Myelodysplastic syndromes update
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Myelodysplastic Syndromes Update. Richard M. Stone, MD Director, Adult Leukemia Program Dana-Farber Cancer Institute and Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, MA. Dana-Farber Cancer Institute. Dana/Mayer Building (Office). Yawkey Center (Clinic).

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Myelodysplastic Syndromes Update

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Myelodysplastic syndromes update

Myelodysplastic Syndromes Update

Richard M. Stone, MD

Director, Adult Leukemia Program

Dana-Farber Cancer Institute and Brigham and Women’s Hospital

Professor of Medicine

Harvard Medical School

Boston, MA


Dana farber cancer institute

Dana-Farber Cancer Institute

Dana/Mayer Building (Office)

Yawkey Center (Clinic)

Brigham and Women’s Hospital


Disclosures

Disclosures

Data monitoring/steering committee: Celgene, Sunesis

Ad hoc consulting: Abbvie, Agios, Amgen, Celgene, Roche

Clinical Research Support: Novartis


Current standard therapy for mds

Current “standard” therapy for MDS

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

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

Higher-risk MDS

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


Is mds cancer

Is MDS ‘Cancer’?

59% of physicians and 46% of non-physician HCPs answered that they routinely describe MDS to patients as a form of cancer

Steensma et al abs 724, ASH 2013


Myelodysplastic syndromes new ideas in 2013 focus on ash 2013

Myelodysplastic Syndromes: New Ideas in 2013, focus on ASH 2013

  • Review of Prognostic Schema

  • The Genomic Landscape in MDS

  • Therapy

    • Lower risk disease

    • Higher risk disease

  • Special Issues

    • Chelation


Myelodysplastic syndromes update

IPSS

*Good = normal, -Y, del(5q), del(20q); intermediate = other karyotypic abnormalities; poor = complex ( 3 abnormalities) or chromosome 7 abnormalities. †Hb < 10 g/dL; ANC < 1800/L; platelets < 100,000/L.

Greenberg P et al. Blood. 1997;89:2079-2088.


Karyotypes for use in ipss r

Karyotypes for use in IPSS-R

From: Greenberg P et al Blood 2012 Sep 20;120(12):2454-65.


Ipss r

IPSS-R

Possible range of summed scores: 0-10

Greenberg P et al Blood 2012 Sep 20;120(12):2454-65.


Ipss r1

IPSS-R

Using IPSS-R:

27% of IPSS lower risk “upstaged”

18% of IPSS higher risk “downstaged”

Greenberg P et al Blood 2012 Sep 20;120(12):2454-65.


Mds mutation landscape

MDS mutation landscape

IPSS independent good prognosis

No clear independent effect

CDKN2A (<1%)

Proliferation

IPSS independent poor prognosis

CBL

2%

Impaired Differentiation

JAK2 3%

BRAF(<1%)

PTPN11(<1%)

RUNX19%

SETBP17%

ETV6

3%

GNAS(<1%)

NRAS4%

KRAS

1%

PTEN(<1%)

TP53

8%

NPM1(2%)

Other

Epigenetic regulation

ASXL1

14%

EZH2 6%

DNMT3A (8%)

SF1

1%

SF3A1

1%

Pre-mRNA splicing

SF3B1

22%

U2AF1

8%

TET2

21%

PRPF40B

1%

IDH1/2

2%

SRSF2

11%

UTX

1%

ATRX

<1%

ZRSR2

5%

U2AF65

<1%


Splicing mutations are common in mds

Splicing mutations are common in MDS

Splicing mutations in:

40-85% of MDS

incl. ~65% of RARS

55% of CMML

5-15% of AML

5% of MPN

15% of CLL

Rare in other tumors

Ebert B, Bernard OA. NEJM Dec 12 2011.


