M l d l ti S dMyelodysplastic Syndromes

Ayalew Tefferi, MDProfessor of Medicine

Mayo Clinic Rochester MNMayo Clinic, Rochester, MN

1

DisclosureDisclosureI have nothing to disclose.I have nothing to disclose.

Pg 2

Incidence and Demographicsof Myelodysplastic Syndromeof Myelodysplastic Syndrome

Incidence after age 70 years >20/100,000

Median age at diagnosis is close to 70 years

No gender preference

Ab t 15 000 di d l i th US About 15,000 cases diagnosed yearly in the US

4540at

e xMenWomen40

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151050Age

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Pg 3Aul et al. Br J Haematol. 1992;82:358.Maynadie et al. Br J Cancer. 1996;74:288.

0-24 25-49 50-54 55-59 60-64 65-70 70-74 75-79 80-84 >85Age in 5-year blocks

HematopoiesisHematopoiesis

Stem cell mutation

Altered immune response

Altered stromal

response

Clonal myelopoiesis

HaploinsufficiencyE i ti h

Altered cytokineresponse

Epigenetic changesp

Ineffective hematopoiesis and increased apoptosis

Cl l l ti

Additional mutations

Leukemic transformation

Clonal evolution

Tefferi A, Vardiman JW. N Engl J Med 2009;361:1872

2016 WHO classification of myeloid malignancies

Acute myeloid leukemia (AML) and related neoplasms Chronic myeloid neoplasms

1 AML with recurrent genetic abnormalitiesAML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11APL with PML-RARAAML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A

1 Myeloproliferative neoplasms (MPN)Chronic myeloid leukemia (CML), BCR-ABL1+

Chronic neutrophilic leukemia (CNL)Polycythemia vera (PV)Primary myelofibrosis (PMF)

AML with t(6;9)(p23;q34.1);DEK-NUP214

AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1Provisional entity: AML with BCR-ABL1AML with mutated NPM1AML with biallelic mutations of CEBPA

PMF, prefibrotic/early stagePMF, overt fibrotic stage

Essential thrombocythemia (ET)

Chronic eosinophilic leukemia, not otherwise specified (NOS)

MPN, unclassifiable

2 MastocytosisProvisional entity: AML with mutated RUNX1

2 AML with myelodysplasia-related changes3 Therapy-related myeloid neoplasms4 AML, not otherwise specified (NOS)

AML with minimal differentiationAML without maturationAML ith t ti

3 Myeloid/lymphoid neoplasms with eosinophilia and rearrangement ofPDGFRA, PDGFRB, or FGFR1, or withPCM1-JAK2

Myeloid/lymphoid neoplasms with PDGFRA rearrangement

Myeloid/lymphoid neoplasms with PDGFRB rearrangement

Myeloid/lymphoid neoplasms with FGFR1 rearrangement

Provisional entity: Myeloid/lymphoid neoplasms with PCM1 JAK2AML with maturationAcute myelomonocytic leukemiaAcute monoblastic/monocytic leukemiaPure erythroid leukemiaAcute megakaryoblastic leukemiaAcute basophilic leukemiaAcute panmyelosis with myelofibrosis

Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2

4 Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)Chronic myelomonocytic leukemia (CMML)

Atypical chronic myeloid leukemia (aCML), BCR-ABL1−

Juvenile myelomonocytic leukemia (JMML)

MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)5 Myeloid sarcoma6 Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis (TAM)Myeloid leukemia associated with Down syndrome

MDS/MPN, unclassifiable

5 Myelodysplastic syndromes (MDS)MDS with single lineage dysplasiaMDS with ring sideroblasts (MDS-RS)

MDS-RS and single lineage dysplasiaMDS-RS and multilineage dysplasia

MDS ith ltili d l i

11/10/2016 6

MDS with multilineage dysplasiaMDS with excess blastsMDS with isolated del(5q)MDS, unclassifiable

Provisional entity: Refractory cytopenia of childhood

6 Myeloid neoplasms with germ line predisposition

Myeloid Disorders

Acute MyeloidLeukemia

Chronic MyeloidDisorders

≥20% blasts <20% blasts≥20% blastsIn bone marrow or blood

OrPresence of t(8;21)(q22;q22), inv(16)(p13;q22),

<20% blasts

t(16;16)(p13;q22), or t(15;17)(q22;q12)

Vardiman et al. Blood. 2002;100:2292.

