MIGUEL A SANZ, MDValencia, Spain

• Professor and Head of Department, of Oncology, Hematology and Bone Marrow Transplant Unit, University Hospital La Fe in Valencia, Spain

• Professor Sanz is chairman of the Spanish PETHEMA Group and leads the working parties of acute promyelocyticleukemia, acute myeloid leukemia and infections in neutropenic patients. He is currently a reviewer for numerous high-profile medical journals including all top hematology journals, and has authored more than 470 peer-reviewed papers, numerous book chapters, and in excess of 1000 abstracts at national and international meetings. Professor Sanz has also lectured widely in Europe, North, central and South America, as well as in Middle East and Asia, serving as lecturer at the American Society of Hematology in 2004, 2005 and 2010.

AML: Best of 2014

Elderly Patients with AML

The 6th International Hematologic Malignancies Conference: Bridging the Gap 2015 (BTG2015)

Beijing, China (January 31, 2014)

Miguel A. Sanz

Departamento de Medicina de la Universidad de Valencia

Servicio de Hematología y Hemoterapia

Hospital Universitario La Fe

Valencia, Spain

Original Article

Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence

Giulio Genovese, Ph.D., Anna K. Kähler, Ph.D., Robert E. Handsaker, B.S., Johan Lindberg, Ph.D., Samuel A. Rose, B.S., Samuel F. Bakhoum, M.D., Ph.D., Kimberly

Chambert, M.S., Eran Mick, B.S., Benjamin M. Neale, Ph.D., Menachem Fromer, Ph.D., Shaun M. Purcell, Ph.D., Oscar Svantesson, M.S., Mikael

Landén, Ph.D., Martin Höglund, M.D., Ph.D., Sören Lehmann, M.D., Ph.D., Stacey B. Gabriel, Ph.D., Jennifer L. Moran, Ph.D., Eric S. Lander, Ph.D., Patrick F.

Sullivan, M.D., Pamela Sklar, M.D., Ph.D., Henrik Grönberg, M.D., Ph.D., Christina M. Hultman, Ph.D., and Steven A. McCarroll, Ph.D.

N Engl J MedVolume 371(26):2477-2487

December 25, 2014

We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes.

3

Study Overview

• Clonal hematopoiesis with somatic mutations was observed in 10% of otherwise healthy people > 65 years of age but in only 1% of those < 50 years of age.

• Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A , ASXL1 , and TET2 ) that have previously been implicated in hematologic cancers.

• The risk of hematologic cancer was substantially increased among these persons:

- Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (HR, 12.9; 95% CI, 5.8 to 28.7).

- 42% of hematologic cancers in persons with previous detectable clonality.

Genovese G et al. N Engl J Med 2014;371:2477-2487 4

Clonal Expansion of Pre-leukemic Mutations

Genovese G et al. N Engl J Med 2014;371:2477-2487

Model for the expansion of a single hematopoietic stem cell into a clonal population, under the influence of a somatic mutation (yellow circle), and the potential conversion of the clone into a hematologic cancer through subsequent mutation (black circle with red rim).

5

Candidate Driver Somatic Mutations

Genovese G et al. N Engl J Med 2014;371:2477-2487 6

DNMT3A in NPM1mut AMLHigh stability & persistence in remission

Schnittger S, et al.-MLL lab (abst. 122, session 617)

• DNMT3A is a stable mutation in NPM1 AML cases

- DNMT3A is retained at relapse in 57/61 (93%) cases with paired

diagnosis – relapse samples.

• DNMT3A as a potential pre-leukemic mutation

- DNMT3A persisted in remission samples in 32/54 (59%)

patients with NPM1 clearance.

• Persistence of DNMT3A at remission is associated to

worse prognosis:

- EFS: 38 vs 96 mos (p=0.03)

- OS: 69 vs. 96 mos (p=0.053)

7

Döhner H, et al. Blood. 2014;124(9):1426-1433

EFS OS

8

RESULTS OF A PHASE 3, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY OF AZACITIDINE

VS CONVENTIONAL CARE REGIMENS IN OLDER PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID

LEUKEMIA

Hervé Dombret1, John F. Seymour2, Aleksandra Butrym3, Agnieszka Wierzbowska4, Dominik Selleslag5, Jun Ho Jang6, Rajat Kumar7, James Cavenagh8, Andre Schuh9, Anna Candoni10,

