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Emerging Therapies in MDS: A Focus on Epigenetics

Emerging Therapies in MDS: A Focus on Epigenetics. Click to edit Master subtitle style. Myelodysplastic Syndrome (MDS) Epidemiology. 10,000-15,000 estimated new cases/year in US (adults) More common than acute myeloid leukemia (AML) 8,000 new cases/year in US

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Emerging Therapies in MDS: A Focus on Epigenetics

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  1. Emerging Therapies in MDS: A Focus on Epigenetics Click to edit Master subtitle style

  2. Myelodysplastic Syndrome (MDS) Epidemiology • 10,000-15,000 estimated new cases/year in US (adults) • More common than acute myeloid leukemia (AML) • 8,000 new cases/year in US • Predominantly a disease of the elderly • Median age > 60 • Incidence greater in men than in women • Incidence increases with age • Median survival 3 months to 6 years depending on risk category Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06. Xie Y, et al. Cancer. 2003;97(9):2229-35; American Cancer Society, www.cancer.org; Aplastic Anemia and MDS International Foundation, www.aamds.org; Kurzrock R. Semin Hematol. 2002;39(3 Suppl 2):18-25; Steensma DP, Tefferi A. Leuk Res. 2003;27(2):95-120. Greenberg P, et al. Blood. 1997;89:2079-88.

  3. Risk Factors for MDS • Greatest risk factor appears to be advancing age • 80%90% of all patients with these disorders > than 60 years • Previous cancer therapy • Mechlorethamine, procarbazine, chlorambucil, etoposide, teniposide (with or without concomitant radiation therapy) and other chemotherapy agents • Exposure to environmental toxins • Benzene, organic solvents, pesticides, radiation • Tobacco smoke • Cigarette smoking • Congenital disorders • Familial disorder • Male sex Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org; accessed 6/20/06. Frogge MH, et al. CE monograph published by Oncology Education Services, Inc. Pittsburgh, PA, 2005. List AF, et al. Hematology. 2004;297-317.

  4. Symptoms of MDS • Many patients have no apparent symptoms, but are diagnosed after routine laboratory tests uncover abnormalities in the circulating blood cells • Fatigue is the most common symptom of MDS • Early symptoms of MDS may include: • Bruising • Increased bleeding (ie, nose and gum bleeds) • Rash • Shortness of breath • Rapid heart rate • Weight loss • Fever • Loss of appetite • None of these symptoms are specific to MDS, and may be attributable to other conditions Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06. Frogge MH, et al. CE monograph published by Oncology Education Services, Inc, Pittsburgh, PA, 2005.

  5. Diagnosis of MDS Key Features • Evidence of ineffective hematopoiesis (anemia, neutropenia, thrombocytopenia) • Hypercellular marrow (rarely, hypocellular marrow) • Evidence of dysplasia by bone marrow examination – typically in more than one lineage List AF, et al. Hematology. 2004;297-317. Myelodysplastic syndromes detailed guide. American Cancer Society. Available at www.cancer.org. Accessed 6/20/06.

  6. MDS Classification • French-American-British (FAB) • World Health Organization (WHO) • International Prognostic Scoring System (IPSS) Bennett J, et al. Br J Haematol. 1982;51:189-99. Harris N, et al. Ann Oncol. 1999;10:1419-32. Greenberg P, et al. Blood. 1997;89:2079-88.

  7. MDS FAB (French-American- British) Classification Category % Blasts in Bone Marrow Survival in Months RA (Refractory anemia) RARS (Refractory anemia with ringed sideroblasts) RAEB (Refractory anemia with excess blasts) RAEB-T (Refractory anemia with excess blasts in transformation) CMMoL (Chronic myelomonocytic leukemia) < 5% < 5% 5-20% 21-30% 1-20% 19–64 21–76 7–15 5–12 8–60+ List AF, et al. The myelodysplastic syndromes. In: Wintrobe’s Hematology2003. Bennett J, et al. Br J Haematol. 1982;51:189-99.