Chronic Myeloid MalignanciesChronic Myeloid Malignancies1. Molecularly-defined

i Chronic myelogenous leukemiai. Chronic myelogenous leukemia BCR-ABL1

ii. Eosinophilia-associated myeloid/lymphoid malignancy PDGFRA-rearranged PDGFRB-rearranged FGFR1 d FGFR1-rearranged

2. Molecularly-undefined

MyelodysplasticSyndromes

Myelodysplastic/Myeloproliferative

overlap

MyeloproliferativeNeoplasms

ErythrocytosisGranulocytosisThrombocytosis

EosinophiliaDyserythropoiesisDysgranulopoiesisAbsence of cytosis

Monocytosis

Mastocytosis

Tefferi A. Leukemia Research, in press

DyserythropoiesisDyserythropoiesisy y py y p

Nuclear dysplasia and multinuclearityABN.CELL DIVISION

Pg 9Megaloblastoid maturation

Ringed SideroblastsRinged Sideroblasts

Pg 10

DysgranulopoiesisDysgranulopoiesisy g py g p

Pseudo Pelger cell

Hypogranular neutrophilsypog a u a eut op s

Pg 11

DysmegakaryopoiesisDysmegakaryopoiesis

Large mononuclearBinucleated

Micromegakaryocyte

Pg 12Multinucleated

Courtesy of Dr. T. VallespiCourtesy of Dr. T. Vallespi

2016 WHO classification of myeloid malignancies

Acute myeloid leukemia (AML) and related neoplasms Chronic myeloid neoplasms

1 AML with recurrent genetic abnormalitiesAML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11APL with PML-RARAAML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A

1 Myeloproliferative neoplasms (MPN)Chronic myeloid leukemia (CML), BCR-ABL1+

Chronic neutrophilic leukemia (CNL)Polycythemia vera (PV)Primary myelofibrosis (PMF)

AML with t(6;9)(p23;q34.1);DEK-NUP214

AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1Provisional entity: AML with BCR-ABL1AML with mutated NPM1AML with biallelic mutations of CEBPA

PMF, prefibrotic/early stagePMF, overt fibrotic stage

Essential thrombocythemia (ET)

Chronic eosinophilic leukemia, not otherwise specified (NOS)

MPN, unclassifiable

2 MastocytosisProvisional entity: AML with mutated RUNX1

2 AML with myelodysplasia-related changes3 Therapy-related myeloid neoplasms4 AML, not otherwise specified (NOS)

AML with minimal differentiationAML without maturationAML ith t ti

3 Myeloid/lymphoid neoplasms with eosinophilia and rearrangement ofPDGFRA, PDGFRB, or FGFR1, or withPCM1-JAK2

Myeloid/lymphoid neoplasms with PDGFRA rearrangement

Myeloid/lymphoid neoplasms with PDGFRB rearrangement

Myeloid/lymphoid neoplasms with FGFR1 rearrangement

Provisional entity: Myeloid/lymphoid neoplasms with PCM1 JAK2AML with maturationAcute myelomonocytic leukemiaAcute monoblastic/monocytic leukemiaPure erythroid leukemiaAcute megakaryoblastic leukemiaAcute basophilic leukemiaAcute panmyelosis with myelofibrosis

Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2

4 Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)Chronic myelomonocytic leukemia (CMML)

Atypical chronic myeloid leukemia (aCML), BCR-ABL1−

Juvenile myelomonocytic leukemia (JMML)

MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)5 Myeloid sarcoma6 Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis (TAM)Myeloid leukemia associated with Down syndrome