Christian Récher11, Irwindeep Sandhu12, Teresa Bernal del Castillo13, Haifa Kathrin Al-Ali14, Giovanni Martinelli15, Richard M. Stone16, Mark D. Minden9, Heidi McIntyre17, Steve Songer17,

Lela Lucy17, CL Beach17, Hartmut Döhner18

1Hôpital Saint Louis, Paris Cedex 10, France; 2Peter MacCallum Cancer Centre, East Melbourne, Australia; 3Wroclaw Medical University, Wroclaw, Poland; 4Medical University of Lodz, Lodz, Poland; 5Algemeen Ziekenhuis Sint-Jan, Brugge, Belgium; 6Samsung Medical Center, Seoul,

Republic of Korea; 7Cancer Care Manitoba, Winnipeg, Canada; 8Barts Health NHS Trust, London, United Kingdom; 9Princess Margaret Cancer Centre, Toronto, Canada; 10Azienda Ospedaliero Universitaria S. Maria della Misericordia di Udine, Udine, Italy; 11Centre Hospitalier Universitaire

de Toulouse, Toulouse Cedex 09, France; 12University of Alberta Hospital, Edmonton, Canada; 13Hospital Central de Asturias, Oviedo, Spain; 14Universitätsklinikum Leipzig, Leipzig, Germany; 15Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi, Bologna, Italy;

16Dana Farber Cancer Institute, Boston, United States; 17Celgene Corporation, Summit, United States; 18Universitätsklinikum Ulm, Ulm, Germany

Presented at the 19th Congress of the European Hematology Association; June 12-15, 2014; Milan, Italy

9

9

Study design of the phase III randomised AZA-AML-001 trial

AZA = azacitidine; CCR = conventional care regimens; allo-HSCT = allogeneic haematopoietic stem cell transplantation; BM = bone marrow; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IC = intensive chemotherapy; LDAC = low-dose cytarabine; BSC = best supportive care; SC = subcutaneous; BID = twice daily; OS = overall survival

Dombret H, et al. Oral presentation at EHA 2014. Abstract LB2433

Key eligibility criteria

• Aged ≥65 years, ineligible for allo-HSCT• Newly diagnosed de novo or secondary AML (BM blasts >30%)• ECOG PS 0–2, or poor-/intermediate-risk cytogenetics

Screening

N=488

• Primary endpoint: OS (including a pre-specified sensitivity analysis that censored patients at the start of subsequent AML therapy)

• Secondary endpoints: 1-year OS, response, safety

Phase III, randomised, multicentre, open-label, controlled study of AZA vs conventional care regimen (CCR) in elderly patients with AML (NCT01074047)

Investigator pre-selection of CCR

CCR (n=247)

• IC (n=44): 7+3

• LDAC (n=158): 20mg SC BID for

10 days every 28 days

• BSC only (n=45)

AZA (n=241)

75mg/m2 SC x7 days every 28 days

Randomisation

10

Baseline Demographics

Characteristic AZA(n=241)

CCR(n=247)

Age (yrs), median (min, max)Age ≥75, n (%)

75.0 (64, 91)138 (57.3)

75.0 (65, 89)127 (51.4)

Male, n (%) 139 (57.7) 149 (60.3)

Geographic region, n (%)Western Europe/IsraelNorth America/AustraliaEastern EuropeAsia

116 (48.1)45 (18.7)46 (19.1)34 (14.1)

122 (49.4)47 (19.0)44 (17.8)34 (13.8)

11

11

Baseline Disease Characteristics

CharacteristicAZA

(n=241)

CCR(n=247)

WHO AML classification, n (%)Not otherwise specified (NOS)Myelodysplasia-related changesOther*

153 (63.5)75 (31.1)13 (5.4)

143 (57.9)83 (33.6)21 (8.5)

Prior MDS, n (%) 49 (20.3) 38 (15.4)

Bone marrow blasts† %median (min, max)>50% BM blasts, n (%)

70.0 (2, 100)173 (71.8)

74.0 (4, 100)193 (78.1)

ECOG 0-1, n (%)ECOG 2

186 (77.2)55 (22.8)

189 (76.5)58 (23.5)

Cytogenetic risk,†‡ n (%)IntermediatePoor

155 (64.3)85 (35.3)

160 (64.8)85 (34.4)

WBC (x109/L), median (range) 3.1 (0, 33) 2.3 (0, 90)

