meeting Abstracts. 2011;29(15S):6504. 43

Clofarabine Purine analog resistant to deamination and phosphorolysis dnt P pool DN A Incorporation Clofarabine Inhibition of DN A Repair / Synthesis 5 N T dck Clofarabine T ransporter Cytochrome C Release CLO F ARABINE Kantarjian HM, et al. Leuk Lymphoma. 2007;48(10):1922-1930. CEL L DE A TH 45

Clofarabine Monotherapy in Newly Diagnosed AML 60 Years, Phase II CLO243 Untreated AML Patients 60 y Treatment Phase clofarabine 30 mg/m 2 /day days 1-5 (1 cycle) CR / CRp Residual Leukemia Leukemic Progression clofarabine 20 mg/m 2 /day days 1-5 (1 cycle) CR / CRp Residual Leukemia or Progressive Leukemia CONSOLIDATION (x 5 cycles max) CONSOLIDATION (x 4 cycles max) Follow-Up Phase Remission Duration and Survival Follow-Up Remission Duration and Survival Follow-Up Survival Follow-Up Characteristic %, N = 112 Median age 71 years (range 60-88) ECOG performance status: 0 1 2 19 59 22 Presence of AHD 37 Secondary AML 10 Karyotype: Unfavorable Intermediate Not reported Kantarjian HM, et al. J Clin Oncol. 2010;28(4):549-555. 55 41 4 46

Disease-Free Survival (%) Clofarabine Monotherapy in Newly Diagnosed AML 60 Years, Phase II Disease-Free Survival (%) Response Clofarabine N = 112 ORR (CR + CRp) 46% CR 38% CRp 8% A 100 90 80 70 60 50 40 30 20 10 Disease-Free Survival Overall responders (CR + CRp) No. at risk B 100 90 80 70 60 50 40 30 20 10 Overall Survival Population CR/CRp All Patients PR/TF 0 4 8 12 1620 24 3228 36 4044 485256 6064 68 7276 80 8488 Time (weeks) 0 4 8 12 1620 24 3228 36 4044 48 5256 6064 68 7276 80 8488 Time (weeks) Abbreviations: IRRP, independent response review panel; ORR, overall response rate; CR, complete remission; CRp, CR with incomplete platelet recovery; ND, not determined. Kantarjian HM, et al. J Clin Oncol. 2010;28(4):549-555. 47

CLO243: Adverse Events (N = 112) AE Clofarabine 30-day mortality 9.8% 60-day mortality 16% Grade 3/4 anemia 43% Grade 3/4 neutropenia 51% Grade 3/4 thrombocytopenia 73% Febrile neutropenia or fever 91% Adverse events Non-laboratory, occurring in > 20% of patients Nausea, vomiting, febrile neutropenia, diarrhea, rash, and fatigue Frequent transient grade 3/4 AST or ALT elevations Elevated bilirubin (11% grade 3) Elevated creatinine (6% grade 3) Kantarjian HM, et al. J Clin Oncol. 2010;28(4):549-555. 48

Overall Survival (%) Clofarabine Monotherapy in Newly Diagnosed AML Patients, European Studies UWCM-001: Newly diagnosed AML > 70 years or 60-69 years with PS > 2 (WHO) BIOV-121: Newly diagnosed AML > 65 years, unsuitable for intensive chemotherapy BIOV-121 Clofarabine 30 mg/m 2, N = 66 Clofarabine 20 mg/m 2, N = 11 UWCM-001 Clofarabine 30 mg/m 2, N = 29 CR 21% 55% 48% CRi 23% 0 7% 30-Day Mortality 21% 9% 14% 30-Day Survival, No CR 35% 36% 31% 100 75 BIO V -1216658 UWCM-001 20 mg UWCM-001 30 mg No. of Patients 66 1 1 29 No. of Events 58 8 28 50 2 P = 0.3 25 BIO V -121 UWCM-001 20 mg UWCM-001 30 mg 17 17 0 3 6 9 12 15 18 21 24 T ime Since Entry (months) Erba HP, et al. ASH 2008. Abstract 558; Burnett AK, et al. J Clin Oncol. 2010;28(14):2389-2395. 49