MDS/MPN, unclassifiable

5 Myelodysplastic syndromes (MDS)MDS with single lineage dysplasiaMDS with ring sideroblasts (MDS-RS)

MDS-RS and single lineage dysplasiaMDS-RS and multilineage dysplasia

MDS ith ltili d l i

11/10/2016 13

MDS with multilineage dysplasiaMDS with excess blastsMDS with isolated del(5q)MDS, unclassifiable

Provisional entity: Refractory cytopenia of childhood

6 Myeloid neoplasms with germ line predisposition

AMLAMLCMMLCMMLMDS/MPNMDS/MPN

PB or BMPB or BMblasts blasts ≥≥20%20%

PB monocytesPB monocytes≥≥ 1 x 101 x 1099/L/L

BM minimal criteria for MDS:BM minimal criteria for MDS:Dyserythropoiesis,Dyserythropoiesis,

Dysgranulopoiesis Dysgranulopoiesis ororDysmegakaryopoiesisDysmegakaryopoiesis

in in ≥≥ 10% of specific lineage cells10% of specific lineage cells

Tefferi A, Vardiman JW. N Engl J Med 2009;361:1872

Yes

No

Auer rods RAEB-2

Yes

No

PBblasts 1%

2-4%

5-19%

5-9%Yes

No

BMblasts 5%

RAEB-1 10-19%

Yes

No

Isolated del(5q) MDS-del(5q)

No

YesNoMultilineagedysplasia

Not fitting elsewhere

UnilineagedysplasiaRCMD

15% ringsideroblasts RARS

NoNot fitting elsewhere

MDS-U RCUD

Retrospective Analysis of the WHO Classification

1.0

p<0.000050.8

0 6urvi

val

0.6

0 4ulat

ive

su

0.4

0 2

cum

u

RCMD del(5q)0.2

0 0

RCMDRSRAEB I

RAEB II

RA

RARS

Pg 15

3603002401801206000.0

monthsGerming, U. Leukemia Research, 2001

Karyotype and prognosis in MDS

(A) Overall survival (n = 1,893) and(B) Risk of acute myeloid leukemia transformation (n = 1,691)

Schanz J, et al. J Clin Oncol 2012;30:820-9.

New cytogenetic risk categories in MDS

1. Very good: 11q- and −Y 2. Good: normal, 5q-, 12p-, 20q- and double including 5q-3. Intermediate:7q-, +8, i(17), +19, +21, other single abnormality, double without 5q- or −7/7q-4. Poor: inv(3)/t(3q)/del(3q), −7, double including −7/del(7q), and three abnormalities 5. Very poor: More than three abnormalities

Schanz J, et al. J Clin Oncol 2012;30:820-9.

Mutations and Cytogenetic Abnormalities in 223 Samples with at Least One Mutation.

Bejar R et al. N Engl J Med 2011;364:2496-2506.

Hazard Ratios for Death from Any Cause, According to Presence (vs. Absence) of Mutation in Each of Seven

Genes.

Bejar R et al. N Engl J Med 2011;364:2496-2506.

Overall Survival, According to International Prognostic Scoring System (IPSS) Risk Category and Mutational

Status.

Bejar R et al. N Engl J Med 2011;364:2496-2506.

Allogeneic Transplant in Patients With MDS

Disease Free SurvivalDisease-Free Survival

Who Is the Best Donor? HLA-ID (N=885)100AUTO (N=173)

VUD (N=198)

FAMNID (N=91)75

FAMNID (N 91)

(N=1378)50

Perc

ent

25

P

de Witte et al. Br J Haematol. 2000;110:620.

00

12 24 36 48 60M th

Pg 24

Months

Identical twin transplant had similar relapse rate and better survivalKroger et al. 2005 BMT 35: 37.

