Update on MDS 2015 - prIME Oncology · Analysis of Combined Datasets From the International Working Group for MDS-Molecular Prognosis Committee Rafael Bejar, MD, PhD Elli Papaemmanuil,

Clinical Update on MDS 2015

Guillermo Garcia-Manero MD

Section of MDS

Department of Leukemia

University of Texas

MD Anderson Cancer Center

Houston, Texas

Natural History of MDS After

Incorporation of HMAs

Prodrome

ICUS, CHIP

LR-MDS HR-MDS

AML

HMA failure

?HMA failure

AML-like?

?

Untreated

HMA?

Lenalidomide

Untreated

HMA

AML-like

SCT

HMA lower-risk failure survival: 14-17 months

HMA higher-risk failure survival: 4-6 months

Jabbour EJ, et al. Cancer. 2015;121(6):876-882. Jabbour EJ, et al. Cancer. 2010;116(19):3830-3834. Steensma DP, et

al. Blood. 2015;126(1):9-16.

Papaemmanuil E, et al. Blood. 2013;122(22):3616-3627.

Genomics of MDS

Somatic Mutations in MDS Are Associated With Clinical

Features and Predict Prognosis Independent of the IPSS-R

Analysis of Combined Datasets From the International

Working Group for MDS-Molecular Prognosis Committee

Rafael Bejar, MD, PhD

Elli Papaemmanuil, PhD

Torsten Haferlach, MD

Seishi Ogawa, MD, PhD

Guillermo Garcia-Manero, MD

Jaroslaw P. Maciejewski, MD, PhD

Mikkael A. Sekeres, MD, MS

Matthew J. Walter, MD

Timothy A. Graubert, MD

Mario Cazzola, MD

Luca Malcovati, MD

Pierre Fenaux, MD, PhD

Eva Hellstrom-Lindberg, MD, PhD

Wolfgang Kern, MD

Jacqueline Boultwood, PhD

Andrea Pellagatti, PhD

David Bowen, MD, PhD

Sudhir Tauro, PhD

Michael J Groves, PhD

Paresh Vyas, MD, PhD

Lynn Quek, MD

Aziz Nazha, MD

Felicitas Thol, MD

Michael Heuser, MD

Lee-Yung Shih, MD

Yasunobu Nagata, MD, PhD

Yusuke Okuno, MD, PhD

Eric Padron, MD

David Sallman, MD

Rami S. Komrokji, MD

Alan F. List, MD

Detlef Haase, MD, PhD

Julie Schanz, MD

Valeria Santini, MD

Michaela Fontenay, MD, PhD

Peter J Campbell, MD, PhD

Heinz Tüchler

Kristen Stevenson, MS

Donna S Neuberg, ScD

Peter Greenberg, MD

Benjamin L Ebert, MD, PhD

On behalf of the IWG for MDS

investigators

Bejar R, et al. Blood. 2015;126: Abstract 907.

Y e a r s

Ov

era

ll S

urv

iva

l (%

)

0 2 4 6 8 1 0 1 2 1 4

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

0 (n = 3 7 7 )

1 (n = 5 9 5 )

2 (n = 4 6 0 )

3 (n = 2 1 0 )

4 (n = 1 2 5 )

5 /6 /7 (n = 2 2 )

S F 3 B 1 o n ly (n = 2 0 7 )

N u m b e r o f M u ta te d G e n e s

Overall Survival by Mutation Number

17 Genes Sequenced in 1996 Patients With OS DataASXL1

CBL

DNMT3A

ETV6

EZH2

IDH1

IDH2

JAK2

KRAS

NPM1

NRAS

RUNX1

SRSF2

TET2

TP53

U2AF1

SF3B1Bejar R, et al. Blood. 2015;126: Abstract 907.

Mutated Genes and Clinical Phenotypes

Mutation

Frequency

26%

0.5%

<.0001

P value

adverse

<.0001

P value

favorable

.01

.01

Gene%

MutFAB WHO

IPSS-

R

Blast

% Plts Sex Age ANC Hgb OS

TP53 8.9

ASXL1 21

SRSF2 15

U2AF1 8.9

NRAS 3.6

RUNX1 10

STAG2 5.6

IDH2 3.4

KRAS 2.3

NPM1 1.5

BCOR 4.7

TET2 26

ZRSR2 6.4

EZH2 5.9

CBL 4.4

RAD21 1.3

PTPN11 1.5

GATA2 1.3

NF1 4.5

ETV6 2.6

PRPF8 2.4

FLT3 0.9

IDH1 2.3

PHF6 2.9

GNAS 0.9

WT1 1.2

ATRX 2.1

U2AF2 1

SMC3 1.3

KIT 1.1

MPL 1.8

DNMT3A 12

JAK2 3.6

SF3B1 22


Final Multivariable Survival Model

HR P value

IPSS-R Risk Groups (vs Very

Low)