  8. MDS World Health Organization (WHO) Classification • Revised MDS classification proposed in 2000 • Changes included: • Eliminated RAEB-T • Redefined AML as  20% blasts • Recognize prognostic impact of multilineage dysplasia in RA and RARS and isolated interstitial deletion of chromosome 5q • CMMoL = Myelodysplastic/myeloproliferative disorder • May provide more uniform and accurate prognostic data Steensma DP, et al. Leuk Res. 2003;27:95-120. Harris N, Jaffe E, Diebold J, et al. Ann Oncol. 1999;10:1419-32.

  9. MDS International Prognostic Scoring System (IPSS) • The first comprehensive prognostic scoring system adopted • Patients are stratified into four well-defined risk groups according to survival and AML transformation • Scoring system based on percentage of bone marrow blasts, karyotype, and cytopenias Greenberg P, et al. Blood. 1997:89(6):2079-88.

  10. MDS Subtypes IPSS Score Prognostic Variable 0 0.5 1.0 1.5 2.0 Bone marrow blast (%) Karyotype* Cytopenias < 5 Good 0/1 5-10 Intermediate 2/3 – Poor 11-20 21-30 *Good: Normal, -Y, del(5q), del(20q); Poor: Complex(>3abnl) or Chr 7 abnl; Intermediate: All others. Greenberg P, et al. Blood.1997:89(6):2079-88.

  11. Causes of Death in MDS No. of Patients Who: Subgroups No. of Patients Died (%) Died With Leukemia (%) Died Without Leukemia (%) Low 235 113 (48) 22 (19) 91 (81) Int-1 295 181 (61) 55 (30) 126 (70) Int-2 171 147 (86) 49 (33) 98 (67) High 58 51 (88) 23 (45) 28 (55) Total 759 492 (65) 149 (30) 343 (70) Greenberg P, et al. Blood. 1997;89:2079-2088.

  12. Goals of Therapy in MDS • Select the therapy best suited for the individual • Performance status, disease classification, IPSS score (cytogenetics, cytopenias, BM blasts), and treatment tolerance • Low/Int-1 IPSS: Improve blood counts (decrease transfusions and infections) • Improve quality of life • Int-2/high-risk IPSS: Prolong survival and delay leukemic progression • Possible cure of disease List AF, et al. Hematology (Am Soc Hematol Educ Program). 2004;297-317. Cheson BD, et al. Blood. 2000:96:3671. NCCN Myelodysplastic Panel Members. Available at: http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf

  13. MDS Treatments • Best supportive care • Transfusions (RBCs, platelets) • Chelation therapy • Colony-stimulating factors (EPO ± G-CSF or GM-CSF) • Chemotherapy • Anti-thymocyte globulin (ATG) ± cyclosporin in patients with hypocellular MDS • Stem cell transplant • Best candidates are younger patients with low % blasts and preserved platelet counts1 • Median age at transplant (IBMTR data) = 38 yrs old1 • Hypomethylating agents • Immunomodulatory drugs • Other novel agents • HDAC inhibitors, farnesyl transferase inhibitors etc. 1Sierra J, et al. Blood. 2002;100:1997-2004.

  14. NCCN Guidelines-Low Risk IPSS CATEGORY Treatment No response Lenalidomide Follow appropriate pathway below del(5q) Azacitidine/ Decitabine or Clinical trial Epoetin alfa (EPO) ± G-CSF No response Clinical trial Serum Epo ≤ 500 mU/ml No response No response Anemia Antithymocyte Globulin (ATG), Cyclosporin A HLADR-15 + Serum Epo > 500 mU/ml Clinically significant cytopenia(s) Low, INT-1 Supportive care Azacitidine/ Decitabine or Clinical trial No response Clinical trial HLADR-15 - ATG or Clinical trial No response Thrombocytopenia, neutropenia Azacitidine/ Decitabine National Comprehensive Cancer Network (NCCN) guidelines v.4.2006. For more information see: http://www.nccn.org.