Management of MDSManagement of MDS Non-Transplant Treatment OptionsNon Transplant Treatment Options

– AML-like induction chemotherapyTreatment with growth factors– Treatment with growth factors

– Drug therapyS ti– Supportive care

Pg 25

Survival trends among 1000 patients with primary MDS stratified by year of diagnosis.Gangat et al. Blood Cancer J. 2016 Apr; 6(4): e414

Effect of Age and Blast Count on DFS in MDS After

TransplantationTransplantation

Age Disease stage

1 0<18 y (n=66) <5% (n=195)

Probability of DFSaccording to age

Probability of DFS according to blasts in BM

1 0

Bone marrow blast influence

1.0

0.8

0 6ity

y ( )18-30 y (n=84)31-45 y (n=165)>45 y (n=137)

( )5-20% (n=131)>20% (n=35)

1.0

0.8

0 6ity 0.6

0.4

Prob

abil0.6

0.4

Prob

abil

0 1 2 3 4 5

0.2

00 1 2 3 4 5

P<0.0001 P<0.00010.2

0

Pg 27Sierra et al. Blood. 2002,100:1997.

Years Years

de Lima et al. Blood 2004;104:857, fludara/busulfan IV, n=96, 22 MDS, 30 age > 50 years.

Pg 28

Actuarial Survival Curve of MDS Patients Age <60 YearsActuarial Survival Curve of MDS Patients Age <60 Years

100(%

)

Not transplanted(n=184)

Low50

75

all s

urvi

val

High Int-2 Int-1

0 25 50 75 100 125 150 175 200 225

0

25

Ove

ra

Transplanted(n=260)

BMT and HLA-

Months

75

100

rviv

al (%

)

Low BMT and HLA-identical siblings

only25

50

Ove

rall

sur

High

Int-2

Int-1Low

Pg 29Cutler et al. Blood. 2004;104:579.

0 25 50 75 100 125 150 175 200 225Months

0O

AZA-001

Log-Rank p=0.0001HR = 0.58 [95% CI: 0.43, 0.77]1.0

CR = 17%; ORR = 35%

0.7

0.8

0.9

ving

0 4

0.5

0.6

rtion

Sur

viv

24.4 months

15 th

50.8%

0.2

0.3

0.4

Pro

por

CCRAZA

15 months 26.2%

0 5 10 15 20 25 30 35 400.0

0.1

©2012 MFMER | slide-30

Time (months) from Randomization

Fenaux P, et al. Lancet Oncology 2009;10:223-232.

Randomized Study of Azacitidine in Patients With MDS: SurvivalPatients With MDS: Survival

1 01.0

0.8 Azacitidine

bilit

y

Supportive Care

• CR = 7%• PR = 16%• Improved 37%

(N=191)

0.4

0.6

al P

roba

b Supportive Care p

ECOG/SWOG randomized study of low-dose Ara-C in 141 high-risk MDS0.2Su

rviv

a

• CR = 11%• PR = 21%

Months

0 6 12 18 24 30 36 42 48 540.0

Pg 31

75 mg/m2/d SC x 7 days every month.Silverman et al. J Clin Oncol. 2002;20:2429.Miller et al. Ann Hematol. 1993;65:162.

D it biDecitabine.• MDACC phase III study - 15 mg/m2 Q 8 hrs for

3 d d i d BSC3 days randomized to BSC.

• CR-9% & overall response rate 17%.

• ADOPT study 20 mg/m2 D1-5 IV Median

Kantarjian et al. Cancer 2006.

• ADOPT study 20 mg/m2 D1-5 IV. Median survival of 19.4 months and CR of 17%.Steensma DP et al. JCO 2009

• EORTC-LG study randomized to 3 day schedule had no survival benefit

Steensma DP et al. JCO 2009

schedule had no survival benefit.Lubbert M et al. JCO 2011

33

MDS-001: follow-up at 4.9 yearsp y

• At 4.9 years, follow-up available for 20 responders– 9 (45%) del(5q) and 11 (55%) non-del(5q)

– median duration of major erythroid response or RBC-TI was 61 weeks (95% CI 19–119 weeks)61 weeks (95% CI, 19 119 weeks)

• Among 6 case reports of lower-risk patients with del(5q) and non-del(5q) who maintained long-term therapy, median RBC-TI was 5.6 years (mean 5.5 years; SD 0.81 years)

• Lenalidomide can induce durable erythroid responsesLenalidomide can induce durable erythroid responses with sustained RBC-TI in patients with lower-risk non-del(5q) and del(5q) MDS

Kurtin SE, List AF. Clin Lymphoma Myeloma 2009;9:E10–13.CI, confidence interval; RBC, red blood cell; SD, standard deviation; TI, transfusion independence.