Myelodysplastic syndromes update

Oncogenic mutations identified in MDS

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


Myelodysplastic syndromes update

Relationship between number of oncogenic mutations and outcome in MDS

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


Lower risk mds

Lower Risk MDS

Failure is a poor option

Novel therapy


Outcomes for ipss low or int 1 mds post hma

Outcomes for IPSS Low or Int-1 MDS post HMA

  • 423 pts with low (n= 141, 33%) and intermediate-1 risk disease (n=282, 67%) by IPSS score at time of HMA Rx

    • seen between 2000 and 2011 in MDS Clinical Research Consortium

    • median age 69 years

    • 15% t-MDS (so don’t really count)

  • 282 (67%) pts received azacitidine alone, 87 (21%) decitabine alone, and 54 (12%) both

    • Median duration of therapy 7 months

    • HMA response: CR 9%, PR 3%, mCR 1%, HR 21%

  • Median overall survival (OS) was 15 months(95% CI: 12-18)

    • 1- and 3-year OS rates of 55% and 27%

    • IPSS-R and MD Anderson PSS predicted outcome

Jabbour, et al ASH 2013 Abstract #388


Arry 614 in lower risk mds

ARRY-614 in Lower risk MDS

  • Dual Inhibition of p38 MAPK (involved in stress-medaited apoptosis and Tie2 (surival factor for AML blasts)

  • Durable hematologic improvement in 14/71 evaluable pts in this phase I stduy

    • 5% became RBC tx-independent and 31% became plt tx-independent

Garcia-Manero, et al ASH 2013 Abstract #387


Higher risk mds

Higher Risk MDS

Combination

Aza+ len?

aza+HDACi?

Novel rx

rigosertib


Epigenetic therapy in mds

Epigenetic Therapy in MDS

  • Theory: Promote transcription of differentiation-associated/tumor supressor genes

    • Histone deacetylase inhibitors (eg, SAHA, phenylbutyrate, depsipeptide)

    • DNA hypomethylating agents (5-azacytidine and decitabine)

      • The most active available category of agents in MDS (5-aza FDA approved 5-04)

    • Value of adding HDACi to DNAMTi unclear

      • ECOG phase II (ASH 2010): no benefit of entinostat +aza


Overall survival azacitidine vs ccr itt population

Overall Survival: Azacitidine vs CCR ITT Population

1.0

0.9

0.8

Difference: 9.4 months

0.7

50.8%

0.6

24.4 months

0.5

15 months

26.2%

0.4

0.3

0.2

0.1

0.0

0

5

10

15

20

25

30

35

40

Log-Rank p=0.0001

HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113

Proportion Surviving

AZA

CCR

Time (months) from Randomization

Survival benefit seen even in non-CR pts.

20

List et al, JCO 2010.

Fenaux P, et al. Lancet Oncology, 2009


Phase iii low dose decitabine q 8h dosing vs supportive care in mds results

EORTC 06011

Median age: 70 years

IPSS int-2/high-risk MDS: 55%/38%

Superior responses and PFS with decitabine vs supportive care; no improvement in OS or time to AML or death

Phase III Low-Dose Decitabine (q 8h dosing) vs Supportive Care in MDS: Results

25

22

Decitabine (n = 119)

Supportive care (n = 114)

20

15

15

14

13

Patients (%)

10

6

5

2

0

0

0

CR

PR

HI

SD

  • Poor cytogenetics: 46%

  • Previous treatment: 20%

Lubbert et al JCO 2011


Myelodysplastic syndromes update

Lenalidomide + Azacitidine

100

CR

90

Hematologic improvement

80

70

60

28

Response Rate (%)

50

40

30

44

20

10

0

Lenalidomide/Azacitidine(N = 36)

  • Lenalidomide 10 mg on Days 1-21

  • Azacitidine 75 mg/m2 on Days 1-5

  • 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%)

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


    Epigenetic therapy in mds1

    Epigenetic Therapy in MDS

    New at ASH 2013

    Cytogenetic and Heme response to aza not always correlated (Serbert et al -389)

    HMA better than int chemo in those w 10-30 % blasts (Nazha et al=278)-retropsective


    Myelodysplastic syndromes update

    Azacitidine + Vorinostat

    • 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

    Eligibility

    Age ≥ 18 years

    Untreated MDS (≥ Int-1) or AML

    And any of the following:

    Total bilirubin ≥ 2 mg/dL

    Creatinine ≥ 2 mg/dL

    ECOG performance status > 2

    Excluded from all other clinical trials:

    • Presence of other active malignancy

    Garcia-Manero et al. Blood 2011


    Phase ii azacitidine vorinostat ny cancer consortium study 6898

    Phase II azacitidine + vorinostat (NY Cancer Consortium Study 6898)

    • N=33 evaluable; IPSS Int-2 or High MDS

    • 23 responders (70%): 10 CR, 4 CRi, (CR+CRi=42%) 9 HI, 5 SD,

    • Median time to response is 2 cycles (8 weeks).