  15. NCCN Guidelines-High Risk Treatment IPSS CATEGORY Hemopoietic stem cell transplant (HSCT) Yes Intensive therapy Candidate* Donor available High intensity therapyr or Supportive care No INT-2, HIGH Azacitidine/Decitabine or Clinical trial or Supportive care Not intensive therapy candidate • High-Intensity Therapy: • Clinical Trials (preferred) • Investigational therapy preferred. • Standard induction therapy if investigationalprotocol unavailable or as a bridge to HSCT.(See text for more detail) • Hemopoietic stem cell transplant (HSCT) • allogeneic-matched sibling including standardand (experimental) reduced intensity preparativeapproaches or matched unrelated donor (MUD) *Based on age, performance status and absence of major comorbid medical conditions that would preclude high dose therapy. National Comprehensive Cancer Network (NCCN) guidelines v.4.2006.

  16. Overview of Epigenetics and Its Role in MDS

  17. NH2 NH2 CH3 H N N O N H O N H Cytosine DNA Methylation 5-Methyl- Cytosine MTASE Cytosine SAM SAH SAM = S-adenosyl methionine; SAH = S-adenosyl homocysteine. www.mdanderson.org/leukemia/methylation.

  18. Hypermethylation and Silencing M M M Expressed (or ready for expression) M M M M M M M M M Silenced Imprinted genes, Inactive X Ectopically Silenced Genes (e.g. tumor suppressor genes) Courtesy of Issa, JP

  19. Tumor Suppressor Gene Methylation • p15INK4b • Inhibitor of the cyclin-dependent kinases CDK4 and CDK6 • Plays a role in transforming growth factor- (TGF-)-mediated growth inhibition • Inactivated by hypermethylation in hematopoietic neoplasms (AML, ALL, MDS, and Burkitt’s lymphoma) Quesnel, et al. Blood. 1998;91:2985.

  20. Association Between Survival and p15 Methylation Status in MDS Unmethylated Methylated P = .049 Quesnel B, et al. Blood. 1998;91:2985-90.

  21. Hypomethylating Agents

  22. Hypomethylating Cytosine Analogs NH2 NH2 NH2 NH2 CH3 N N N N N N O O O O N N N N Ribose Deoxyribose Cytosine 5-methyl-cytosine 5-aza-cytidine 5-aza-2′-deoxycytidine (decitabine) (azacitidine) Santini V, et al. Ann Intern Med. 2001;134(7):573-86.

  23. How Hypomethylating AgentsWork • Act as cytosine nucleoside analogs that reverse aberrant DNA methylation • Incorporate into DNA and trap DNA-methyltransferase, depleting cells of DNA-methyltransferase • Decitabine contains deoxyribose and is incorporated into DNA while azacitidine, which contains ribose, is incorporated into both RNA and DNA • 10-20% azacitidine incorporation into DNA Leone G, et al. Haematologica. 2002;87:1324-41; Kuykendall JR. The Annals of Pharmacotherapy.2005;39:1700-1709.

  24. CH3 CH3 CH3 Mechanism of Epigenetic Therapy CH3 Fully methylated DNA CH3 CH3 CH3 STOP STOP CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 Silencing Maintained Silencing CH3 CH3 CH3 CH3 CH3 CH3 DNAreplication Fully methylated DNA Mtase CH3 Epigenetic Therapy CH3 Unmethylated DNA CH3 CH3 CH3 CH3 CH3 CH3 CH3 Reactivated GeneExpression CH3 CH3 Hemi-methylated DNA Differentiation - Apoptosis - Senescence - Enhanced Immune Response Courtesy of Issa JP.

  25. Phase 3 Clinical Experience with Decitabine in Advanced MDS

  26. Decitabine Phase 3 Study Design (D-0007) • Open-label, 1:1 randomized, multicenter study in US and CA • Schedule: 3-hour infusion of 15 mg/m2 q 8 hrs x 3 days RANDOMIZED Decitabine + Supportive Care* (n = 89) • Stratification • IPSS classification • Prior chemotherapy • Study center Eligible Patients (n = 170) Supportive Care*(n = 81) *Antibiotics, growth factors, and/or transfusions. Kantarjian , et al. Cancer. 2006;106:1794-1803.

  27. Decitabine Phase 3Patient Eligibility and Study Design • Patient population • de novo or secondary MDS • IPSS  0.5; all FAB subgroups • Primary endpoints • Overall response rate (CR + PR), IWG criteria • Time to AML transformation or death • In the primary endpoint analysis, a P value less than .024 was required to achieve statistical significance • Secondary endpoints • Duration of response, cytogenetic response rate, transfusion requirements, QOL, survival, febrile neutropenia, toxicity Kantarjian HM, et al. Cancer. 2006;106:1794-1803.