Low 1.08 .542

Intermediate 1.97 <.0001

High 2.56 <.0001

Very High 4.36 <.0001

Mutated Genes (vs

Unmutated)

TP53 2.35 <.0001

RUNX1 1.51 .0002

EZH2 1.58 .0006

NRAS 1.44 .019

SF3B1 0.82 .041

CBL 1.35 .056

U2AF1 1.22 .069

ASXL1 1.17 .090

TET2 0.88 .104

IDH2 1.31 .111

KRAS 1.22 .362

NPM1 1.2 .546

Hazard Ratio (95% CI)


Clinical Implications of Genomics in MDS• Whole-exome sequencing of 114 untreated MDS patients

• Independent prognostic value of TP53 mutations

• Four or more driver mutations independently prognostic in MDS.

Takahashi H, et al. Blood. 2015;126: Abstract 3940. Takahashi H, et al. Oncotarget. [In Press].

Somatic Mutations in “Normal” Individuals

Jaiswal S, et al. N Engl J Med. 2014;371(26):2488-2498.

Can We Predict Development of

Therapy-Related MDS?

Wong TN, et al. Nature. 2015;518(7540):552-555.

4 years

Small cell lung ca

Limited stage t-MDS

XRT+ 4 cycles of cisplatin + etoposide

BMPB

0

20

40

60

80

SCLCt-MDS

VA

F (

%)

4 years

SCLC t-MDS

TP53 p. H193R 24 73

UID36491

Takahashi E, et al. Blood. 2015;126: Abstract 1663.

6 years

Rectal adenocarcinoma

T2N0M0 t-MDS

XRT+ capecitabine

BMPB

0

10

20

30

40

50

Rectal Cancert-MDS

VA

F (

%)

6 years

Rectal Cancer t-MDS

TET2 p.L1212* 6 45

UID4473


3 years

Small cell lung cancer

Limited stage t-AML

XRT+ 4 cycles of carboplatin + etoposide

BMPB

0

10

20

30

40

50

SCLCt-AML

VA

F (

%)

3 years

SCLC t-AML

IDH2 p.R140Q 14 46

UID6982


Adult Murine Hematopoiesis

LYMPHOID

PROGENITOR

COMPARTMENT

= KLMYELOID

PROGENITOR

COMPARTMENT

ERYTHROCYTES

ST-HSC

MP

P

LMPP

CLP

LT-HSC

CMP

GMPMEP

PRO T-CELL PRO B-CELLPLATELETS MONOCYTESGRANULOCYTES

Lin-ckit+sca1+CD34-CD135-

Lin-ckit+sca1+CD34+CD135-

Lin-ckit+sca1+CD34+CD135+

Lin-ckit+sca1-

CD34+CD16/32-

Lin-ckit+sca1-

CD34-

CD16/32-

Lin-ckit+sca1-

CD34+CD16/3

2+

Lin-ckit+sca1+CD34+CD135bright

Iwasaki H, et al. Immunity. 2007;26(6):726-740.

= KSLHSC

COMPARTMENT

N=2

Short-Term in TERT-ER Mice: Effect Aza on HSPC

0

5 0

1 0 0

1 5 0

2 0 0

L T -H S C

Ce

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um

be

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we

igh

t-n

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on

tro

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0)

G 0

V e h ic leA Z A

G 5

A Z AV e h ic le

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

S T -H S C

Ce

ll n

um

be

r (

we

igh

-no

rm

ali

ze

d

an

d r

ela

tiv

e t

o C

on

tro

l G

0)

4 1 8 0

G 0

V e h ic leA Z A

G 5

A Z AV e h ic le

*

0

5 0

1 0 0

1 5 0

C M P

Ce

ll n

um

be

r (

we

igh

t-n

orm

ali

ze

d

an

d r

ela

tiv

e t

o C

on

tro

l G

0)

G 0

V e h ic leA Z A

G 5

A Z AV e h ic le

3 9 8 4****

**

****

0

5 0

1 0 0

1 5 0

2 0 0

G M P

Ce

ll n

um

be

r (

we

igh

t-n

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0)

G 0

V e h ic leA Z A

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3 9 9 6

3 9 8 4

****

****

**

Colla S, et al. Cancer Cell. 2015;27(5):644-657. Gañán-Gómez I, et al. Blood. 2015;126: Abstract 2852.