Erythropoietin and Darbepoetin in MDSErythropoietin and Darbepoetin in MDS

Darbepoetin in 37 patients with MDSWeekly dose of 150 µg SC

Responders Nonresponders

Epoetin response in randomized study by FAB subgroups

Responders Nonresponders

Serum EPO <100 IU/l 11/13 (84.6%) 6/21 (28.5%)

Epoetin α Placebo P value

RA 50 5.9 0.0072

RBC transfusions <2/month 13/15 (86.6%) 11/22 (50%)RAS 37.5 18.2 0.6

RAEB 16.7 11.1 1.0Marrow blasts <5% 14/15 (93.3%) 7/22 (31.8%)

Hypoplastic bone marrow 4/15 (26.6%) 2/22 (9%)

RAEB 16.7 11.1 1.0

Pg 35

RA = refractory anemia; RAS = RA with ringed sideroblasts; RAEB = RA with excess blasts.Musto et al. Br J Haematol. 2005;128:204.Italian Cooperative Study Group. Br J Haematol. 1998;103:1070.

MDS treatment algorithmMDS treatment algorithm

Is 5q- present?

Symptomatic Asymptomatic

Watch and waitq p

No

Watch and wait

What is the IPSS score?Yes

Favorable UnfavorableEPOETIN

E i t l

> 50 < 50

Pg 36

LenalidomideExperimental

therapy RIC Myeloablativetransplant

N A t f MDSNewer Agents for MDSDeacetylase Inhibitors and Kinase InhibitorsDNMT Inhibitors:

- Oral 5-AZA (CC-486)- INCB –JAK inhibitor

- LGH447- Pim kinase - Oral DAC + cytidine

deaminase inhibitor (E7772).

- MEK162- MEK1/2

- Volasertib- PLK1( )

- SGI-110

5‐AZA + Lenalidomide in MDS

©2012 MFMER | slide-38Sekeres et al. Blood 2012;120:4945.

LEN and AZA have non-overlapping MOA’s

5- AZA + Vorinostat in MDS- Study 6898 of th N Y k C C tithe New York Cancer Consortium

C h t N A C D V i t t D I t 1 I t 2 Hi h Ri k U l RCohort No Aza Cmg/m2 Subcutaneous (SC)

Days(azaC)

VorinostatMg dailyPO

Days(Vorinostat)

Int-1 Int-2 High Risk Unclassified

Response

1 13 55 1-7 400 3-16 3 3 5 2 70

2 13 75 1-7 600 3-9 3 4 4 2 73

3 14 55 1-7 400 3-9 2 5 3 3 67

N=40Response rates- CR- 10, CR (i)-4, HI – 9, SD – 5, NR -5.

Median time to response – 2 cycles/ 2 months.

N 40

©2012 MFMER | slide-39

p y

Silverman LR et. al ASH 2013

Questions About Iron Chelation in MDSIron Chelation in MDS

Does iron overload affect survival? Which risk group? Does iron overload affect QoL? Does iron chelation affect either survival

Q L?or QoL? Could iron chelation improve cytopenias? Could iron chelation increase infection risk? Could iron chelation increase infection risk? What would be the cost of “benefit” from

iron chelation? What is the best way to monitor efficacy of iron chelators?

Serum ferritin? T2* MRI (heart)? Magnetic susceptometry by superconduction quantum-interference device (SQUID;

Pg 40

by superconduction quantum-interference device (SQUID; liver)? Liver biopsy?

MDS treatment algorithmGangat et al; MCP

HMA Cli i l P lHMA – Clinical Pearls• 5-AZA and DAC FDA approved for higher risk pp g

MDS.

