11/3/2014

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Therapies For MDS: Where Are We Going?

David Steensma, MD FACPAssociate Professor of Medicine, Harvard Medical School

Adult Leukemia Program, Dana-Farber Cancer Institute

Hematological Oncology Service, Brigham & Women’s Hospital

Aplastic Anemia & MDS International Foundation Patient & Family ForumMiami Area – November 2014

Disclosures

Data monitoring committee: Amgen

Scientific advisory board: Genoptix, Celgene, Boehringer Ingelheim,

Off-label / experimental use: only azacitidine, decitabine and lenalidomide are FDA approved for MDS

How Are Patients With MDS Treated In November 2014?

Hypomethylating agents / DNA methyltransferase inhibitors /

epigenetic drugs

Azacitidine (Vidaza ®)Approved May 2004

Decitabine (Dacogen ®)Approved May 2006

Iron chelators

Lenalidomide (Revlimid ®)Approved December 2005

FDA Approved for MDS-Related Indications FDA Approved for Other Indications

Immunomodulatory drug (iMiD)

Deferasirox (Exjade ®)Approved November 2005

Blood cell (hematopoietic)growth factors

Epoetin alfa (Procrit ®)

Darbepoetin alfa (Aranesp ®)

Filgrastim, G-CSF (Neupogen ®)

Pegfilgrastim (Neulasta ®)

Red cell growth factors

White cell / myeloid growth factors

Romiplostim (NPlate ®)

Eltrombopag (Promacta ®)

Platelet growth factors

Immunosuppressive drugs (ATG, CsA)

Chemotherapy or stem cell transplant

Thalidomide, androgens, other biologicsDeferoxamine (Desferal ®)

Approved 1968

Medications currently commonly used for patients with MDS

A general approach to MDS

Cytopenia(s) Disease feature First-line therapy

Anemia only Del (5q) Lenalidomide

No del(5q), sEPO <500 ESA ± G-CSF

No del(5q), sEPO >500 ?Immunotherapy

Neutropenia or thrombocytopenia or both

None established; observation, growth factors, aza/decit reasonable

Lower-risk MDS (assessed using IPSS-R, etc.)

Higher-risk MDS

Allogeneic SCT candidate? Therapeutic approach

Yes Proceed to transplant ASAP; a hypomethylating agent (HMA) or cytotoxic chemotherapy may be useful as a “bridge”

No Azacitidine; decitabine as alternate

Supportive care for all (transfusions and antimicrobials PRN, ?iron chelation)

Partly based on 2014 NCCN guidelines; see www.nccn.org

What Are The Greatest Needs In The MDS Field?

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MDS clinical research priorities

• More accurate diagnostic methods– Current techniques are to some extent subjective– Molecular testing is helping in ambiguous cases

• Better prognostication– There are limits to this, but helps decide on therapy

• Better systems of health care delivery– In the US we use our health care dollars poorly /

inefficiently

• Improved therapy

Largest specific unmet therapeutic needs

• Increase proportion of aza/decitabine responders– Current complete response rate 10-20%– Current overall response rate 40-50%– Average duration of response 8-11 months– Need to increase also depth of response and duration

• Treatments for patients after aza/decitabine stop working

• Treatments for “higher” lower risk patients– Defined by molecular genetics or other features

• Who else does lenalidomide work for besides people with del(5q)?

• Other curative therapies besides transplant

Outcomes after azacitidine or decitabine failure of patients with MDS

Comparison to decitabine failures @ MDACC: median survival 4.3 months, n=87

Prébet T et al, J Clin Oncol 2011; Aug 20;29(24):3322-7. Epub 2011 Jul 25.Jabbour E et al, Cancer 2010; 116:3830–3834.

