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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/Mayer Building (Office). Yawkey Center (Clinic).

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Myelodysplastic Syndromes Update

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  1. 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

  2. Dana-Farber Cancer Institute Dana/Mayer Building (Office) Yawkey Center (Clinic) Brigham and Women’s Hospital

  3. Disclosures Data monitoring/steering committee: Celgene, Sunesis Ad hoc consulting: Abbvie, Agios, Amgen, Celgene, Roche Clinical Research Support: Novartis

  4. 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

  5. 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

  6. 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

  7. 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.

  8. Karyotypes for use in IPSS-R From: Greenberg P et al Blood 2012 Sep 20;120(12):2454-65.

  9. IPSS-R Possible range of summed scores: 0-10 Greenberg P et al Blood 2012 Sep 20;120(12):2454-65.

  10. 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.

  11. 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%

  12. 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.

  13. Oncogenic mutations identified in MDS Papaemmanuil E et al. Blood 2013;122:3616-3627

  14. Relationship between number of oncogenic mutations and outcome in MDS Papaemmanuil E et al. Blood 2013;122:3616-3627

  15. Lower Risk MDS Failure is a poor option Novel therapy

  16. 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

  17. 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

  18. Higher Risk MDS Combination Aza+ len? aza+HDACi? Novel rx rigosertib

  19. 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

  20. 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

  21. 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

  22. 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.

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. Response Rates in 32 MDS Patients (RAEB/t) Previously treated with Azanucleosides OS by Dose & Schedule Raza et al. Blood 2011; 3822

  29. 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

  30. 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)

  31. 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

  32. 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

  33. 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

  34. 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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