MDS

Low risk

(IPSS low, INT-1)

(BM blasts < 10%)

High risk

(IPSS INT-2, high)

(BM blasts > 10%)

• Iron chelation

• Growth factors

(Epo + G-CSF)

• MTI (5-AZA/decitabine)

• Lenalidomide (5q-)

• Immunomodulation

• Clinical trial

Age <60

• Intensive chemotherapy


• Clinical trial

Age ≥60


• Clinical trial

• Intensive chemotherapy1

1Consider in younger patients

with diploid cytogenetics2 Consider earlier in younger

patients

Failure/

Progression

Allo SCT

Proposed Treatment Algorithm for

Patients With MDS

Any age

Atallah E, et al. Cancer Invest. 2008;26(2):208-216.

Giagounidis A, Platzbecker U, Germing U, Götze K, Kiewe P, Mayer KT, Ottmann O,

Radsak M, Wolff T, Haase D, Hankin M, Wilson D, Zhang X, Laadem A, Sherman

ML, Attie KM

D·MDS Deutsche MDS-Studiengruppe

Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients With Low or

Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results From the Phase 2

PACE-MDS Extension Study

Giagounidis A, et al. Blood. 2015;126: Abstract 92.

Abstract 92

Luspatercept in MDS: Background

Erythropoiesis

TGF-β Superfamily

Ligands: GDF11, etc.

Smad2/3

Suragani RN, et al. Nat Med. 2014;20(4):408-414. Zhou L, et al. Blood. 2008;122(2):308-319.

Luspatercept

Fusion protein containing

modified activin receptor

type IIB (ActRIIB)

Activin Receptor

Domain

Human IgG Fc

Domain

• Mechanism is distinct from

erythropoietin

• Acts on late-stage

erythropoiesis to increase

mature RBCs in the

circulation

Efficacy Summary: HI-E Response Rate

Patient Subgroup

0.125-0.5 mg/kg

(N = 9)

n (%)

0.75-1.75 mg/kg

(N = 17)

n (%)

LTB patients (N = 7) 0/2 (0%) 2/5 (40%)

HTB patients (N =

19)2/7 (29%) 5/12 (42%)

All patients (N = 26) 2/9 (22%) 7/17 (41%)

HI-E (IWG):

LTB: Hemoglobin increase ≥1.5 g/dL for ≥8 weeks

HTB: Reduction of ≥4 units RBCs transfused over 8 weeks

HI-E, hematologic improvement-erythroid

IWG, International Working Group

LTB, low transfusion burden; HTB, high transfusion burden

Data as of 03 Oct 2014

Giagounidis A, et al. Blood. 2015;126: Abstract 92.

Low-Dose Hypomethylating Agents Are

Effective in Patients With Low- or

Intermediate-1-Risk Myelodysplastic

Syndrome: A Report on Behalf of the MDS

Clinical Research Consortium

Short N, Garcia-Manero G, Montalban Bravo G, Sasaki K, Sekeres M,

Komrokji R, Steensma D, DeZern A, Roboz G, Kadia T, Borthakur G,

DiNardo C, Miller D, Estrov Z, Pemmaraju N, Daver N, Verstovsek S,

Kantarjian H, Jabbour E

Short N, et al. Blood. 2015;126: Abstract 94.

Abstract 94

Response N (%)

CR 33 (36)

mCR 8 (9)

HI 13 (14)

ORR 54 (59)

SD 31 (34)

PD 6 (7)

Low-Dose HMAs in LR-MDS:

Response

• Median time to best response: 2 months (range: 1-20)

• Median number of cycles received: 9 (range: 2-32)


Transfusion Dependence

at BaselineN

Transfusion Independence

N (%)

RBCs 34 10 (29)

Platelets 5 3 (60)

RBCs + platelets 5 1 (20)

Total 44 14 (32)


Transfusion Response



Cytogenetic Response (N = 38)

Cytogenetic Response N (%)

CCyR 8 (21)

PCyR 11 (29)

NR 19 (50)



Survival

Median, mos 1-year rate, %

EFS 20 62

OS NR 86


Phase I Oral Aza Study

Response To Therapy (N = 41)

Disposition

MDS (N = 29)N (%)

