Myelodysplastic Syndromes

Guillermo Garcia-Manero, MDUniversity of Texas

MD Anderson Cancer CenterHouston, Texas

Natural History of MDS After Incorporation of HMAs

ProdromeICUS, CHIP

LR-MDS HR-MDS

AMLHMA failure?

HMA failureAML-like??

UntreatedHMA?lenalidomide

UntreatedHMA AML-likeSCT

HMA lower-risk failure survival: 14-17 monthsHMA higher-risk failure survival: 4-6 months

Jabbour E, et al. Cancer. 2015;121(6):876-882. Jabbour E, et al. Cancer. 2010;116(16):3830-3834. Steensma DP, et al. Blood. 2015;126(1):9-16.

AML, acute myeloid leukemia; CHIP, clonal hematopoiesis of indeterminate potential; HMA, hypomethylating agents; HR, high risk; ICUS, idiopathic cytopenias of undetermined significance; LR, low risk; MDS, myelodysplastic syndrome; SCT, stem cell transplant

Genomics of MDS

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

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

Frequency of Clonal Hematopoiesis

Comorbidities and MDSPrognosticFactor

Coefficient Score

Age >65 0.582 2

ComorbidityScore (ACE -27)

Mild or moderate

0.301 1

Severe 0.782 3

IPSS Int 2 0.512 2High 0.769 3

Naqvi K, et al. J Clin Oncol. 2011;29(16):2240-2246.

Fuster JJ, et al. Science. 2017;355(6327):842-847.

Clonal Hematopoiesis and Atherosclerosis

Implications of Clonal Hematopoiesis

• Abstract #115: (Severson et al): CHIP and solid tumors

• Abstract #421: (Molenar et al): TET2 mutations and atherosclerosis

• Abstract #424: (Madanat et al): Mutations and smoking

• Abstract #426: (Cook et al): CHIP and inflammation

Non-del5q- Lower-Risk MDS• Phase III CC-486 (oral azacitidine)• Attenuated schedules of HMA• Phase III oral decitabine E7727• Phase III ACE-536• PD1/PDL1 inhibition• Splicing inhibitors (H3Bio)• LSD1 inhibitor• antiCD38, antiCD123

Phase I Oral Aza Study Response to Therapy (N = 41)

DispositionMDS

N = 29N (%)

CMML N = 4 N (%)

AML N = 8N (%)

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)Garcia-Manero G, et al. Leukemia. 2016;30(4):889-896. Garcia-Manero G, et al. J Clin Oncol. 2011;29(18):2521-2527.

ResponseDAC

N = 70n (%)

AZA N = 39n (%)

P

CR 26 (37) 14 (36) .90mCR 6 (9) 2 (5)HI 17 (24) 3 (8)ORR 49 (70) 19 (49) .03SD 18 (26) 17 (44)PD 3 (4) 3 (8)

DAC vs AZA in LR-MDS: Response (IWG)

Median number of cycles: 9 (range: 1-41)Jabbour E, et al. Blood. 2017;130(13):1514-1522.

Jabbour E, et al. Blood. 2017;130(13):1514-1522.

DAC vs AZA in LR-MDS: OS

Successful Emulation of IV Decitabine Pharmacokinetics With an Oral Fixed-Dose Combination

of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine, in Subjects With Myelodysplastic

Syndromes (MDS): Final Data of Phase I Study

Garcia-Manero G, Odenike O, Amrein P, Steensma DP, DeZern A, Michaelis LC, Faderl S, Kantarjian H, Lowder JN, Taverna P, Oganesian

A, Zhang X, Azab M, Savona MR; ASTX727 Investigative Team

ASH 2016 Abstract 114

ASTX727 Phase I Results 5 Days Total DAC AUC: Oral/IV ASTX727 Oral Dose (mg) 5-Days Total (AUC last) % of AUC

Cohort DAC1 E7727 N Oral IV (Oral/IV)1 20 40 52 260 753 35%2 20 60 6 346 899 39%3 20 100 6 482 992 49%4 40 100 6 1120 775 144%5 30 100 193 701 852 85%

1DAC oral dose not adjusted by weight or BSA 2One significant outlier excluded from the PK analysis 3Includes 13-patient dose expansion

• Cohort 4 oral DAC (at 40 mg) exposure achieved primary objective and exceeded that of IV DAC at 20 mg/m2 (Oral/IV 144%)

• Cohort 5 oral DAC (at 30 mg) exposure was 85% of IV DAC at 20 mg/m2

• Oral DAC dose of 35 mg in ASTX727 (ongoing phase II) should achieve AUC of ~ 85%-140% of IV DAC

Garcia-Manero G, et al. Blood. 2016;128: Abstract 114.