    • Abnormal karyotype or FISH result persists in 45% of patients

    • Cycles administered range from 1 to 26+ with a median of 6 cycles.  

    • Median duration of response is 16 months overall

      • 9.5, 23 and 27 months, respectively for cohorts 1, 2 and 3. 

    Silverman LR et al Abstract #386 ASH 2013 annual meeting


    S1117 us canada intergroup study

    S1117 (US/Canada Intergroup) study

    Power:

    81% probability of detecting a 20% difference in ORR

    (with alpha 0.05)

    Azacitidine monotherapy

    (7 days x 75 mg/m2/day)

    n=80

    Eligible:

    Higher-risk MDS or CMML

    (5-19% blasts or

    IPSS Int-2/High)

    n=80

    Azacitidine + lenalidomide

    (10 mg/d for 21/28 days)

    Azacitidine + vorinostat

    (600 mg/day)

    n=80

    Primary endpoint: overall response rate [ORR] (IWG 2006)

    Secondary endpoints: overall and progression-free survival, safety

    Principal investigator: Mikkael Sekeres, Cleveland Clinic


    On 01910 na rigosertib multikinase inhibitor

    ON 01910.Na (rigosertib) - multikinase inhibitor

    Cell-cycle functions and localizations of Plk1

    ON 01910.Na

    Multikinase inhibitor

    Polo-like kinase 1 modulator?

    PI3Kab/Akt/ERK pathway inhibitor

    Induces Bim, inhibits Mcl-1 activation

    Reduces cyclin D1 levels

    Barr F et al Nature Reviews Molecular Cell Biology 2004; 5: 429-441


    Myelodysplastic syndromes update

    Response Rates in 32 MDS Patients (RAEB/t)

    Previously treated with Azanucleosides

    OS by Dose

    & Schedule

    Raza et al. Blood 2011; 3822


    Rigosertib on01910 na randomized trial for post hma failure

    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

    DID NOT MEET PRIMARY ENDPOINT OF OS BENEFIT

    ON 01910.Na 1800 mg/24 hr as a 72-hr continuous infusion

    on Days 1, 2, and 3 of a 2-week cycle

    n=180

    Randomize 2:1

    Primary Endpoint:

    Overall survival

    Secondary Endpoints:

    IWG 2006 response, AEs, etc

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

    n=90


    New therapy higher risk in mds

    New Therapy higher risk in MDS

    Oral Aza- ORR=48%, 17% CR (Garcia-Manero-1554)

    Novel HMA: SGI-110 (elderly AML, 13% CR)-ORR 30%

    PDL1 pathway up regulated (Yang -2787)


    Transfusion therapy results in iron overload

    Transfusion therapy results in iron overload

    Moderate transfusion requirement:

    2 units / month

    24 units / year

    ~ 100 units / 4 years

    High transfusion requirement:

    4 units / month

    48 units / year

    ~ 100 units / 2 years

    100 units: ≥ 20 g iron

    Normal body iron: 3-4 g

    200–250 mg

    iron


    Chelation in mds

    Chelation in MDS?

    • Ferritin levels and transfusion burden correlate with poor outcome

    • It is possible to lower iron burden with an oral agent: deferasirox

    • While consensus statements recommend chelation, at least in chronically transfused lower risk pts, there are no studies which prospectively document a clinical benefit


    Myelodysplastic syndromes update

    Matched-Pair Analysis of Transfused Patients With MDS and Ferritin >500 ng/mL Receiving Iron Chelation Therapy or Not: Düsseldorf Registry

    Neukirchen et al, Leuk Res, 2012

    • About half rec’d Deferoxamine/Deferasirox only

    • Serum ferritin levels:

      - Mean 1954 ng/mL in chelated group, 945 ng/mL in non-chelated

    Similar data: Lysons, Abs 2775, ASH 2013


    Mds update acknowledgements

    MDS: Update- Acknowledgements

    • L Ades, L Olva, L Angelucci, W Platzbecker (Europe)

    • H Kantarjian, A (Houston, TX)

    • Raf Behar, (Boston, MA)

    • Key DFCI Colleagues: Dan DeAngelo and David Steensma


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