MDS FDA-approved Drugs

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1 MDS: Current Thinking on the Disease, Diagnosis, and Treatment Mikkael A. Sekeres, MD, MS Associate Professor of Medicine Director, Leukemia Program Dept of Hematologic Oncology and Blood Disorders Taussig Cancer Institute MDS FDA-approved Drugs The view from 30,000 feet: Definitions What MDS looks like in the U.S. Treatment lower risk Treatment higher risk MDS FDA-approved Drugs The view from 30,000 feet: Definitions What MDS looks like in the U.S. Treatment lower risk Treatment higher risk (Gail Roboz, MD) 1

2 MDS - definition A heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell Characterized by a hyperproliferative bone marrow, dysplasia of the cellular elements, and ineffective hematopoiesis MDS definition in English An abnormal bone marrow stem cell ( Grandfather or Grandmother cell, Adam or Eve cell) gives rise to other abnormal cells These abnormal cells grow quickly and crowd out the normal bone marrow cells, which die and fail to make the usual blood components (red blood cells, white blood cells, platelets) MDS - History First published reports date back to First literature review (of 143 people with MDS) in 1973 First classification system in 1976, revised in 1982 World Health Organization (WHO) system in 1997, and again in

3 Bone Marrow Basics Stem Cells Bone Marrow EPO Blood Stream Red Blood Cells White Blood Cells Platelets Red Blood Cells Bone Marrow Basics (II) Oxygen White Blood Cells Oxygen Tissues (Heart, Liver, Kidneys) Infection Platelets Wound MDS in the Bone Marrow (I) Stem Cells Bone Marrow Blood Stream 3

4 MDS in the Bone Marrow (II) Stem Cells Bone Marrow Red Blood Cells White Blood Cells Platelets Blood Stream MDS in the Bone Marrow (III) Cytokines Stem Cells Bone Marrow Red Blood Cells White Blood Cells Platelets Blood Stream MDS in the Bone Marrow (III) Cytokines EPO Stem Cells Bone Marrow Red Blood Cells White Blood Cells Platelets Blood Stream 4

5 MDS in the Bone Marrow (III) Cytokines EPO Stem Cells Bone Marrow EPO Red Blood Cells White Blood Cells Platelets Blood Stream MDS Subtype Percentage of Peripheral Blasts FAB Classification Percentage of Bone Marrow Blasts AML Median Percentage of Transform Survival (months) MDS Diagnoses RA < 1 < RARS < 1 < RAEB < > RAEBt > CMML < 5 < 20 > Bennett JM et al. Br J Haematol. 1982;82: % Blasts 10-19% Blasts Slide courtesy of David Steensma >20% Blasts = AML! 5

6 International Prognostic Scoring System Calculation of prognostic score Score BM Blast % < Cytogenetics Good Intermediate Poor Cytopenias 0/1 2/3 Estimation of prognosis Overall IPSS Subgroup Median Survival Score (Years) 0 Low Intermediate Intermediate >2.5 High 0.4 Cytopenias: ANC < 1.5, HGB < 10.0, PLT < 100,000 Good Risk: [-Y,del(5q), del(20q),nl]; Intermediate Risk: [8+,other]; Poor Risk: [Chr. 7 abn, >3 abn] Greenberg P, et. al. Blood 1997:89: Lumpers Splitters 6

7 MDS Classification The Ultimate Simplification Lower Risk (Low rate of AML transformation) RA, RARS RCMD, RCMD-RS MDS-U, MDS del (5q) IPSS Low, Int-1 (Score 0-1.0) Higher Risk (High rate of AML transformation) RAEB (-1, -2) IPSS Int-2, High (Score > 1.5) MDS FDA-approved Drugs The view from 30,000 feet: Definitions What MDS looks like in the U.S. Treatment lower risk Treatment higher risk (Gail Roboz, MD) MDS Incidence Rate: U.S. (II) AML 3.7 Average 3-year survival = 45% Rollison et al. Blood 2008;112:45. 7

8 MDS Prevalence Not yet determined in the U.S. In Germany, one study from Dusseldorf reports it to be ~17/100, people. If we assume this is similar in the U.S., would translate to ~60,000 people. Germing et al. Blood 2009;114. MDS: Risk Factors MDS Risk Factors Factor Evidence Increasing Age ++++ Male Gender ++++ Chemotherapy Agents/RT ++++ Benzene/Solvents +++ Smoking ++ Pesticides/Herbicides/Fertilizers ++ Ionizing Radiation + Hair Dye + Slide Courtesy of S. Strom 8