  28. Decitabine Phase 3 IWG Response Criteria • Independent review of bone marrow and best response • Complete response (CR) • <5% blasts in bone marrow • Hgb  11, ANC  1500, platelets > 100,000, no blasts • No dysplasia • No transfusions or growth factors • Minimum duration 8 weeks • Partial response (PR) • 50% decrease in marrow blasts • Other response criteria same as CR IWG = international working group; Hgb = hemoglobin; ANC = absolute neutrophil count.Kantarjian HM, et al. Cancer. 2006;106:1794-1803.Cheson BD. Blood. 2000;96:3671-74.

  29. Decitabine Phase 3 Demographics (ITT Population) Parameters Decitabine n = 89 (%) Supportive Care n = 81 (%) Sex (male) 59 (66) 57 (70) Median Age 70 70 Median Time From Diagnosis (months) 7.3 8.8 Type of MDS De novo Secondary 77 (87) 12 (13) 70 (86) 11 (14) Previous MDS Therapy 20 (22) 16 (20) IPSS High risk Intermediate-2 Intermediate-1 23 (26) 38 (43) 28 (31) 21 (26) 36 (44) 24 (30) ITT = intent to treat.Kantarjian HM, et al. Cancer. 2006;106:1794-1803.

  30. Decitabine Phase 3 Response to Decitabine (ITT) IWG Response Rate,Onset, and Duration* Decitabine (n = 89) Supportive Care(n = 81) Overall Response Rate (CR+PR)Complete response (CR) Partial response (PR) Hematologic improvement (HI) 15 (17%)†8 (9%)7 (8%)12 (13%) 0 (0%)0 (0%)0 (0%)6 (7%) †P value < .001 from two-sided Fisher’s exact test Onset and Duration of Response (Months) Median time to response (CR+PR) Median duration of response (CR+PR) 3.3 (2.0 – 9.7)10.3 (4.1 - 13.9)‡ N/A Best response observed after 2 cycles (median number of cycles = 3) *Cheson BD. Blood. 2000 96:3671-74. Kantarjian HM, et al. Cancer. 2006;106:1794-1803.‡For patients with a confirmed date of progression.

  31. Response in Patients with AML at Baseline Decitabine n = 9 (%) Supportive Care n = 3 (%) Overall Response* 5 (56) 0 (0) Complete Response† 3 (33) 0 (0) Partial Response 2 (22) 0 (0) *IWG AML Response Criteria. †One patient was a CRi (morphologic complete remission with incomplete blood count recovery). Cheson et al. J Clin Oncol. 2003;21:4642-49; Kantarjian HM, et al. Cancer. 2006;106:1794-1803; Data on File, MGI PHARMA.

  32. Decitabine Phase 3 Median Time to AML or Death MDS Group DecitabineMonths (range) Supportive Care Months (range) Log-rankP Value All Patients 12.1 (0.3*-22.3) n = 89 7.8 (0.3-21.0*) n = 81 .160 Treatment Naive 12.3 (0.3*-20.1*) n = 69 7.3 (0.3-21.0*) n = 65 .082 Int-2/ High Risk 12.0 (0.4*-22.3) n = 61 6.8 (0.3-21.0*) n = 57 .028 High Risk 9.3 (0.4*-19.9) n = 23 2.8 (0.3-13.5) n = 21 .010 *Censored data. Kantarjian HM, et al. Cancer. 2006;106:1794-1803; Data on File, MGI PHARMA.

  33. 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 Decitabine Phase 3 Survival by Response 100 P = .007 90 80 70 60 Percent Alive 50 40 30 Analyzed population = All patients 20 Nonresponders (N=155) 10 Responders (N=15) 0 Days Kantarjian HM, et al. Cancer. 2006;106:1794-1803.