CMML (N = 4) N (%)

AML (N = 8)N (%)

Ongoing 8 (28) 2 (50) 2 (25)

Terminated 21 (72) 2 (50) 6 (75)

Median duration of oral therapy,

# of cycles, (range) 6.0 (1–23+) 7.0 (3–17+) 4.5 (1– 14+)

Cycle 7 Response Assessment* 13 (45) 2 (50) 2 (25)

CR / PR / HI 4 (31) 1 (50) 0 (0)

SD 8 (61) 1 (50) 2 (100)†

Progression 1 (8) 0 (0) 0 (0)*IWG 2003 or 2006†Subjects did not meet criteria for progression or response by IWG 2003


Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC ,

Faderl S, Griffiths E, Harb WA, Tibes R, O’Connell C, Redkar S, Lowder JN,

Taverna P, Oganesian A, Nawabi R, Azab M, Garcia-Manero G

Results of First in Human (FIH) Phase 1

Pharmacokinetic (PK) Guided Dose-

Escalation Study of ASTX727, a

Combination of the Oral Cytidine Deaminase

Inhibitor (CDAi) E7727 With Oral Decitabine,

in Subjects With Myelodysplastic

Syndromes (MDS)

Savona M, et al. Blood. 2015;126: Abstract 1683.

Abstract 1683

Study DesignASTX727-01: Phase I Dose Escalation Cohorts


Decitabine PK Profile, IV vs Oral,

Without/With CDAi


• ASTX727 cohorts 4 and 5 achieve LINE-1 demethylation

>10%

Pharmacodynamics:ASTX727-01 LINE-1 Demethylation: Overall

Summary for 5 Cohorts


Time on Study and to Response


Early Intervention in MDS

NCT02269280

LR-MDS

Transfusion dependent

Transfusion independent

AZA x 3 days

DAC x 3 days

AZA x 5 days

Observation

Multicenter via Evans MDS Consortium

TP53 Mutation Effect on HMA

Therapy in MDS

Takahashi H, et al. Blood. 2015;126: Abstract 3940. Takahashi H, et al. Oncotarget. [In Press].

Randomized Phase II Study of SGI-110 in MDS/CMML1

Biologically Effective

Dose

60 mg/m2 daily x 5

Highest Well Tolerated

Dose 90 mg/m2 daily x 5

R

A

N

D

O

M

I

Z

A

T

I

O

N

• Primary endpoint: Overall response rate (CR, PR, mCR, HI)

• Secondary endpoints: Transfusion independence, LINE-1 demethylation,

time to AML, overall survival

IWG 2006

MDS

Response

Criteria

Treatment continued until unacceptable toxicity, disease progression

Major Eligibility

Previously Treated

MDS/CMML

or

Treatment-Naïve

MDS/CMML

• IPSS Int-1,2

and HR

• ECOG PS 0-2

• Adequate

hepato-renal

function

1 Data presented with data cutoff end of July 2014

Garcia-Manero G, et al. Blood. 2015;126: Abstract 529.

A Final Report: Phase I/II Study of

Sequential Azacitidine (AZA) and

Lenalidomide (LEN) in Patients With

Higher-Risk MDS and AML

DiNardo CD, Daver N, Jabbour E, Kadia T, Borthakur G,

Konopleva M, Pemmaraju N, Yang H, Wei Y, Pierce S, Wierda W,

Bueso-Ramos C, Patel KP, Cortes JE, Ravandi F, Kantarjian HM,

Garcia-Manero G

MD Anderson Cancer Center

DiNardo CD, et al. Lancet Haematol. 2015;2(1):e12-20.

AZA + LEN Response

Phase I N = 28 CR CRi ORR Median

OS, wks

Median

Courses

Response

Duration, wks

LEN DOSE

<25 mg 11 0 0 0% 12 3 (1-6) NA

25 mg 3 2 0 67% NR 6 (6-12) 81 (35-127)

>25 mg 14 2 0 14% 16 2.5 (1-12) 81 (78-85)

Phase I PTS 28 4 0 14%

(P = .014)

17 3 (1-12) 81 (35-127)

Phase II N = 60 CR CRi ORR Median

OS, wks

Median

Courses

Response

Duration, wks

LEN DOSE

IIa: 50 mg 20 2 3 25% 21 2 (1-12) 18 (2-98)

IIb: 25 mg 40 9 13 55% 75 4 (1-16) 27 (2-71)

Phase II PTS 60 11 16 45%

(P = .029)

60 3 (1-16) 24 (2-98)

Phase I + II N = 88 15 16 35%* 33 3 (1-16) 29 (2-127)

*13 of 31 responding patients went on to SCT; 10 of 13 continue in sustained CR

DiNardo CD, et al. Lancet Haematol. 2015;2(1):e12-20.