9 How is MDS Diagnosed? Many are asymptomatic but have abnormal blood tests Anemia, low platelets, or low white cells Those who do have symptoms may complain of: Fatigue Decreased appetite or energy Infections Bleeding Anyone a stranger to this??? U.S. MDS Characteristics Cross-sectional analysis of 4514 MDS patients in the U.S. in Age (Median) Newly diagnosed 71 years Established years Sex (Mean) Male (Newly diagnosed) (Established) 55% 51-57% 57% Duration of MDS (Median) months MDS Status Primary 88 93% Secondary 7 12% Secondary Chemotherapy 55 80% Cause Radiation 6 21% Chemical exposure 2 9% Sekeres et al. J National Cancer Inst 2008;100:1542 9

10 U.S. MDS Characteristics Median Hgb: 9.1 g/dl (IQ range 8-10) Median Plt: 100k/mm 3 (IQ range ) Median ANC: 1780/mm 3 (IQ range ) Circulating Blasts: 1-5%: 16% >5%: 10% Sekeres et al. J National Cancer Inst 2008;100:1542 MDS Epidemiology in the U.S. 23% 13% 29% 18% Sekeres et al. J Nat Cancer Inst 2008;100:1542 MDS FDA-approved Drugs The view from 30,000 feet: Definitions What MDS looks like in the U.S. Treatment lower risk Treatment higher risk (Gail Roboz, MD) 10

11 Therapy in MDS (I) Squeeze every last ounce of production out of the remaining functional stem cells with Erythropoiesis Stimulating Agents (ESAs) and Growth Factors (GFs) ESAs/GF in MDS: Who Responds? Score > +1 Good response (74%, n=34) RA, RARS, RAEB Score 1 to +1 Intermediate response (23%, n=31) Score < 1 Poor response (7%, n=29) Treatment response score s-epo < U/L >500 3 Transf <2 units/m +2 U RBC/m = or >2 units/m 2 Hellström-Lindberg E et al. Br J Haematol. 2003;120:1037 ESA/GF for Low-risk MDS Golshayan et al. Br J Haem 2007;137:

12 What are ESAs? Erythropoietin (Procrit) Often administered weekly Darbepoietin (Aranesp) Given weekly, or every 2 or 3 weeks Therapy in Lower-risk MDS (II) Block the effects of those nasty cytokines (chemicals that kill normal bone marrow cells) Clinical Development of Lenalidomide in Low/Int-1-risk MDS: Completed Trials MDS-001 N = 43 Phase I/II initiated Feb 2002 Del 5q MDS-003 N = 148 Phase II initiated July 2003 Non del 5q MDS-002 N = 214 Phase II initiated July 2003 Slide courtesy of A. Raza 12

13 Feature Lenalidomide in del (5q) MDS: Transfusion Response MDS-02/03 (%) MDS-01/PK (%) Total (%) No. Patients Erythroid response, n (%) TI 99 (66) 15 (79) 114 (68) Minor (> 50% ) TI + minor 13 (9) 112 (75) 1 (5) 16 (84) 14 (8) 128 (76) Time to response, weeks Median Range List et al. Blood 2006;108:251a. Percent Res sponding Del (5q): Duration of Transfusion Response Data as of 04Dec06 (N=114) Median duration TI =2.2 years Median F/U: 1.3 yr (Min 0.1 Max 4.4 yr) Years List et al. Blood 2006;108:251a. MDS-004: Randomized Study Design Planned enrollment (n = 205) Double-blind phase** * S T R A T I F Y R A N D O M I Z E D LEN, orally 5 mg/day for 28 days of each 28-day cycle LEN, orally 10 mg/day for 21 days of each 28-day cycle Placebo R E S P O N S E Responders (at least minor erythroid response at week 16): Continued double-blind treatment for up to 52 weeks, relapse or progression Non responders: Discontinued double-blind treatment and entered open-label treatment or withdrew from study Week *Patients stratified by IPSS score and cytogenetic complexity prior to randomization. **Bone marrow assessments performed at baseline, 12 wk & every 24 wk thereafter. 13