9% didn’t tolerate AZA (69% were not responding, 31% had an initial response)

55% “primary” failure (progression in 60% , stable disease without response in 40%)

36% secondary failure after initial response (best response: CR 20% , PR 7%, HI 73%)

Reasons for “failure” in azacitidine failure study

Outcomes after failure

Median overall survival for whole cohort post-AZA: 5.6 months

2 year survival: 15%

Favorable factors: female, younger (<60), better risk karyotype, <10% blasts, some response to azacitidine

• Data available on 435 pts – from AZA001, J9950, J0443, French compassionate program

• Overall median survival after azacitidine failure: 5.6 months

Prébet T et al J Clin Oncol 2011; 29:3322-7Jabbour E et al Cancer 2010;116(16):3830-4

Subsequent therapy Number of patients (%) Median survival

Allogeneic transplant 37 (9%) 19.5 months

Investigational therapy (e.g. IMiD, HDACi, other)

44 (10%) 13.2 months

Intensive cytotoxic therapy (e.g., 3&7)

35 (8%) 8.9 months

Low-dose chemotherapy (e.g. LDAC, 6-MP)

32 (7%) 7.3 months

Palliative / supportive care 122 (28%) 4.1 months

Subsequent therapy unknown 165 (38%) 3.6 months

Need for additional therapeutic options in MDS : Outcomes after azacitidine / decitabine failure are poor

Switch to the other hypomethylating agent (0 responses one European series, but 19-40% in H. Lee Moffitt series)

Continue the current therapy anyway, with or without adding a second agent (e.g. deacetylase inhibitor) – may delay progression

Supportive care only – feels like “giving up”

Clinical trial enrollment – lots of trips to major center

Off-label therapy (e.g., low-dose cytarabine, clofarabine) – doesn’t work very well overall

Allogeneic stem cell transplant – only a few pts eligible

Options when azacitidine or decitabine fail to produce a response, or after an initial response is lost…

Why Has Therapy of MDS Been So Challenging?

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Unlike leukemia, there are no widely useful MDS “cell lines”.

Several animal models now exist, but may not be

representative. This makes screening targeted agents more

challenging.

Images from medieval Bestiarum Vocabulum

Challenge #1 to narrowly

targeted therapies

Genetically modified mouse for disease modeling

Genomic architecture of MDS. Frequency of driver mutations identified in the sequencing

screen or by cytogenetics in the cohort of 738 patients, broken down by MDS subtype.

Papaemmanuil E et al. Blood 2013;122:3616-3627

Long “tail” of lesions present at

<2% level

Challenge #2 to developing

narrowly targeted therapies

TET221%

Epigenetic regulation

Proliferation

Other

Impaired Differentiation

EZH26%

JAK23%

NRAS

4%

ASXL114%

RUNX19%

TP538%

DNMT3A

(8%)

ETV63%

CBL 2%

KRAS1%

UTX 1%

IDH1/22%

NPM1(2%)

SF3B122%

GNAS(<1%)

BRAF(<1%)

PTEN(<1%)

PTPN11(<1%)

ATRX<1%

CDKN2A (<1%)

IPSS independent good prognosis

IPSS independent poor prognosis

No clear independent effect

ZRSR25%

SRSF211%

U2AF18%

Pre-mRNA splicing SF3A11%

PRPF40B1%

U2AF65<1%

SF11%

SETBP1

7%

MDS mutation landscape: Obvious targets are few

Targetable mutation

Time →

Clo

ne

size

→

Walter MJ et al N Engl J Med 2012; 366:1090-1098

Clonal architecture of MDS progression to AML: 6 patient examples

Challenge #4 to narrowly targeted

therapies

Painful.

Challenge #5 (to any new therapies)

Despite that, there are many new agents in development…

Bejar and Steensma, Blood 2014

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Really, a lot! (But not all agents are created equal)

Bejar and Steensma, Blood 2014

What Is Coming Next?

Predicting the future accurately is notoriously difficult. Where are our robot housekeepers, rocket trains, and flying cars?! Some themes

• Combination therapies – lots of “aza plus” studies ongoing or getting going

• Increased use of targeted therapies (even if targets not entirely understood)

• Using old drugs in new ways (e.g., oral formulations of azacitidine and decitabine, altered schedules)

• Greater use of allogeneic stem cell transplant –expanded donor pool and stem cell source options, bioengineered cellular products, older patients

New nucleoside analogues

• SGI-110: second-generation hypomethylating agent – dinucleotide of decitabine and deoxyguanosine