  34. Decitabine Phase 3 Cytogenetic Evaluations Patients Evaluable for Cytogenetic Evaluations Decitabinen = 26 (%) Supportive Caren = 21 (%) Cytogenetic responses Major Response Minor Response 9* (35) 1 (4) 2 (10) – *1 additional patient who was randomized to supportive care crossed over to decitabine and had a major cytogenetic response and clinical CR. Kantarjian HM, et al. Cancer. 2006;106:1794-1803.

  35. Decitabine Phase 3: Percent of Patients RBC Transfusion-Free Per Cycle Decitabine 100 Supportive Care 90 80 70 % of Patients RBC Transfusion-Free 60 50 40 30 20 10 0 0 1 2 3 4 5 6 Decitabine N= 89 83 64 44 37 26 23 Supportive Care N= 81 75 63 40 28 23 15 Note: Last cycles less than 35 days long with 0 transfusions are not considered in this analysis. Kantarjian HM, et al. Cancer. 2006;106:1794-1803.

  36. Quality of Life MeasurePercent Change from Baseline for Global Health Status 45 * P < .05 Decitabine Supportive Care 35 * * 25 15 % Change From Baseline 5 -5 -15 -25 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Kantarjian HM, et al. Cancer. 2006;106:1794-1803.

  37. Decitabine Phase 3 Adverse Events (>10% Incidence) Decitabine (n = 83)* Supportive Care (n = 81) Grade 3 Grade 4 Grade 3 Grade 4 Hematologic Neutropenia 10% 77% 25% 25% Thrombocytopenia 22% 63% 27% 16% Anemia 11% 1% 14% 1% Febrile neutropenia 17% 6% 4% 0% Nonhematologic Pneumonia 13% 2% 7% 2% *Exposed to decitabine. Kantarjian et al. Cancer. 2006;106:1794-1803.

  38. Decitabine Phase 3 Summary and Conclusions • Decitabine therapy was superior to supportive care • Response rate 17% (CR 9%, PR 8%) • Durable responses (median 10.3 months) • Responders remained or became transfusion independent and symptoms improved • Delayed time to AML progression or death • Responders had longer survival • 24 months responders vs 14 months in non-responders (P = .007) • Well tolerated with manageable toxicity profile Kantarjian et al. Cancer. 2006;106:1794-1803.

  39. Decitabine Exposure in Phase 2 and 3 Studies Phase 2 Phase 3 Multiple cycles of decitabine therapy may be required for optimal response 91-01 95-11 97-19 D-0007 N 29 66 87 89 ORR (CR + PR) 13 (45%) 17 (26%) 23 (26%) 15 (17%) CR 8 (28%) 14 (21%) 19 (22%) 8 (9%) PR 5 (17%) 3 (5%) 4 (5%) 7 (8%) Median # cycles 4 4 4 3 Saba HI, et al. Blood . 2005;106:706a [abstract 2515]. Kantarjian HM, et al. Cancer. 2006;106:1794-1803. Saba HI, et al. Semin Hematol. 2005;42(3 suppl 2): S23-S31. Wijermans PW, et al. Leukemia. 1997;11:1-5. Wijermans PW, et al. J Clin Oncol.2000;18:956-962.

  40. Alternative Dosing with Decitabine

  41. Decitabine Reduced-Dose Schedule (100 mg/m2/course): 3-Arm Dosing Study • 3 decitabine treatment arms: • 10 mg/m2 IV over 1 hr daily x 10 days • 20 mg/m2 IV over 1 hr daily x 5 days • 20 mg/m2 SQ (10 mg SQ BID) daily x 5 days • Preferential randomization to arm with higher CR started after 45th patient • Courses were given every 4 weeks • Total = 100 mg/m2/course (75% of phase 3 MDS trial dose) • Study group • 95 patients treated (77 MDS, 18 CMML) • 65% patients Int-2/High Risk • 69% male, 65% were  60 yrs of age SQ = subcutaneous; CR = complete response.Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.

  42. 3-Arm Dosing Study: Overall Response Response n = 95 (%) Complete Response (CR) 32 (34) Partial Response (PR) 1 (1) Marrow CR 10 (11) Marrow CR + other HI 13 (14) Hematologic Improvement (HI) 13 (14) Single lineage 9 (9) 2 or 3 lineage 4 (4) Objective Response 69 (72%) Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.