12

*Therapy-related myeloid neoplasms or AML with recurrent genetic abnormalities†Centrally adjudicated‡Per modified NCCN Clinical Practice Guidelines, 2010 12

Overall Survival (ITT)13

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 4 8 12 16 20 24 28 32 36 40

Surv

ival

Pro

bab

ility

Time from Randomization (months)Number at risk:Azacitidine 241 174 133 109 73 44 22 5 3 2 0CCR 247 150 108 80 53 40 25 10 3 1 0

AZA

CCR

*Stratified by ECOG PS and cytogenetic riskMedian follow-up for OS was 24.4 months. 193 deaths in the AZA arm (80.1%) and 201 deaths in the CCRarm (81.4%)

Median [95% CI] OS: AZA = 10.4 mos [8.0, 12.7] vs. CCR = 6.5 mos [5.0, 8.6]

1-Year Survival: 46.5% vs 34.2% (Δ 12.3%; 95%CI: 3.5%, 21.0%)

Unstratified analysis: HR=0.84 [95%CI: 0.69, 1.02]; log-rank p=0.0829

Stratified* analysis: HR=0.85 [95%CI: 0.69, 1.03]; log-rank p=0.1009

6.5 mos

10.4 mos

34.2%

46.5%

13

Subanalysis of AZA-AML-001 trialOutcomes according to cytogenetic risk

CI = confidence interval Döhner H, et al. Oral presentation at ASH 2014. Abstract 621

Median OS of patients with int-risk cytogenetics treated with AZA was prolonged by 2.9 months compared with those treated with CCR

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12 16 20 24 28 32 36 40

Surv

ival

Pro

bab

ility

Time from randomisation, months

13.0 months

10.1 months log-rank p=0.4119

AZA (n=155)CCR (n=160)

• 1-year OS: AZA: 55.2%; CCR: 45.5% (Δ9.7%; 95% CI: –1.4%, 20.8%)

OS: intermediate-risk cytogenetics

14

Subanalysis of AZA-AML-001 trialOutcomes according to cytogenetic risk

Patients with poor-risk cytogenetics treated with AZA had significantly longer median OS than those treated with CCR

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12 16 20 24 28 32 36 40

Surv

ival

Pro

bab

ility

Time from randomisation, months

log-rank p=0.0185

6.4 months

3.2 months

AZA (n=85)CCR (n=85)

• 1-year OS: AZA: 30.9%; CCR: 14.0% (Δ16.9%; 95% CI: 4.4%, 29.5%)

15Döhner H, et al. Oral presentation at ASH 2014. Abstract 621

OS: poor-risk cytogenetics

Subanalysis of AZA-AML-001 trialOutcomes in AML patients with

myelodisplasia-related changes

Seymour JF, et al. Oral presentation at ASH 2014. Abstract 10

OS: whole population OS: patients preselected to LDAC

• 1-year OS: AZA: 50.7%; CCR: 33.8% (Δ16.9%; 95% CI: 1.5%, 32.2%)

• 1-year OS: AZA: 55.1%; LDAC: 31.3% (Δ23.8%; 95% CI: 4.7%, 43.0%)

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12 16 20 24 28 32 36 40

Surv

ival

pro

bab

ility

Time from randomisation, months

12.7 months

6.3 months

log-rank p=0.0357

AZA (n=75)CCR (n=83)

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12 16 20 24 28 32 36 40

Surv

ival

pro

bab

ility

Time from randomisation, months

log-rank p=0.2292

13.2 months

6.3 months

AZA (n=49)LDAC (n=50)

AZA prolonged median OS vs CCR in AML patients with AML-MRC

16

Median OS was more than twice as long with AZA vs LDAC in patients preselected to LDAC

IDH mutants are an interesting target in AML

17

AG-221, an Oral, Selective, First-in-Class,

Potent Inhibitor of the IDH2 Mutant Enzyme,

Induces Durable Remissions in a Phase 1

Study of IDH2 Mutation Positive Advanced

Hematologic Malignancies

Eytan M Stein1, Jessica K Altman2, Robert Collins3, Daniel J DeAngelo4, Amir T Fathi5,

Ian Flinn6, Arthur Frankel3, Ross L Levine1, Bruno C Medeiros7, Manish Patel8,

Daniel A Pollyea9, Gail Roboz10, Richard M Stone4, Ronan T Swords11, Martin S Tallman1,