• ASTX727 cohorts 4 and 5 achieved LINE-1 demethylation from baseline of >10% (comparable to historical data of DAC IV)

ASTX727 Phase I Results PD (LINE-1 Demethylation) by Cohort

Garcia-Manero G, et al. Blood. 2016;128: Abstract 114.

Luspatercept Increases Hemoglobin and Reduces Transfusion Burden in Patients With

Low-Intermediate Risk Myelodysplastic Syndromes (MDS): Long-Term Results From

Phase 2 PACE-MDS Study

Platzbecker U, Germing U, Gotze K, Kiewe P, Wolff T, Mayer K, Chromik J, Radsak M, Donovan E, Wilson DM, Zhang X, Laadem A, Sherman ML, Attie KM,

Giagounidis A

ASH 2016 Abstract 3168

Increase in Mean Hemoglobin in LTB Patients With >3 Months of Treatment (Extension Study)

LTB: Low transfusion burden patients (<4 units/8 wk, Hb <10 g/dL)

Months# patients

Hem

oglo

bin

Cha

nge

(SE)

Fro

m B

asel

ine

(g/d

L)4

3

2

1

0

• 16/22 (73%) HI-E responders; median time to response: 2.2 months

Data as of 09 Sep 2016Platzbecker U, et al. Blood. 2016;128: Abstract 3168.

LR-MDS

Transfusion dependent

Transfusion independent

AZA x 3 daysDAC X 3 daysAZAX 5 days

Observation

Early Intervention in LR MDS(US North American MDS Consortium)

NCT02269280. Funded Edward P Evans FoundationCleveland Clinic: M. Sekeres; Dana Farber Cancer Center: D. Steensma; Johns Hopkins: A Dezern; MD Anderson: Garcia-Manero; Moffitt Cancer Center: R Komrokji; Weill-Cornell: G Roboz

HMA Failure Lower-Risk MDS

• PD1/PDL1 inhibition

• Toll-like receptor inhibition: OPN-305

n events mos290 204 15290 201 17

LR MDS Post HMA Failure: Outcome

Jabbour EJ, et al. Cancer. 2015;121(6):876-882.

• Median follow-up: 16 (1-80) months• Median TFS and OS: 15 and 17 months

OPN-305 in MDS: Clinical Activity Response N (%)HI-E major 3 (20)HI-E minor 5 (33)Stable disease 4 (27)No response 2 (13)Progressive disease 3 (20)Too early 5 (25)Median number courses to response 2 (2-7)IWG 2006 criteria. 3 of 5 TE patients technically HI-E Major

8 (53)

Garcia-Manero G, et al. Blood. 2016;128: Abstract 227.

Higher-Risk MDS

• PD1/PDL1 Inhibition • SGI-110 (guadecitabine)• Ph II AZA +/- durvalumab• Ph II Aza + rigosertib• Ph II ruxolitinib + AZA• Aza + Abt-199

Initial Results of a Phase 2 Study of Guadecitabine (SGI-110), A Novel Subcutaneous Hypomethylating

Agent, for Patients With Previously Untreated Intermediate-2 or High Risk Myelodysplastic

Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Montalban-Bravo G, Bose P, Alvarado Y, Daver N, Ravandi F, Borthakur G, Takahashi K, Andreeff M, Cortes J, DiNardo C, Jabbour E, Kadia T, Kornblau S, Ohanian M, Alfonso A, Huang X, Nogueras-Gonzalez GM, Bodden K, Littles K,