• HMA Overall response rates- 45-50%.p

• CR rates 7-17%.

• Time to response 3 4 cycles/ months• Time to response 3-4 cycles/ months.

• Median duration of response 12-18 months.

• Survival after progression 3-6 months.

Silverman L et al, JCO 2002Fenaux P et al, Lancet Oncology 2009Garcia- Manero, G et al, Blood 2006

ASH 2015- Oral

A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat vs. Azacitidine MonotherapyLenalidomide or with Vorinostat vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Mikkael A Sekeres MD MS Megan Othus PhD Alan F List MD OlatoyosiMikkael A. Sekeres, MD, MS, Megan Othus, PhD, Alan F. List, MD, Olatoyosi Odenike, MD, Richard M. Stone, MD., Steven D. Gore, MD, Mark R. Litzow, MD, Rena Buckstein, MD, Mario R. Velasco, MD, Rakesh Gaur, MD, MPH, Ehab Atallah, MD, Eyal C. Attar, MD, Frederick R. Appelbaum, MD, Harry P. Erba, MD, PhDPhD

North American Intergroup Randomized Phase 2 MDS Study S1117: Study DesignPhase 2 MDS Study S1117: Study Design

AZA (IV/SC) Groups: SWOG, ECOG,AZA (IV/SC)75 mg/m2/d (d1-7)

N=92Higher-risk MDS or

Groups: SWOG, ECOG,Alliance, NCIC

Total Sample Size: 276

AZA (IV/SC) + LEN (PO)75 mg/m2/d (d1-7) + 10mg/d x 21d

N=93

MDS or CMML Primary Objective: 20%

improvement of ORR (CR/PR/HI) based on N=93

AZA (IV/SC) + Vorin (PO)(IPSS >1.5 and/or

( )2006 IWG Criteria

Secondary Objectives: OS,RFS LFS( ) ( )

75 mg/m2/d (d1-7) + 300mg BID (d3-9)N=91

and/or blasts >5%)

RFS, LFS

Power 81%, alpha 0.05 for each combo arm vs. AZA

03/2012 – 06/2014Sekeres et al. ASH 2014: LBA - 5

S1117 Relapse Free SurvivalS1117- Relapse Free SurvivalRelapse−free survival for patients on therapy > 6 months

0.8

1.0AzaAza+LenAza+Vor 0.8

1.0AzaAza+LenAza+Vor

0.4

0.6

Surv

ival

pro

babi

lity

0.4

0.6

Sur

viva

l pro

babi

lity

0.0

0.2

0 5 10 15 20

Aza vs Aza+Len log−rank p = 0.45Aza vs Aza+Vor log−rank = 0.29Aza vs Combo arms log−rank p = 0.3 0.0

0.2

0 5 10 15 20

Aza vs Aza+Len log−rank p = 0.74Aza vs Aza+Vor log−rank p = 0.11Aza vs Combo arms log−rank p = 0.6

0 5 10 15 20Months since response

AzaAza+LenAza+Vor

33 19 7 4 134 23 8 5 120 13 9 5 1

N at risk0 5 10 15 20

Months since response

AzaAza+LenAza+Vor

21 14 5 228 19 6 3 115 13 9 5 1

N at risk

Sekeres et al. ASH 2014: LBA - 5

All study patients Patients who had been on study for > 6 months

ASH 2015- Oral

A Randomized, Placebo-Controlled, Phase II Study of Pracinostat in Combination withStudy of Pracinostat in Combination with Azacitidine (AZA) in Patients with Previously Untreated Myelodysplastic Syndrome (MDS)

Guillermo Garcia-Manero, MD1, Jesus G. Berdeja, MD2, Rami S. Komrokji, MD3, James Essell, MD4, Roger M Lyons MD5 Michael Maris MD6 Amy E DeZern MD MHS7 Mikkael A Sekeres MD MS8 andRoger M. Lyons, MD , Michael Maris, MD , Amy E. DeZern, MD, MHS , Mikkael A. Sekeres, MD, MS and Gail J Roboz, MD9