ECOG E2906, Clofarabine vs Standard Daunorubicin and Cytarabine in 60 Years Newly Diagnosed AML Age 60 years R Cytarabine 100 mg/m 2 /day CIVI x 7 d Daunorubicin 60 mg/m 2 /day IV x 3 d Clofarabine 30 mg/m 2 /day IV QD x 5d Cytarabine 1500 mg/m 2 IV x 6 d Clofarabine 20 mg/m 2 /day IV x 5 d Response assessed at day 21 National Institutes of Health. Available at: www.clinicaltrials.gov. Accessed September 2011. 50

Relapsed / Refractory AML No single regimen or approach is considered standard Important predictors of response are the duration of previous remission and number or previous salvage regimens 67

Results of Randomized Trials in Patients With Relapsed or Refractory AML Treatment N 2nd CR, % Median duration 2nd CR, mo Early Death, % Median OS, mo HDAraC vs HDAraC + Mit 162 32 vs 44 9 vs 5 10 vs 16 8 vs 6 EMA vs EMA + GM-CSF 72 81 vs 89 4 vs 5 8 vs 5 9 vs 10 MAE vs MAE + G-CSF 129 25 vs 17 9 vs 10 10 vs 16 5 vs 4 MEC vs MEC + lintuzumab 191 23 vs 29 NA NA 8 vs 6 HDAraC vs HDAraC + laromustine 178 19 vs 35 332 vs 275 days 2 vs 11 177 vs 128 days HDAraC + Mit vs IDAC + Mit 186 52 vs 45 5.3 vs 3.3 32 vs 17 5 vs NA HDAraC + Amsa vs HDAraC + Mit 52 53 vs 60 11 vs 12 15 vs 8 8 vs 11 HDAraC vs HDAraC + Amsa 36 14 vs 53 NA 25 vs 25 2 vs 6 HDAraC vs HDAraC + Eto 131 40 vs 45 12 vs 25 NA 5 vs 5 MAE vs MAE + G-CSF 58 42 vs 54 14 vs 12 8 vs 0 NA Abbreviations: CR = complete remission; OS = overall survival; HDAraC = high-dose cytarabine; Mit = mitoxantrone; IDAC = intermediate-dose AraC; NA = not available; Amsa = amsacrine; Eto = etoposide; MAE = Mit + AraC + Eto; G-CSF = granulocyte-colony stimulating factor. Karanes C,et al. Leuk Res.1999;23:787-794; Thomas X, et al. Leukemia. 1999;13:1214-1220; Greenberg PL, et al. J Clin Oncol. 2004;22:1078-1086; Feldman EJ, et al. J Clin Oncol. 2005;23:4110-4116; Giles FJ, et al. Blood (ASH Annual Meeting Abstracts). 2006;108. Abstract 1970; Kern W, et al. Leukemia. 2000;14: 226-231; Martiat P, et al. Eur J Haematol. 1990;45:164-167; Larson 69 RA, et al. Br J Haematol. 1992;82:337-346; Vogler WR, Leukemia. 1994;8:1847-1853; Ohno R, et al. Blood. 1994;83:2086-2092.

Clofarabine / Cytarabine vs Cytarabine in Older Relapsed or Refractory AML Patients Randomize Phase III (CLASSIC I) Relapsed or Refractory AML > 55 years 1-2 prior induction therapies Placebo + Cytarabine Placebo IV + cytarabine 1 g/m 2 IV daily on D1-5 up to 2 induction cycles, 1 consolidation cycle (daily on D1-4) n = 157 Clofarabine + Cytarabine Clofarabine 40 mg/m 2 IV + cytarabine 1 g/m 2 IV daily on D1-5 up to 2 induction cycles, 1 consolidation cycle (daily on D1-4) n = 162 Stratified by Refractory (no response or CR1 < 6 months) Relapsed CR1 > 6 months Maximum of 3 cycles of treatment Faderl S, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):6503. ClinicalTrials.gov Identifier: NCT00317642