Garcia-Manero G, Berdeja JD, Komrokji RS, Essell J, Lyons RM,

Maris M, DeZern AE, Sekeres MA, Roboz GJ

A Randomized, Placebo-Controlled,

Phase II Study of Pracinostat in

Combination With Azacitidine (AZA) in

Patients With Previously Untreated

Myelodysplastic Syndrome (MDS)

Garcia-Manero G, et al. Blood. 2015;126: Abstract 911. Garcia-Manero G, et al. Blood. 2015;126: Abstract 2861.

Sekeres M, et al. Blood. 2015;126: Abstract 908.

Abstract 911

Aza + Pracinostat in MDS: Overall Survival

Median Follow Up = 15.4 months

One Year Survival: Pracinostat = 57.1%

Placebo = 57.4%

HR = 1.21


Garcia-Manero G, Atallah E, Medeiros B, Arellano M, Khaled SK,

Patnaik M, Odenike O, Sayar SH, Tummala MK, Patel P, Maness-

Harris L, Stuart R, Traer E, Karamlou K, Yacoub A

Final Results From a Phase II

Study of Pracinostat in

Combination With Azacitidine

in Elderly Patients With Acute

Myeloid Leukemia (AML)

Abstract 453

Aza + Pracinostat in AML: Overall Survival

EFS: 7.7 months (0.9-21.2+); 1-year survival 62%Garcia-Manero G, et al. Blood. 2015;126: Abstract 453.

A Phase II Study of the

Combination of Oral Rigosertib

and Azacitidine in Patients With

Myelodysplastic Syndromes (MDS)

Navada SC, Silverman LR, Hearn K,

Odchimar-Reissig R, Demakos E, Alvarado Y, Daver N, DiNardo C,

Konopleva M, Borthakur G, Fenaux P, Fruchtman S, Azarnia N,

Garcia-Manero G

Navada S, et al. Blood. 2015;126: Abstract 910.

Abstract 910

Combination Trial Design

Sequence Suggested by Preclinical Findings

Treatment Regimen:

Week 1: Oral rigosertib BID

(560 mg AM/280 mg PM)

Week 2: Oral rigosertib +

azacitidine (75 mg/m2/day

SC or IV)

Week 3: Oral rigosertib BID

Week 4: No treatment

Week 1

Oral

Rigosertib

only

Week 4

No Treatment

Week 2

Oral Rigosertib

+

Azacitidine

(SC or IV)

Week 3

Oral

Rigosertib

only


Efficacy Results Number of MDS patients treated

Evaluable for response (8 Ph1, 22 Ph2)

37

30

Overall response 23 (77%)

Hematologic

response*

Complete remission

Partial remission

Marrow CR

Stable disease

Progressive disease

6 (20%)

0

16 (53%)

6 (20%)

1 (3%)

Hematologic improvement* 1 (3%)

Not evaluable 3 (10%)

Too early to evaluate 4 (13%)

Median duration of treatment (months) 4 (1-27+)* Per IWG 2006


Efficacy: MDS Patients With Prior HMA Failure

Number of patients evaluable for

response (3 Ph1, 8 Ph2)

11

(8 AZA, 2 DAC, 1 both)

Number of prior HMA cycles 4-20

Hematologic response per IWG 2006 7 (64%)

CR 1

PR 0

mCR 4

mCR with concurrent HI 2

Stable disease 3

Progressive disease 1

Hematologic improvement (trilineage) 3

HMA-naïve patients (N = 19) response

per IWG16 (84%)


Overall Survival and Subgroup

Analysis From a Randomized Phase

III Study of Intravenous Rigosertib vs

Best Supportive Care in Patients

With Higher-Risk Myelodysplastic

Syndrome After Failure

of Hypomethylating Agents

(ONTIME Trial of ON 01910)

Garcia-Manero G, Fenaux P, Al-Kali A, Baer MR, Sekeres M, Roboz G, Gaidano G,

Scott B, Greenberg P, Platzbecker U, Steensma DP, Kambhampati S, Godley L,

Collins R, Atallah E, Wilhelm F, Darnis-Wilhelm I, Azarnia N, Maniar M,

Silverman LR, for the ONTIME Investigators

Garcia-Manero G, et al. Blood. 2014;124: Abstract 163. Garcia-Manero G, et al. Lancet Oncol. [In press].