Results:Characteristic AZA +Pracinostat AZA P

value

CR i hi 6 l 18% 31%CR within 6 cycles 18% 31%

Hematologicalimprovement

35% 55%

PFS (months) 10.7 9.7 NS

EFS (months) 8.6 9.0 NS

OS (months) 15.7 18.8 NS

Discontinuation rate 26% 10%

Grade III febrile 33% 18%Grade III febrile neutropenia

33% 18%

Grade III fatigue 24% 0%

N = 102

ASH 2015- Oral

Telomerase Inhibitor Imetelstat Therapy in Refractory Anemia with Ring Sideroblasts with or without Thrombocytosis

Ayalew Tefferi, MD,1* Aref Al‐Kali, MD,1 Kebede H. Begna, MD,1 Mrinal M. Patnaik, MBBS,1T L L h PhD 1 Xi li W S D 2 Yi W PhD 3 d C ti A H MD4Terra L. Lasho, PhD,1 Xiaolin Wang, ScD,2 Ying Wan, PhD,3 and Curtis A. Hanson, MD4

1Division of Hematology, Mayo Clinic, Rochester, MN; 2Geron Corporation, Menlo Park, CA; 3Janssen Research & Development, LLC, Raritan, NJ; 4Division of Hematopathology, Mayo Clinic, Rochester, MN

@(hTR(hTERT)

MF (n=60)

MF Pilot Study (n=33)@(hTR)

Screening

Exploratory Cohorts (n=27)

Screening RARS/RARS-T (n=9)

Blast-Phase MF (n=9)

@Dose: Imetelstat, 2-hour intravenous infusion of 9.4 mg/kg every 3 weeks for Arm A and 9 4 mg/kg every week x 4 and then every 3weeks for Arm A and 9.4 mg/kg every week x 4 and then every 3 weeks for Arm B.

Tefferi A. et al ASH 2015

ASH-2015

Eltrombopag for the Treatment of Thrombocytopenia of Low and Intermediate-1 IPSS Risk Myelodysplastic Syndromes:

Aristoteles Giagounidis, MD, PhD1, Uwe Platzbecker, MD2, Ulrich Germing, MD3, Katharina Götze, MD4, g , , , , , g, , , ,Philipp Kiewe, MD5, Karin Mayer, MD6, Oliver Ottmann, MD7, Markus Radsak, MD8, Thomas Wolff, MD9,

Detlef Haase, MD10, Monty Hankin11, Dawn Wilson11, Xiaosha Zhang11, Adberrahmane Laadem, MD12, Matthew L. Sherman, MD11 and Kenneth M. Attie, MD11

Thrombopoietin receptor (TPOR) o bopo et ecepto ( O )agonists

Molecule

Eltrombopag Romiplostim

Oral, non-peptide agonist Peptide S.C. agonistMolecule

Binding site

Transmembrane domain of the TPOR and of c-MPL

different from TPO bindingExtracellular domain, same as endogenous TPO binding sitedifferent from TPO binding

siteendogenous TPO binding site

Endogenous No yesgTPO competitor No yes

Signal Different than that of Similar pathway of endogenous gtransduction endogenous TPO

p y gTPO

Study design

R d i ti

Eltrombopag

Wk 24Randomization 2:1

Patients

Eltrombopag+ Standard care

(n = 116)Eltrombopag

+ Standard careCR and R

(N = 174)

Placebo+ Standard care

(n = 58)Standard Care

Dose start: 50 mg with increases every 2 weeks up to 300 mg daily.

Mean changes in PLT counts at 8 and 24 weeksweeks

8 weeks 24 weeks8 weeks 24 weeks

Placebo PlaceboEltrombopag Eltrombopag

At 8 weeks median PLT counts increased from 18 (IQR 10-25) Gi/L to 44 (IQR (18-70) Gi/L in the eltrombopag arm vs no significant change in the placebo arm.