Clofarabine / Cytarabine vs Cytarabine in Older Relapsed or Refractory AML Patients Response Clofarabine / Cytarabine Cytarabine All patients: ORR CR Refractory: ORR CR Relapsed: ORR CR Toxicity 47% 35% 46% 33% 49% 38% Clofarabine / Cytarabine n = 161 23% 18% 23% 18% 23% 18% Cytarabine n = 155 Grade > 3 AE 98% 86% Discontinuation due to AE 11% 3% Serious AE 60% 49% Death due to AE 14% 5% Death due to treatment-related AE 6% 2% 30-day mortality 16% 5% 60-day mortality 24% 17% Faderl S, et al. ASCO Meeting Abstracts. 2011;29(15S):6503. ClinicalTrials.gov Identifier: NCT00317642

Percent Percent EFS Clofarabine / Cytarabine vs Cytarabine in Older Relapsed or Refractory AML Patients 100 90 80 70 60 50 40 30 20 10 0 HR = 0.63 (0.49, 0.80) P = 0.0001 Clofarabine / cytarabine, n = 162 HR = 0.63 Cytarabine, n = 157 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 OS 100 90 80 70 60 50 40 30 20 10 0 HR = 1.00 (0.78, 1.28) P = 0.9951 Median: Clo+Ara-C: 6.6 mos Ara-C: 6.4 mos Clofarabine / cytarabine, n = 162 HR = 1.00 Cytarabine, n = 157 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time (Months) Clofarabine / cytarabine Cytarabine P Clo+Ara-C Ara-C 4-month EFS 38% 17% < 0.0001 Median OS 6.6 mo 6.4 mo 0.9951 Faderl S, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):6503. 72

Future Directions: Targeted Therapy Target Inhibitor Rationale Phase FLT3 Midostaurin, sorafenib, AC220 TKI of FLT3 II, III MLL Stromal interaction NFkB P-gp LSC Apoptosis Azacitidine, decitabine Plerixafor Bortezomib Zosuquidar, valspodar Amonafide Parthenolides AEG35156 (XIAP oligonucleotide) Reverses hypermethylation of tumor suppressor genes Breaks SDF-1 bond between leukemic cell and stroma With anthracyclines, enhances apoptosis of leukemic cells Blocks anthracycline efflux P-gp resistant topoisomerase inhibitor Enhances apoptosis of LSC, inhibits NFkB, activates p53 Inhibits XIAP II II II II, III I Preclinical I/II Fernandez HF. Hematology Am Soc Hematol Educ Program. 2010;2010:56-61. 73

Agents in Early Development Drug Class Monoclonal antibodies Newer alkylating agents Newer topoisomerase II inhibitors Newer nucleoside analogues Hypomethylating agents FTase inhibitors Aminopeptidase inhibitors FLT3 inhibitors Mechanism of Action CDC and ADCC DNA alkylation and DNA cross-linking Prevention of relegation of DNA during DNA replication causing DNA strand breaks Inhibition of RNR and DNA polymerase; induction of apoptosis Inhibition of DNA methylation Inhibition of FTase, inhibition of angiogenesis, and induction of cellular adhesion AADR Inhibition of FLT3 phosphorylation, induction of apoptosis Blum W, et al. Best Pract Res Clin Haematol. 2008;21:29-41; Stasi R, et al. Cancer Treat Rev. 2008;34:49-60; Stone RM. Best Pract Res Clin Haematol. 2007;20:39-48; Sievers EL, et al. Blood. 1999;93:3678-3684; Löwenberg B, et al. J Clin Oncol. 2010; epub August 23, 2010; Stapnes C, et al. Expert Opin Investig Drugs. 2009;18:433-455. 74

Newly diagnosed Summary Use genetic markers at diagnosis and response to guide therapeutic decisions Think about transplantation sooner rather than later Currently there is no great standard therapy Relapse Encourage clinical trial participation Although 7 + 3 is not a great gold standard, it is the regimen to which novel regimens should be compared Current outcomes for relapsed/refractory AML are abysmal Demonstrating a survival advantage is difficult Possibly consider CR as an endpoint Agent approval based on phase II studies of unmet medical need is difficult 75

Next Genetics of response to guide the use of conventional pathways or experimental approaches Treating MRD How to combine targeted therapies 76