– delivered as a subcutaneous injection

– allows a longer half-life and more extended decitabine exposure

• 15 pts with Int-2/High risk MDS– Median age 74; all had previous aza/decitabine

– 5 responders (33%), duration 28-224 days

– Most common AE: injection site pain, diarrhea

O’Connell C et al, EHA 2013, abstract P189

N BM CR (+HI) HI ORR

All patients 32 6 (1) 4 10/32 (31%)

3-day infusions 17 4 (1) 3 7/17 (41%)

3-day pivotal (1800 mg/d) 13 4 (1) 2 6/13 (46%)

0 20 40 60 80

0

20

40

60

80

100

Weeks

Su

rviv

al p

rob

ab

ility

(%

)

BM Blast Response

Not Assessed

Progressive Disease

Stable BM Blast Count

50%+ BM Blast Decrease

OS by Marrow

Blast Response

Median:

68 wks

Raza et al. Blood 2011; 3822

Rigosertib after Azacitidine

Slide borrowed from Dr. Rami Komrokji

11/3/2014

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Rigosertib (ON01910.Na)randomized trial for post-HMA failure

Eligible patients:•MDS (FAB) with 5-30% blasts and at least one cytopenia; WBC < 25x109/L

•No response or progression after ≥6 cycles azacitidine or ≥4 cycles decitabine•Not an allogeneic stem cell transplant candidate, or refused transplant

•No low-dose cytarabine within last 2 years•Bilirubin <1.5 and creatinine <2 mg/dL

ON 01910.Na 1800 mg/24 hr as a 72-hr continuous infusionon Days 1, 2, and 3 of a 2-week cycle

Primary Endpoint:Overall survival

Secondary Endpoints:IWG 2006 response, AEs, etc

Best Supportive Care (BSC) or Low-Dose Cytarabine (LDAC)

Randomize 2:1

n=180

n=90

8 months median survival

6 months median survival

Oral rigosertib for lower-risk patients

• 34 evaluable patients– Transfusion dependent, IPSS Low/Int-1 MDS– 8 got continuous dosing, 26 intermittent

• Of intermittent dosing, 50% became transfusion independent– For 2 pts, this lasted >9 months

• Urinary adverse events most common– Urgency/frequency 38%– Dysuria 15%– Hematuria 15%– More common with continuous dosing

Raza A ASCO 2013 Abstract 7031

Eltrombopag vs Placeboin IPSS Low- or Intermediate-1–Risk MDS and low platelet count

receiving supportive care

• Phase II , national, multicentre, prospective, randomized, single blind study for patients with plt ct <30

Patients (N = 69)

Eltrombopag+ Standard care

(n = 46)

Placebo+ Standard care

(n = 23)

Wk 24Randomization 2:1

Eltrombopag+ Standard care

Standard Care

CR and R

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

Response EltrombopagN= 9

PlaceboN=5

Response, n 3 0

Complete Rresponse, n 5 0

NR 1 5

Total, n (%) 8 (89) 0 (0)

WHO bleeding grade ≥ 2, events 0 8*

Platelet responses at 16 weeks:

Time to Response:

•In 4 cases, early responses after 1 week;

•In 2 cases by 8 weeks and in 2 cases by 12 weeks.

Median daily eltrombopag dose eltrombopag at response was 75

mg (IQR 50-175 mg).

Combination Therapy

Example: At least 2 clinic trials in development combine:

Azacitidine+

Deferasirox (Exjade)

Approach: Improve upon existing therapies

Advantage: drugs are already FDA approved for MDS

Positive results can quickly change practice!

• Multicenter, single-arm open-label phase II continuation study (N = 36)

• Patient eligibility

– Higher-risk MDS: CMML-2, RAEB-1 or -2, IPSS intermediate 2 or high (score ≥ 1.5), or revised IPSS score 4 or 5

– No previous treatment with lenalidomide or azacitidine

• Maximum of seven 28-day treatment cycles administered

– Lenalidomide 10 mg on Days 1-21

– Azacitidine 75 mg/m2 on Days 1-5

– After 7 cycles, patients could continue azacitidine monotherapy off study

• Median patient follow-up: 12 mos (range: 3-55)

Sekeres MA, et al. Blood. 2012;120:4945-4951.

