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Treatment of MDS in 2014 and Beyond Treatment Goals in MDS

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Treatment of MDS in 2014 and Beyond Treatment Goals in MDS 5/22/2014 Treatment of MDS in 2014 and Beyond Treatment goals in MDS • Get rid of it May 17, 2014 • If you can’t do that, make life better and longer – Improve blood counts Gail J. Roboz, M.D. – Improve quality of life Director, Leukemia Program – Decrease time to progression/leukemia Associate Professor of Medicine Hematopoietic Growth Factors: Hematopoietic Growth Factors: What are they? What are they? • Erythropoietin (EPO,Procrit®, Epogen®) – red • Synthetic versions of proteins normally • Granulocyte colony stimulating factor (GCSF, made in the body to stimulate growth of red Neupogen®) – white cells, white cells and platelets • Granulocyte-macrophage colony stimulating • Promote growth and differentiation factor (GM-CSF, Leukine®) – white • Thrombopoietin (TPO, romiplostim, Nplate®) – • Inhibitors of apoptosis (cell death) platelets • Darbepoietin (Aranesp®) • Peg-filgrastim (Neulasta®) • Note, these are not FDA-approved for MDS Erythropoietin (epo) in MDS Erythropoietin (epo) in MDS • Anemia is presents in >80% of MDS pts at dx • Often high endogenous epo levels • Transfusions help, but many issues • Many different doses and schedules • Recombinant EPO is FDA-approved for treating • Higher response rates with epo + G-CSF if anemia associated with kidney failure epo ≤500 mU/mL and transfusions <2 • Has been used since about 1990 in MDS U/month • Response rates in about 15-30% of patients • Poor probability of response if epo >500 • Many different studies including >1000 patients mU/mL and transfusions >2 U/month • Part of the NCCN MDS treatment guidelines 1. Casadevall N, et al. Blood. 2004;104:321-327. 2. Hellstrom-Lindberg E. Br J Haematol. 1995;89:67-71. 3. Hellstrom-Lindberg E, et al. Br J Haematol. 1997;99:344-351. 4. Ludwig H. Semin Oncol. 2002;29:45-54. 1 5/22/2014 Erythropoietin (epo) in MDS Problem • Varying response criteria in clinical trials: usually • Studies of EPO in solid tumor patients showed complete response is increase in hgb to at least increased heart attacks, stroke, heart failure, blood 11.5 without transfusions, partial response clots, increased tumor growth, death, especially increase of hgb by at least 1.5 g/dl or reduction in when hgb >12 transfusion requirements • Responses usually in 12-16 weeks • Has resulted in concern for MDS patients, but NO DATA yet showing these effects in MDS patients • Generally well-tolerated • Side effects: hypertension, fever, headache, • Has had major effects on insurance coverage nausea, chest pain EPO in MDS: Good or Bad? Stimulating White Blood Cells • Don’t treat the number, treat the patient • Will be difficult to do a study in MDS proving • Not for routine treatment EPO is safe, so concern will remain • Active infections, recurrent/resistant • Note: JCO study, Jadersten et al (vol 26, July infections, neutropenic fever 2008): Erythropoietin and granulocyte-colony stimulating factor treatment associated with • Can be combined with red cell growth improved survival in MDS factors to improve responses in some • Mostly low-risk patients patients • Erythroid response 39%, median duration 23 mos • Side effects: fever, bone pain, injection site • Improved survival in pts requiring fewer than 2 reactions units/month • Does stimulating white cells cause • No increased AML leukemia?? Romiplostim in MDS Summary Original Article Lenalidomide in the Myelodysplastic Syndrome • In patients receiving azacitidine, romiplostim vs with Chromosome 5q Deletion placebo: Alan List, M.D., Gordon Dewald, Ph.D., John Bennett, M.D., Aristotle Giagounidis, – increased PLT counts over time and increased M.D., Azra Raza, M.D., Eric Feldman, M.D., Bayard Powell, M.D., Peter Greenberg, M.D., Deborah Thomas, M.D., Richard Stone, M.D., Craig Reeder, M.D., Kenton PLT count nadir during treatment cycles Wride, M.S., John Patin, M.S., Michele Schmidt, R.N., Jerome Zeldis, M.D., Robert – reduced incidence of clinically significant Knight, M.D., for the Myelodysplastic Syndrome-003 Study Investigators thrombocytopenic events – reduced incidence of PLT transfusions – fewer Grade ≥ 3 bleeding events N Engl J Med • Romiplostim plus azacitidine well-tolerated Volume 355(14):1456-1465 October 5, 2006 2 5/22/2014 Kaplan-Meier Estimate of the Duration of Independence from Red-Cell Lenalidomide: Erythroid Response Data Transfusion Data Parameter Del 5q (n=148) Erythroid response Transfusion indep 99 (67%)* Minor (>50% ↓) 13 (9%) Median duration of transfusion independence † >104 wks Median Hgb rise 5.4 g/dL (1.1–11.4) Median time to initial response 4.6 wk (1–49) *P<0.001; †not reached at median follow-up of 104 wk 90% of responses occur within the first 3 months List A et al. N Engl J Med 2006;355:1456-1465 List A et al. N Engl J Med 2006;355:1456-1465 Practical issues with lenalidomide Epigenetic Therapy • CBC weekly for at least first 8 weeks, significant neutropenia and thrombocytopenia • Dose adjustments may be necessary for thrombocytopenia and neutropenia, but they may be indicative of response, especially in 5q- patients Revlimid® (lenalidomide) prescribing information. Available at: www.celgene.com/PDF/RevlimidPI.pdf CALGB 9221 Phase 3 Trial of Subcutaneous Randomized Study of Azacitidine in Azacitidine vs Supportive Care Patients With MDS: Results Supportive Care R ≥4 mo unless transformation to 1.0 AML, higher FAB type, (N=191) • CR = 7% A progressive BM failure, or death • PR = 16% N 0.8 Azacitidine RA D Supportive Care • Improved 37% RARS O A M S 0.6 RAEB Response*: Continue I S RAEB-T Z x 4 cycles E No response*: Off study 0.4 S CMML A T Azacitidine S (n=191) 0.2 I 75 mg/m2/day for 7 days every Survival Probability Probability Survival O 28 days N 0.0 0 6 12 18 24 30 36 42 48 54 *Not IWG response 4 week months 75 mg/m2/d SC x 7 days every month. Silverman LR, et al. J Clin Oncol. 2002;20:2429-2440. Kornblith AB, et al. J Clin Oncol. 2002;20:2441-2452. Silverman et al. J Clin Oncol. 2002;20:2429 3 5/22/2014 Effect of Azacitidine on Azacitidine vs Supportive Care: Quality of Life and Transfusions Most Frequent Adverse Events (>30%) Improvement in: Adverse event Azacitidine (n=220), % Supportive care (n=92), % Nausea 70.5 17.4 – Fatigue Anemia 69.5 64.1 – Dyspnea Thrombocytopenia 65.5 45.7 – Physical functioning Vomiting 54.1 5.4 Pyrexia 51.8 30.4 – Positive affect Leukopenia 48.2 29.3 – Psychologic distress Diarrhea 36.4 14.1 45% became transfusion-independent Fatigue 35.9 25 Injection site erythema 35.0 0.0 9% had a 50% reduction in transfusions Constipation 33.6 6.5 Neutropenia 32.3 10.9 Silverman LR, et al. J Clin Oncol. 2002;20:2429- Ecchymosis 30.5 15.2 2440. Kornblith AB, et al. J Clin Oncol. 2002;20:2441- Silverman LR, et al. J Clin Oncol. 2002;20:2429-2440. 2452. Kaminskas E, et al. Clin Cancer Res. 2005;11:3604-3608. Azacitidine vs. conventional care regimens Azacitidine Treatment Prolongs Overall Survival in Higher-Risk MDS Patients Compared with Conventional Care Regimens: Results of the AZA-001 Phase III Study P Fenaux, MD, GJ Mufti, MD, V Santini, MD, C Finelli, MD, A Giagounidis, MD, R Schoch, MD,A List, MD, S Gore, MD, J Seymour, MD, E Hellstrom-Lindberg, MD, J Bennett, MD, J Byrd, MD, J Backstrom, MD, L Zimmerman, BSN, D McKenzie, MS, CL Beach, PharmD and L Silverman, MD on behalf of the International Vidaza High-Risk MDS Survival Study Group P et al. Lancet Oncology 2009;10(3):223-232. Overall Survival: Azacitidine vs CCR Important features of this trial ITT Population Log-Rank p=0.0001 1.0 HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 • 79 sites in 15 countries 0.9 0.8 Difference: 9.4 months • Median age 69 years (38-88) 0.7 • 113 pts (32%) met WHO criteria for AML 0.6 50.8% 0.5 24.4 months • 18 pts with IPSS Int-1 0.4 15 months 26.2% • 8 patients sent for allo transplant (did not 0.3 AZA Proportion Surviving Proportion 0.2 CCR affect overall survival) 0.1 0.0 • Azacitidine given for median 9 cycles 0 5 10 15 20 25 30 35 40 Time (months) from Randomization 23 4 5/22/2014 Secondary endpoints also Further analysis of AZA-001 favored aza • OS better for AZA in all cytogenetic subgroups, esp - • AZA better survival and better tolerated than 7/del7q LDAC (Fenaux, Br J Hematol 2010) • Time to AML 17.8 mos AZA, 11.5 mos CCR, p<0.0001 • Older pts with 20-30% blasts improved OS with AZA (Fenaux, JCO 2010) • Improved RBC Transfusion Independence with AZA • Ongoing treatment with AZA beyond time of – 45% with AZA vs 11% with CCR, p<0.0001 first response improved quality of response • Infections Requiring IV Antimicrobials (Silverman, Cancer 2011) – Reduced by 33% with AZA vs CCR 25 26 Decitabine in MDS Phase III Study of Decitabine in Myelodysplastic Syndrome • Nucleoside analogue (5-aza-2’- Open-label, 1:1 randomized, multi-center study in the US and Canada deoxycytidine) R A Decitabine + Supportive • FDA approved on 5/2/06 for: N Care* D – Previously treated and untreated MDS Stratification (N = 89) Eligible O Patients • IPSS Classification – De novo and secondary MDS (N = 170) M • Prior Chemotherapy I • Study Center – All FAB subtypes Z E – IPSS Int-1, Int-2, and high-risk groups Supportive Care* D (N = 81) *Antibiotics, Growth Factors and/or Transfusions Schedule: 15 mg/m2 IV 3 hour infusion q 8 hrs x 3 days 27 Kantarjian et al, Cancer. 2006 Apr 15;106(8):1794-803 Phase III Decitabine vs.
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