Pierce S, Bueso-Ramos C, Kantarjian H, Garcia-Manero G

ASH 2016 Abstract 346

Response Category

Global [n = 44]N (%)

MDS [n = 38]N (%)

CMML [n = 6]N (%)

ORR 31 (71) 26 (68) 5 (83)CR 14 (32) 12 (32) 2 (33)mCR 14 (32) 11 (29) 3 (50)HI 3 (7) 3 (8) 0 (0)CR + mCR 28 (64) 23 (61) 5 (83)CCyR 7/33 (21) 7/28 (25) 0 (0)

• Median number of cycles: 6 (range 1-20)• Median number of cycles to response: 3 (range 1-6)• Median number of cycles to complete cytogenetic response: 4 (range 1-7)• Median response duration: 4 cycles (0-14)• Stopping rule for response not met

Montalban-Bravo G, et al. Blood. 2016;128: Abstract 346.

SGI-110: Response

Higher-Risk MDS HMA Failure• Ph III rigosertib• PD1/PDL1 inhibition• Ph II omacetaxine (Short et al, ASH 2017, Abstract #2967)

– ORR 34%– 7.6-month median survival– 22% 1-year OS

• Ph II CC-486• Aza+ABT-199 failures• SGI-110 failures

Targeting Hypomethylating Failure

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, et al. Lancet Oncol. 2016;17(4):496-508.

ONTIME Trial: Median Overall Survival for Patients 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

Garcia-Manero G, et al. Lancet Oncol. 2016;17(4):496-508.

Post-HMA HR-MDS (N = 225)

Key Eligibility Criteria:- Failed HMA <9 months DoT- <80 years of age

Randomization2:1

IV rigosertib +

BSCN = 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– α for ITT = .0397; α for IPSS-R VHR = .01– Trial can succeed in two ways

Physician’s Choice

+BSC

N = 75

Follow-up

Design of New Phase III INSPIRE Trial

29

02468

101214

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

Rel

ativ

e ex

pres

sion

Days on Therapy

PD-L1

Sequential PD1/PDL1 Activation Post HMA

0

10

20

30

40

50

60

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

Rel

ativ

e Ex

pres

sion

Days on Therapy

PD-1

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

Safety of Pembrolizumab in Patients With Myelodysplastic Syndrome After Failure of

Hypomethylating Agents: A Phase 1b Study

Garcia-Manero G, Tallman M, Martinelli G, Ribrag V, Yang H, Balakumaran A, Chlosta S, Zhang Y, Smith BD

ASH 2016 Abstract 345

• 3 (11%) patients experienced hematologic improvement– Erythroid response in 2 (7%) patients– Platelet response in 1 (4%) patient

aPer IWG 2006 criteriaData cut-off: May 27, 2016

Best Overall Responsea N = 27n % (90% CI)

Overall response rate 1 4 (0-16)

Complete response 0 0 (0-10)

Partial response 1 4 (0-16)

Bone marrow complete response 3 11 (3-26)

Stable disease 14 52 (35-69)

Progressive disease 9 33 (19-51)

Clinical Activity of Pembrolizumab

Garcia-Manero, et al. Blood. 2016;128: Abstract 345.

*SD as best response†Withdrew from study or was lost to follow-upData cut-off: May 27, 2016

0 20 40 60 80 100 120

mCR

PD

PR

Completed

DeathIPSS-HiIPSS-Intermediate-2IPSS-Intermediate-1

Missing

SD

†

†

†

Time of Last Assessment, Weeks

*

Exposure and Best Response

Garcia-Manero, et al. Blood. 2016;128: Abstract 345.