Lenalidomide + Azacitidine Trial

Slide borrowed from Dr. Rami Komrokji

11/3/2014

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• Median CR duration: 17+ mos(range: 3-39+)

• Median OS among CR: 37+ mos (range: 7-55+)

• 8 patients evolved to AML at median of 18 mos after CR

• Treatment well tolerated; FN was most common grade 3/4 AE (22%)

0

10

20

30

40

50

60

70

80

90

100

Lenalidomide/Azacitidine

(N = 36)

Res

po

nse

Rat

e (%

)

CR

Hematologic improvement

44

28

Lenalidomide + Azacitidine

Sekeres MA, et al. Blood. 2012;120:4945-4951.Slide borrowed from Dr. Rami Komrokji

Eligibility

Age ≥ 18 yearsUntreated MDS (≥ Int-1) or AMLAnd any of the following:

Total bilirubin ≥ 2 mg/dLCreatinine ≥ 2 mg/dLECOG performance status > 2Excluded from all other clinical trials:

– Presence of other active malignancy

Garcia-Manero et al. Blood 2011

Dose and schedule

AZA 75 mg/m2 IV QD days 1 to 5

Vorinostat 200 mg PO TID days 1 to 5

Cycles repeated every 28 days

Patients (N=30) CR (%) CRp (%) ORR (%)

ALL 8 (26) 1 (3) 30

Diploid (7) 3 (42) 0 42

-5/-7 (16) 3 (10) 1 (3) 13

+8 (3) 2 (66) 0 66

Azacitidine + Vorinostat combination trial in sicker patients

Slide borrowed from Dr. Rami Komrokji

Eligible:Higher-risk MDS or

CMML(5-19% blasts or IPSS Int-2/High)

Azacitidine monotherapy(7 days x 75 mg/m2/day)

Azacitidine + lenalidomide(10 mg/d for 21/28 days)

Azacitidine + vorinostat(600 mg/day)

Principal investigator: Mikkael Sekeres, Cleveland Clinic

n=80

n=80

n=80

Primary endpoint: overall response rate [ORR] (IWG 2006)Secondary endpoints: overall and progression-free survival, safety

Power:81% probability of

detecting a 20% difference in ORR (with alpha 0.05)

S1117 (US/Canada Intergroup) study

Altering the cytokine milieu

Previous attempts

• TNF alpha antagonists such as those approved for autoimmune conditions (etanercept, infliximab)

• Pentoxifylline/ciprofloxacin/dexamethasone

• Thalidomide

• Amifostine [thiophosphate free radical scavenger] (0 responses in Mayo trial)

• Siltuximab [anti-IL6 antibody] (2011-2012 75 patient randomized trial, 0 responses)

Phospho-Smad2 IHC

Zhou L, et al. BLOOD 2008; 112:3434.

the possibility that excessive activin receptor signaling contri-

butes to ineffective erythropoiesis and anemia in this disease.

A better understanding of activin receptor signaling in eryth-

ropoiesiswill requirestudieswith model systemsthat preserve

microenvironmental context and the complex network of

cellular interactions present in vivo.

2.2.2 Bone physiology and pathophysiology

Activins, inhibin, follistatin, and certain BMPsareimplicated

in the regulation of bone metabolism, but their respective

roles are still unclear. Activin A is produced by osteoblasts,

osteoclasts, and bone marrow cells, and there is agreement

that activin A promotesosteoclast development in vitro; how-

ever, the effect of activin on osteoblast development in vitro

variesdramatically depending on experimental conditions [32].

Thesimplest explanation for thesediscordant findingsmay be

that the net effect of activin A on osteoblastogenesis is criti-

cally dependent on microenvironmental context [32], in which

case the physiologic role of activin in bone would be most

reliably determined by inhibition of activin signaling in an

in vivo setting. Although administration of activin in vivo

stimulatesboneformation in rats, thesefindingsdo not neces-

sarily shed light on theroleof endogenousactivin. Asdescribed

below, activin A has been implicated as an important

mediator of bone loss in multiple myeloma.

