Combination Therapies in Higher-risk MDS

Transcription

1 Combination Therapies in Higher-risk MDS Mikkael A. Sekeres, MD, MS Associate Professor of Medicine Director, Leukemia Program Taussig Cancer Institute

2 U.S. Classification of MDS Patients 26% 18% 23% 15% 29% 18% Fewer higher-risk established patients Sekeres et al. J National Cancer Inst 2008;100:1542

3 LEN + AZA: Clinical Rationale Previous Studies

4 Single-agent LEN in Higher-risk del 5q MDS Ades et al. Blood 2009;113:3947

5 Responses: Single-agent LEN in Higher-risk MDS Of the 47 patients 29 MDS patients 6 CR (21%) all with isolated del (5q) 2 Marrow CR (7%) 4 HI (14%) 18 AML patients 1 CR (6%) Ades et al. Blood 2009;113:3947

6 Overall Survival: Single-agent LEN in Higher-risk MDS Ades et al. Blood 2009;113:3947

7 MDS-003: Adverse Events List et al. NEJM 2006;355:1456.

8 MDS-002: Most Common Drug-Related Adverse Events (NCI CTC) Adverse Event Neutropenia Thrombocytopenia Rash Pruritis Fatigue Diarrhea All Grades N (%) 60 (28) 56 (26) 47 (22) 45 (21) 33 (15) 32 (15) Grade 3 N (%) 53 (25) 43 (20) 9 (4) 2 (1) 8 (4) 3 (1) Raza et al. Blood 2006;108:250a.

9 Overall Survival: Azacitidine vs CCR Log-Rank p= HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 Proportion Surviving months 50.8% 24.4 months 26.2% CCR AZA Time (months) from Randomization Fenaux P, et al. Lancet Oncology 2009;10:

10 Toxicity: AZA vs. CCR

11 Final Results From A Phase I Combination Study of Lenalidomide and Azacitidine in Patients with Higher-risk Myelodysplastic Syndromes Mikkael A. Sekeres, Alan F. List, David Cuthbertson, Ronald Paquette, Deborah Latham, Manuel Afable, Katarina Paulic, Thomas Loughran, Jaroslaw P. Maciejewski Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio; H. Lee Moffitt Cancer Center, Tampa, Fl; University of California, Los Angeles, CA; Penn State University, Hershey, PA, USA.

12 Len + AZA: Dosing Table Dose Level Azacitidine Schedule 75 mg/m 2 SC days mg/m 2 SC days mg/m 2 SC days mg/m 2 SC days 1-5, mg/m 2 SC days 1-5, mg/m 2 SC days 1-5, 8-12 Lenalidomide Schedule 5 mg PO days mg PO days mg PO days mg PO days mg PO days mg PO days 1-21 Sekeres et al. JCO 2010 Mar 30 [Epub ahead of print]

13 Len + Aza: Baseline Characteristics Characteristic Age Female/Male (n) Time from Diagnosis Baseline: Hgb Plt ANC Epo Blast % IPSS (n): Int-1 Int-2 High Median (range), n=18 68 years (52-78) 7/11 5 weeks (2-106) k

14 Len + Aza: Toxicity Results No DLTs reached through all dosing cohorts Median ANC decrease 26% within first 8 weeks Median Plt decrease 0% (mean=24%) within first 8 weeks Cycle 2 delayed for 5 patients (<9 days) for recovery of counts or other reasons Sekeres et al. JCO 2010 Mar 30 [Epub ahead of print]

15 Len + Aza: Non-heme Toxicity Sekeres et al. JCO 2010 Mar 30 [Epub ahead of print]

16 Len + Aza: Response Results ORR = 12/18 (67%) 8 CR (44%) 3 HI (17%) 1 BM CR (6%) Sekeres et al. JCO 2010 Mar 30 [Epub ahead of print]

17 Len + AZA: Go-forward Dose Dosing Cohort AZA Dose LEN Dose IPSS Risk Group Grade 3/4 non-heme Toxicities Maximum Response 1 75 mg/m2 SC days mg PO days Int-1 2 Int CR 1 progression 2 75 mg/m2 SC days mg PO days Int-2 1 High 2 1 CR 1 HI 1 stable disease 3 75 mg/m2 SC days mg PO days Int-2 2 High 0 2 CR, 1 stable disease 4 50 mg/m2 SC days 1-5, mg PO days Int-1 2 Int CR, 1 stable disease 5 50 mg/m2 SC days 1-5, mg PO days Int-2 1 High 5 1 HI 1 stable disease 1 progression 6 50 mg/m2 SC days 1-5, mg PO days Int-1 1 Int-2 1 High 2 1 CR 1 HI 1 BM CR

18 Len + Aza: Conclusions Not as toxic as we thought! Go-forward dose established for Phase II Great response rates (A lucky start???) similar to AZA-001, but with higher CR rate Sekeres et al. Blood 2008;112:221a.

19 Intergroup Phase 2 MDS Proposal Higher-risk MDS (IPSS >1.5) AZA + LEN (Concomitant) N=119 Not Possible Sample Size = 9500!!! 12-month Treatment AZA + LEN (Sequential) N=119 AZA + Vorin N=119 Re- Randomize Ad Infinitum Treatment

20 One other approach to combination therapy

21 Dose regimen of ATO + GO GO 3mg/m 2 day 8 ATO 0.25 mg/kg x 5 days and 0.25 mg/kg twice a week for 11 weeks Total 1-2 Cycles Week 1 Week 2 Week 3 Week 4 Week 12 Week 24

22 ATO + GO: Baseline Characteristics Characteristic # with MDS RAEB-1 RAEB-2 CMML-2 # with 2 o AML Median Age (years) Previous therapies Months from diagnosis (n=30) % 6

23 ATO + GO: Responses Characteristic IWG MDS Responses (n=30) PR HI - N HI - Plt HI - Plt + N Stable Disease/Progression N=30 (%) 9 (30) 3 (33) 3 (33) 2 (22) 1 (11) 21 IWG AML Responses (n=12) PR Stable Disease/Progression 3 (25) 3 (100) 9

24 ATO + GO: Heme Toxicities Adverse Events (n=30) Patients with Any Event Patients with Grade 3/4 Event Event No. % No. % Thrombocytopenia 16 53% 14 47% Neutropenia 20 67% 19 63% Anemia 22 73% 11 37%

25 Combination Therapies: Conclusions Finally coming of age! Next step is to determine markers of response (real-time and predictive) Role in MDS relapsed/refractory At first blush, toxicities not substantially higher than single agents.

26 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!