14 MDS-004: Responses (RBC-TI) * RBC-TI (% %) * 33 * 54 Protocol defined ( 26 weeks) Fenaux et al. Blood 2009;114:944a 8 * 48 IWG ( 8 weeks) 61 *P < vs placebo Bars represent 95% CI Placebo (n = 67) LEN 5 mg (n = 69) LEN 10 mg (n = 69) LEN in Lower-risk Non-del (5q) Variable Erythroid response, n (%) Transfusion Independence Median Hgb change (g/dl) Range Daily Dose N = (41) 26 (26) ( ) 21-Day Dose N = (45) 30 (26) ( ) All Patients N = (43) 56 (26) ( ) Time to initial response, weeks Median Range Responses similar across FAB, IPSS groups Raza et al. Blood 2006;108:250a dependent (%) Transfusion Ind Non-del (5q): Duration of Transfusion Response Median duration TI: 41 weeks Range: weeks N = 56 Censored Time (Weeks) Raza et al. Blood 2006;108:250a. 14

15 MDS FDA-approved Drugs The view from 30,000 feet: Definitions What MDS looks like in the U.S. Treatment lower risk Treatment higher risk (Gail Roboz, MD) Goal of Therapy: Higher-risk MDS Prevent methyl groups from inactivating tumor suppressor genes and be directly cytotoxic kill those bad cells! Azacitidine Survival Study Screening/Central Pathology Review Investigator CCR Tx Selection Randomization BSC was included with each arm. Tx continued until unacceptable toxicity, AML transformation, or disease progression AZA 75 mg/m 2 /d x 7 d q28 d [n=179] Conventional care regimens Best Supportive Care (BSC) [n=105] Low Dose Ara-C (LDAC, 20 mg/m 2 /d x 14 d q28-42 d) [n=49] Std Chemo (7 + 3) [n=25] Fenaux P, et al. Blood. 2007;110(11):817a. 15

16 Overall Survival: Azacitidine vs CCR ITT Population Proportion Surviving months Log-Rank p= HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Difference: 9.4 months 50.8% 24.4 months 26.2% CCR AZA Time (months) from Randomization Fenaux P, et al. Blood. 2007;110(11):817a. Decitabine Phase III Study Design R A N Eligible D Patients O (IPSS > 0.5) M N = 170 I Z E D Stratification IPSS Classification Prior ChemoRx Supportive Care* + Decitabine (N = 89) Supportive Care* (N = 81) DAC 15 mg/m2 q 8hrs x 3days q 6wk Response assessed after 2nd cycle, with 2 more cycles given if CR. Kantarjian et al. Cancer 2006;106:1794 Decitabine in MDS: Results (I) Kantarjian et al. Cancer 2006;106:

17 EU DAC Phase III: Overall survival Median (months): 10.1 vs Decitabine HR = 0.88, 95% CI (0.66, 1.17) 50 Logrank test: p= Supportive care (months) O N Number of patients at risk : Supportive care Decitabine Wijermans et al. Blood 2008;112:226 Why No Survival Advantage for DAC? Number of treatments courses given Different populations and comparator groups How the drug was given DAC: Alternative Dosing Kantarjian et. al., Blood 2006;Prepublished online

18 Goal of Therapy: Higher-risk MDS (II) Replace the bone marrow! Stem Cell Transplantation: Approximation of Life Expectancy (Years) Immediate Transplant Transplant in 2 Years Transplant at Progression Low Int Int High Cutler C, et al. Blood Prepublished online March 23, 2004; D /Blood RIC vs. High-dose Conditioning Bone Marrow Transplants Scott et al. Leukemia 2006;20:

19 FDA-approved Therapies for MDS: Conclusions More prevalent than we know anemia does not occur simply from aging! Therapies maximize production of remaining functional stem cells; block the effects of dysplastic stem cells; kill dysplastic stem cells; or replace the bone marrow. Call LEUK if you come to sunny Cleveland and would like to be seen. Thanks! Cleveland Clinic Leukemia Program Jaroslaw Maciejewski, MD, PhD Yogen Saunthararajah, MD Anjali Advani, MD Matt Kalaycio, MD Ed Copelan, MD Ronald Sobecks, MD Manuel Afable, MD Ricki Englehardt, RN Kristy Grimes, RN Barb Tripp, RN, NP Tina Piks, RN Josephine Chan, PhD April Smith, BA Katarina Paulic, BA Randy Davis, BA Stephani Day, MS And Our Patients! 19