  43. Comparison of outcome and side effects by dose schedule Parameter 5 Day IV 5 Day SQ 10 Day IV n 64 14 17 CR / treated (%) 25 (39) 3 (21) 4 (24) Median no. courses 5 8 9 Median duration of therapy in mos (range) 5.4 (1.0 – 20.4+) 9.7 (0.5 – 22.9+) 10.8 (1.9 – 17.7+) Median days to granulocytes recovery* 24 14 27 Median days to platelet recovery† 20 31 27 Median days to delivery of subsequent courses 35 35 40 No. courses requiring hospitalization (%) 50 (12) 14 (14) 23 (23) *To 109/L or above; †To 50 x 109/L or above; Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.

  44. 3-Arm Dosing Study DataSummary • Low-dose schedules of decitabine have significant activity • 34% complete response rate* and a 73% objective response rate† across all 3 arms • The optimal dose was 20 mg/m2 IV x 5 days (CR = 39%) • Primary toxicity across all arms was myelosuppression • Lower frequency vs. higher dose regimen • The dose of 10 mg/m2 IV x 10 days was associated with higher incidence of myelosuppression and hospitalization • A dose schedule of 20 mg/m2 IV x 5 days represents an excellent therapeutic option and offers an alternative dosing schedule *Response criteria for CR and PR were as for AML but required response durability for at least 4 weeks (PR also requiring that blasts decrease by >50%). †CR + PR + marrow CR + HI.Kantarjian H, et al. Blood. 2006;108(in press). First Edition Paper, prepublished online Aug 1, 2006; DOI 10.1182/blood-2006-05-021162.

  45. Phase 3 Clinical Experience with Azacitidine in MDS

  46. Azacitidine Phase 3 Study Design (CALGB 9221) • Randomized, crossover trial • Schedule: 75 mg/m2/day SQ x 7 days q 28 days R A N D O M I Z E D Supportive Care A SSESS CR: 3 Cycles (n = 92) Eligible Patients (n = 191) HI: Continue Azacitidine+ SupportiveCare NR: Off study SC: Pts worsening (n = 99) azacitidine Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.

  47. Azacitidine Phase 3 Patient Eligibility and Study Design • Patient population • FAB classification for MDS • Symptomatic cytopenia requiring active therapy • Cancer-free for 3 years with no radiation or chemotherapy for 6 previous months • Endpoints • Analysis of response (CR, PR, improved) • Time to treatment failure • Effects on RBC and platelets • Quality of life • Overall survival Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.

  48. Azacitidine Phase 3 Response Criteria • Complete response (CR) • Normal bone marrow or < 5% blasts in the bone marrow • Normal peripheral blood counts • No blasts • No transfusions • Partial response (PR) • ≤ 50% initial bone marrow blasts • Trilineage response • No blasts • No transfusions • Improved • Monolineage or bilineage response • Transfusions ≤ 50% of baseline Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.

  49. Azacitidine Phase 3 Demographics (ITT Population) Parameters Azacitidine n = 99 (%) Supportive Care n = 92 (%) Sex (male) 72 (73) 60 (65) Median Age 69 67 Median Time From Diagnosis (days) 77 87 Previous MDS therapy 16 (16) 17 (18) FAB RA RARS RAEB RAEB-T CMMoL Other* 17 (17) 5 (5) 32 (32) 27 (27) 7 (7) 11 (11) 20 (22) 3 (3) 34 (37) 18 (20) 7 (8) 10 (11) *Includes 19 AML, one classifiable acute leukemia, and one undefined MDS. Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.

  50. Azacitidine Phase 3Response Rates Azacitidine(n = 99) Supportive Care(n = 92) Overall Response (CR + PR) Complete response Partial response Hematologic improvement 16 (16.2%)* 6 (6.1%) 10 (10.1%) 19 (19%) 0% 0% 0% 6% *P < .0001 (CR + PR) Median Duration of Response(CR + PR + improved) (months) 15† N/A †95% CI, 11 to 20 months Kaminskas E. Clin Cancer Res. 2005;11:3604-8. Silverman LR, et al. J Clin Oncol. 2002;20:2429-40.

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