There are also conflicting observations regarding bone

effects of inhibins, which are released by the gonads into the

circulation and also produced near their sites of action in

many tissues, including bone. In various cell-culture models,

inhibin blockstheboneeffectsof activin and BMPs [42], con-

sistent with its ability to antagonize these ligands in

cell-based assays [16]. Whereas inhibinscan suppressosteoblas-

togenesis and osteoclastogenesis in cell-culture systems [42],

transgenic expression of human inhibin A in mice increases

bone mass and strength [43]. It is unclear whether these ana-

bolic effectsof inhibin in vivoaredueto inhibition of activins,

BMPs, TGF-b, or a combination of these ligands, because

bone contains multiple BMPs and BMP-trapping proteins

II

Betaglycan

InhibinFollistatin

FLRG

IIII II II

ActRIIA ActRIIB

ALK4 ALK7 Other*

P

LY-2157299

Smad2 Smad3

Smad4

Sotatercept

Modified

propeptide

Neutralizing

antibody

Activins GDFs / BMPs*Exogenous Inhibitors

Smad6 Smad7

Gene expression

Figure 2. Act ivin receptor signaling pathw ay and exogenous inhibitors. Act ivins and some GDFs bind type II receptor (e.g.,

ActRIIA) with high af f inity and trigger format ion of a ternary complex with type I receptor (e.g., ALK4). Act ivated type I

receptor then phosphorylates Smad2/3 (regulatory Smads), which form a heteromeric complex with Smad4 (co-Smad) that

t ranslocates to the nucleus and regulates gene expression. Smad6/7 (inhibitory Smads) mediate feedback on kinase act ivity of

type I receptors, and small molecule inhibitors (e.g., LY-2157299) also target this act ivity in ALK4, ALK7, and ALK5. Sotatercept

is an ActRIIA fusion protein that sequesters act ivins and related ligands in a manner similar to that of the endogenous traps

follistat in and FLRG. Inhibins compet it ively inhibit binding of act ivins and BMPs to type II receptor (facilitated by betaglycan)

and thereby prevent assembly of act ive ternary complex. Neither neutralizing ant ibodies nor modif ied propept ide domains

related to this pathway have reached a clinical stage of development.

* ActRIIA/ActRIIB may mediate BMP signaling via the Smad1/5/8 pathway under some conditions.

ActRII: Activin receptor type II; ALK: Activin receptor-like kinase; BMP: Bone morphogenetic protein; FLRG: Follistatin-related gene; GDF: Growth and differentiation

factor; Smad: Protein homolog of SMA (small body size) in C. elegans and MAD (mothers against decapentaplegic) in Drosophila.

S. Z. Fields et al.

90 Expert Opin. Investig. Drugs (2013) 22(1)

Ex

pert O

pin

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Zhou L et al. Cancer Res 2011;71:955-963

Fields et al: Expert Opin. Investig. Drugs (2013) 22(1)

ACE-0536

Constitutive Activation of TGF-β Signaling Suppresses Hematopoiesis in MDS

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ACE-011

Extracellular Domain

Fc Domain

Human IgG1

ActivinReceptorType IIA(ActRIIA)

ACE-011 (Sotatercept)

• high affinity ActRIIA receptor fusion protein which act as a “ligand trap”

• sustained inhibition of Activin-A & TGF-β superfamily ligand

ACCELERON Pharma

Dose

1 2

ActRIIA

TGF-β Superfamily

Ligands

TGF-Family Regulation of Erythropoiesis by Activin-AErythroid Differentiation Factor

Do

se E

scal

atio

n

Dose Finding PhaseSotatercept

0.5 mg/Kg SC q 21 d

1 mg/Kg SC q 21 d

2 mg/Kg SC q 21 d

n=20

n=20

n=20

Eligibility- Low/Int-1

- WHO MDS

- MDS/MPN

- Hgb<9g/dl

Endpoints:1O - HI-E (IWG 2006)