Phase II Study of Nivolumab or Ipilimumab With Azacitidine In

Patients With MDS

Garcia-Manero G, Daver N, Montalban-Bravo G, Jabbour E, DiNardo C, Kornblau S, Bose P, Alvarado Y, Ohanian M, Borthakur G, Cortes JE, Naqvi K, Pemmaraju N, Huang

X, Nogueras-Gonzalez GM, Bueso-Ramos CE, Gasior Y, Bayer VR, Pierce S, Yang H, Colla S, and Kantarjian HM

ASH 2016 Abstract 344

ICPI in MDS: Study DesignHMA Failure Cohorts Previously Untreated CohortsCohort #1: Single-agent nivolumab

Cohort #4: 5-azacitidine + nivolumab

Cohort #2: Single-agent ipilimumab

Cohort #5: 5-azacitidine + ipilimumab

Cohort #3: Combination nivolumab and ipilimumab

Cohort #6: 5-azacitidine + nivolumab and ipilimumab

• Each cohort max of 20 patients• In HMA failure cohorts: add back azacitidine after 6 cycles of ICPI if

no response• Stopping rules for toxicity and response

Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.

CR mCR NR PD SD HI-N HI-P TE ORR

Nivo [N = 15] 0 0 8 (53) 6 (40) 1 (6) 0

Ipi [N = 18] 1 (6) 2 (12) 9 (56) 2 (12) 2(12) 2 (11) 5 (30)

Aza+Nivo [N = 20] 6 (35) 6 (35) 2 (11) 2 (11) 1 (5) 3 (15) 13 (80)

Aza+IPI [N = 20] 6 (29) 4 (20) 2 (10) 2 (10) 2 (10) 1 (5) 3 (15) 13(62)

ICPI in MDS: Clinical Responses

Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.

Survival Nivolumab Cohort in MDS

Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.

Survival Ipilimumab Cohort in MDS

Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.

Survival Azacitidine and Ipilimumab Cohort

Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.

Results of a Phase II Study of Guadecitabine (SGI-110) in Higher Risk MDS, CMML or Low Blast Count AML Patients Refractory to or

Relapsing After Azacitidine (AZA) Treatment

Sebert M, Bally C, Peterlin P, Beyne-Rauzy O, Legros L, Gourin MP, Sanhes L, Wattel E, Gyan E, Park S, Stamatoullas A, Banos A, Laribi K, Jueliger S, Bevan L, Chaffaut C, Sapena R, Samey B, Chermat F, Chevret S, Ades L,

Fenaux P

ASH 2016 Abstract 347

Median OS of Responders: 19.7 mo

Median OS of Nonresponders : 5.7 mo

Survival

Sebert M, et al. Blood. 2016;128: Abstract 347.

• Median follow-up 11.9 months• Median OS from inclusion: 6.7 months (95% CI [5.6-11.8])

CLO and LDAC in HR MDS Post HMA: Survival by Response Status

Jabbour E, et al. Cancer. 2017;123(4):629-637.

FLT3 Inhibitors Under Development

Preclinical Phase I Phase II Phase III

VX-322 IMC-EB10 Sorafenib Midostaurin

VX-398 KW-2449 MLN-518 CEP-701

MC-2002 AP-24534 Quizartinib

MC-2006 CHIR-258 Crenolanib

PLX3397 FLX925

Ready to Open Targeted Trials in MDS

• IDH-2 inhibition (MDACC 2016-0981)

• Two ABT-199 MDS studies– AZA+ABT-199 front line– AZA+ABT-199 HMA failure MDS

Practical use of NGS in MDSGene Implication

CHIP/CCUS (DNMT3A, TET2,ASXL1,JAK2,SF3B1,P53,PPMD1)

ObservationIncreased risk of T-MN

P53 Favor HMAPoor outcome alloSCT

Flt-3 At HMA failure

IDH-2 Consider IDH2 inhibitor

IDH-1 Consider clinical trial

NPM1 Consider ARA-C based therapy

RAS At HMA failureConsider clinical trial

≥3 mutations Poor prognosis

Conclusion and Needs• Increased role of genomic annotation in MDS• New targets: CD33, CD123, Bcl-2, TGF-b, TLR, SF3B1,IDH, Flt-3,

NPM1• Lower-dose HMAs for lower-risk MDS• Potent oral forms of HMAs: CC-486, ASTX727• Second-generation HMAs: SGI-110• Combinations: + PD1/PDL1 inhibitors• 5 ongoing phase III trials: CC-486, rigosertib, ACE-536, SGI-110 for

failures, ASTX7727• Need: p53, RAS, transplant integration

49

Thanks!!ggarciam@mdanderson.org

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