Sam Agresta12, Bin Fan12, Meredith Goldwasser 12, Hua Yang12, Katharine Yen12 and

Stéphane de Botton13

1Memorial Sloan-Kettering Cancer Center, New York, NY; 2Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; 3University of

Texas Southwestern, Dallas, TX; 4Dana-Farber Cancer Institute, Boston, MA; 5Massachusetts General Hospital Cancer Center, Harvard

Medical School, Boston, MA; 6Sarah Cannon Research Institute, Nashville, TN; 7Stanford Comprehensive Cancer Center, Stanford

University, Stanford, CA; 8Florida Cancer Specialists, Sarasota, FL; 9University of Colorado Cancer Center, Aurora, CO; 10Weill Cornell

Medical College, New York Presbyterian Hospital, New York, NY; 11Sylvester Comprehensive Cancer Center, University of Miami Hospitals,

Miami, FL; 12Agios Pharmaceuticals, Cambridge, MA; 13Institut Gustave Roussy, Villejuif, France

Oral presentation:

Dec 7, 2014

4:30 PM

West Building, 2001-2003-2014-2016

Moscone CenterStein EM., et al. AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant Enzyme, Induces Durable Remissions in a Phase 1 Study of

IDH2 Mutation Positive Advanced Hematologic Malignancies. Oral Presentation at: Annual Meeting and Exposition of the American Society of Hematology 2014;

December 6-9; San Francisco, CA.18

AG-221 for AML patients with mutatedIDH-2

• AG-221, an oral inhibitor of mutated IDH2, is well

tolerated in pts with advanced myeloid malignancies

• Leads to effective 2-HG inhibition >90% in pts with

IDH2-R140 or -R172 mutation (≥100 mg/day)

• Significant clinical activity

- Overall response rate 56% (25/45)

- 6 CR + 9 CR with incomplete recovery

- Durable responses (6 pts on-study >6 mos.)

Stein E, et al. ASH 2014 (abst. 115, session 616) 19

Vosaroxin (LBA-6) in combination with cytarabine improves survival in patients with first

relapsed/refractory AML: results of phase III VALOR trial

• Vosaroxin is a novel anticancer quinolone derivative

• Topoisomerase II inhibitor

• Non P-glycoprotein substrate

• P53-independent activity

• Additive/synergistic effect with cytarabine

Ravandi F, et al. ASH 2014 (Late breaking abstracts) 20

Vosaroxin (LBA-6) in combination with cytarabine improves survival in patients with first

relapsed/refractory AML: results of phase III VALOR trial

• Refractory or AML in first relapse

• Dec 2010-Sept 2013

• 711 pts randomized in a 1:1 ratio

• Up to 2 induction & 2 consolidation courses

Cytarabine 1 g/m2 IV d 1-5Cytarabine 1 g/m2 IV days 1-5

+Vosaroxin 90 (70)mg/m2 IV d1 & d4

Vs.

21Ravandi F, et al. ASH 2014 (Late breaking abstracts)

Benefit of vosaroxin (LBA-6) is observed in patients not undergoing alloHSCT and/or ≥60 years

OS by treatment arm (censored at alloHSCT)

OS by treatment arm in patients aged ≥60

22Ravandi F, et al. ASH 2014 (Late breaking abstracts)

Improved Overall Survival with Gemtuzumab Ozogamicin (GO) Compared with Best Supportive Care (BSC) in Elderly Patients with Untreated Acute Myeloid Leukemia (AML) Not Considered Fit for Intensive Chemotherapy: Final Results from the Randomized Phase III Study (AML-19) of the EORTC

and Gimema Leukemia Groups

Conclusions:

• Compared with BSC including hydroxyurea as necessary, GO 6 mg/m2 day 1 and 3 mg/m2 day 8 significantly improved OS in elderly AML pts not considered fit for intensive chemotherapy, with an acceptable safety profile.

• The benefit of GO were greater in pts presenting with better-risk cytogenetics, high CD33 expression on blast cells, or secondary disease.

23Amadori S et al. Oral presentation at ASH 2014.

Castaigne S et al. Blood 2014;124:376

FINAL analysis of the ALFA-0701 study

Conclusion:

• Final analysis of the ALFA

0701 study with a longer

follow up confirms the

efficacy of adding GO to

standard chemotherapy in

AML treatment on EFS

and RFS.

• However, the gain in OS

was no longer observed.

24