2O - HI-E duration

- Progression

Ongoing Randomized Phase II Study of Sotatercept (ACE-011) in Lower Risk MDS

What About Stem Cell Transplant And

Immunotherapy? 800 to 1000 transplants in the

US annually for MDS indication

Genetic Predictors of ResponseAnalysis of MDS patients treated with stem cell

transplantation or hypomethylating agents

Rafael Bejar MD, PhD

ASH Oral PresentationDecember 10th, 2012

Kristen E. Stevenson MS

Petar Stojanov

J. Eric Zaneveld

Michal Bar-Natan MD

Bennett Caughey

Hui Wang PhD

Guillermo Garcia-Manero MD

Hagop M. Kantarjian, MD

Corey Cutler MD, MPH

Jerome Ritz MD

Kristian Cibulskis

Gad Getz PhD

David P. Steensma MD

Richard M. Stone MD

Rui Chen PhD

Donna S. Neuberg ScD

Benjamin L. Ebert MD, PhD

MDS Cohorts and Sequencing Methods

Eric Zaneveld - Hui Yang - Rui ChenBennett Caughey & Mick Correll

Stem Cell Transplant CohortHaloPlex PCR

Hypomethylating Agent Cohort48-plex sheared DNA libraries

Realignment and Analysis using GATK pipeline at the Broad Institute

Petar Stojanov

ASXL1 DNMT3A GNAS LUC7L2 NOTCH2 PTPN11 TET2

ATRX EED IDH1 MAML1 NPM1 RUNX1 TP53

BCOR ETV6 IDH2 MPL NRAS SF3A1 U2AF1

BRAF EZH2 JAK2 MYBL2 PHF6 SF3B1 U2AF2

CBL FLT3 KIT NF1 PRPF40B SRSF2 WT1

CBLB GATA2 KRAS NOTCH1 PRPF8 SUZ12 ZRSR2

Targeted the coding regions of

74 genes including 42 known to

be mutated in MDS

Illumina HiSeq 2000

Agilent SureSelect

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SCT Cohort – Treatment Outcomes

Kristen Stevenson and Donna Neuberg

Gene

Adjusted

HR

(95% CI)

p-value

TP53 (n = 14)3.90

(1.85, 8.22)<0.001

DNMT3A (n = 14)3.54

(1.45, 8.64)0.005

TP53 and DNMT3A Mut Absent (n=46)

TP53 or DNMT3A Mut Present (n=26)

p < 0.001

Overall Survival After Transplant

HR for Overall SurvivalImmune Reconstitution after Stem Cell Transplantation

Primary areas for translational research

– Develop new ways to enhance reconstitution of donor stem cells to reduce the risk of infection

– Develop new approaches to manipulate the immune system to prevent and treat GVHD

– Develop new methods to enhance graft-versus-leukemia (GVL) and reduce the risk of relapse after transplant

Immune Reconstitution after Stem Cell Transplantation

Develop methods to isolate virus-specific T cells from stem cell transplant donors

e.g Anti-CMV, anti-EBV

Monitor immune reconstitutionin transplant patients to identify mechanisms of immune tolerance

Develop bio-engineered leukemia vaccines to enhance GVL

Prodigy®

CyTOF®

WDVax

Adaptive Immnotherapy

Chimeric Antigen Receptor Modified T-cell

Tumor Cell

MDS Cell

Cytotoxic T lymphocyte

GVAX: GM-CSF Secreting Tumor Cell Vaccine

• Collect MDS cells prior to transplant

• In the laboratory, treat the sick MDS cells to make them a target for the donor’s immune system (GM-CSF transduction)

• Generate vaccine

• Give vaccine after transplant to reduce risk of relapse

• Trials ongoing…

If I can help…

david_steensma@dfci.harvard.edu

or

dsteensma@partners.org

(617) 632-3712

11/3/2014

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Sarah Cahill PA-CKatherine Edmonds NPAdriana Penicaud PA-CSusan Buchanan PA-CIlene Galinsky NP &

Clinical Research CoordinatorsRegulatory Team

DFCI Adult Leukemia Clinical Program:Richard Stone MD

Daniel Deangelo MD PhDMartha Wadleigh MD

Gregory (Goyo) Abel MD MPH (pop sci)R. Coleman Lindsley MD PhD

(translational)

Harvard Medical School quadrangleDana-Farber Cancer Institute

Thank you!