ONTIME Trial: Median Overall Survival for Pts With

Primary HMA Failure - Blinded, Centralized Assessment

Per Prebet 2011, “Primary HMA Failure” was defined as either no response to or

progression during HMA therapy


Post-HMA HR-MDS (N = 225)

Key Eligibility Criteria:

- Failed HMA < 9 months DoT

- < 80 years of age

Randomization

2:1

IV rigosertib

+

BSC

N = 150

Overall Survival

- Interim analysis

(86 events)

- Intent-to-treat

analysis

(171 events)

• Stratification at randomization

Very High Risk vs other IPSS-R

US vs Europe vs Asia

• Statistical analysis

– for ITT = 0.0397; for IPSS-R VHR = 0.01

– Trial can succeed in two ways

Physician’s

Choice

+

BSC

N = 75

Follow-up

Design of New Phase III INSPIRE Trial

0

5

10

15

20

0 2 3 5 6 8 10 11 15 17 21 22 24 28 31

Rel

ativ

eex

pre

ssio

n

Days on Therapy

20

40

60

0 2 3 5 6 8 10 11 15 17 21 22 24 28 31

PD-L2

0

2

4

6

8

10

12

14

0 2 3 5 6 8 10 11 15 17 21 22 24 28 31

Rela

tiv

e e

xp

ressio

n

Days on Therapy

PD-L1

0

20

40

60

80

100

0 2 3 5 6 8 10 11 15 17 21 22 24 28 31

Rela

tiv

e E

xp

ressio

n

Days on Therapy

CTLA4

0

1 0

2 0

3 0

4 0

5 0

6 0

0 2 3 5 6 8 1 0 1 1 1 5 1 7 2 1 2 2 2 4 2 8 3 1

Relat

iveExp

ressio

n

D a y s o n T h e r a p y

6 0

8 0

1 0 0

1 2 0

1 4 0

1 6 0

1 8 0

2 0 0

0 2 3 5 6 8 1 0 1 1 1 5 1 7 2 1 2 2 2 4 2 8 3 1

P D - 1

Dynamics of PD-L1, PD-L2, PD-1 and CTLA4 Expression in

Patients Treated With Different Forms of Epigenetic Therapy

Yang H, et al. Leukemia. 2014;28(6):1280-1288.

Effect of Mutations on SCT Outcomes

Gene

Adjusted

HR

(95% CI)

P

value

TP53 (n = 14)3.90

(1.85, 8.22)<.001

DNMT3A (n =

14)

3.54

(1.45, 8.64).005

TP53 and DNMT3A Mut Absent (n = 46)

TP53 or DNMT3A Mut Present (n = 26)

P<.001

Overall Survival After Transplant

HR for Overall Survival

Bejar R, et al. J Clin Oncol. 2014;32(25):2691-2698.

Assessing Risk Post SCT in MDS

• Genomic analysis may allow risk SCT assessment in MDS

• German study of N = 308 pts (MDS/AML)

• 54-gene panel

• Median age 58 (19-75)

• 75% of patients active disease at SCT

• Complex cytogenetics, IDH2, NRAS, PTPN11, PHF6 poor risk factors

• P53 negated by complex cytogenetics

• Haploidential SCT and transplant not in response also poor predictors

Heuser M, et al. Blood. 2015;126: Abstract 912. Yoshizato T, et al. Blood. 2015;126: Abstract 711. Bejar R, et al.

J Clin Oncol. 2014;32(25):2691-2698.

In Conclusion

• Increased role of genomic annotation in MDS:

– IDH1, IDH2, RAS, Flt-3, and SCT

• Better understanding of cellular effect of HMAs

• Newer agents: antiCD33, antiCD123, ABT-119, TGF-b inhibitors

• Lower-dose HMAs for lower-risk MDS

• Potent oral forms of HMAs: CC-486, ASTX727

• Second-generation HMAs: SGI-110

• Combinations: + PD1/PDL1 inhibitors??

• Rigorsetib for HMA failures

• 3 ongoing phase III trials: CC-486, Rigosertib, ACE-536

Documents

Update on MDS 2015 - prIME Oncology · Analysis of Combined Datasets From the International Working Group for MDS-Molecular Prognosis Committee Rafael Bejar, MD, PhD Elli Papaemmanuil,