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Background

A randomized trial of anthracycline dose intensification during induction in younger patients with acute myeloid leukemia: Results of Eastern Cooperative Oncology Group study E1900.

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  1. A randomized trial of anthracycline dose intensification during induction in younger patients withacute myeloid leukemia: Results of Eastern Cooperative Oncology Group study E1900 Hugo F. Fernandez, MD; Zhuoxin Sun, PhD; Mark R. Litzow, MD; Selina M. Luger, MD; Elisabeth M. Paietta, PhD; Gordon Dewald, PhD; Rhett P. Ketterling, MD; Jacob M. Rowe, MD; Hillard M. Lazarus, MD; Martin S. Tallman, MD

  2. Background • In younger adults (<60 years old) with newly diagnosed AML: • Daunorubicin 45mg/m2/dayCR rates of 50 -75% • Anthracycline dose-intensification during induction may improve CR: • SWOG daunorubicin 70mg/m2/d • High CR rates in young group • CALGB 9621- daunorubicin 90-95mg/m2/d • High CR rates/ tolerable toxicity • OS improvement not demonstrated in a randomized trial.

  3. E1900: Objectives Primary Objective: To compare OS between two induction regimens daunorubicin 45mg/m2 vs. 90mg/m2/d Secondary Objectives: Evaluate impact of allogeneic SCT in AML patients with unfavorable prognostic factors Evaluate impact pre HSCT GO on DFS Planned accrual goal: 830 patients Closed November 2008- 657 patients.

  4. Eligibility • De novo Acute Myeloid Leukemia • Per WHO 2001 criteria • Age 16-60 years • No prior treatment • No MDS > 6 months • Allogeneic or autologous HSCT candidate

  5. ECOG Protocol E1900:Schema Risk Allocation Autologous SCT Busulfan IV 0.8 mg/kg Every 6 hrs x 16 doses Cyclophosphamide 60mg/kg/d x 2 High Intermediate Allogeneic HSCT Daunorubicin45 mg/m2/day x 3 or 90 mg/m2/day x 3 + Cytarabine 100 mg/m2/day x 7 CR HiDAC x 2; PBSC Harvest after 2nd course Favorable Intermediate Indeterminate Gemtuzumab Ozogamicin 6 mg/m2 IV x 1 Persistent AML: 2nd cycle of Daunorubicin 45mg/m2/d x3 Cytarabine 100mg/m2/d x7 Closed to accrual 10/2007

  6. Results • 657 patients entered • Age: median 48 (17 to 60 ) years • Patient demographics similar • Disease characteristics similar • Data base closed as of March 1, 2009 • 547 evaluable for response

  7. Disposition of Patients

  8. Results: Toxicity • Induction deaths were similar • 45mg/m2 : 4.5%; • 90mg/m2 : 5.5% • Grade 3/4 toxicity similar • High-dose daunorubicin arm • Cardiac toxicity not increased • Did not impact delivery of HSCT

  9. Post-remission • Patients allocated to: • Allogeneic: high risk • Autologous : favorable, intermediate • Recovered from induction toxicity • 341/657 (51.9%) registered to second step • 49.9% transplanted • 34 received allogeneic transplant • 136 received autologous transplant

  10. Overall Survival by Induction Treatment-All Patients 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.003 0.0 0 10 20 30 40 50 60 70 80 Months Induction Treatment TOTAL FAIL CNSR MEDIAN 45 mg/m2/day 330 199 131 15.7 90 mg/m2/day 327 168 159 23.7 OS by Induction-All Patients

  11. 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.002 0.0 0 10 20 30 40 50 60 Months Induction Treatment TOTAL FAIL CNSR MEDIAN 45 mg/m2/day 238 128 110 16.5 90 mg/m2/day 221 94 127 28.6 OS by Induction: <55years

  12. Overall Survival by Treatment -- Age>=55 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.63 0.0 0 10 20 30 40 50 60 Months Induction Treatment TOTAL FAIL CNSR MEDIAN 45 mg/m2/day 78 49 29 12.6 90 mg/m2/day 96 58 38 16.3 OS by Induction:≥55 Years

  13. Cytogenetic Risk

  14. 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.004 0.0 0 10 20 30 40 50 60 70 Months Induction Treatment TOTAL FAIL CNSR MEDIAN 45 mg/m2/day 180 95 85 20.7 90 mg/m2/day 178 71 107 34.3 OS by Induction: Favorable and Intermediate

  15. 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 Log Rank Test p=0.45 0.0 60 0 10 20 30 40 50 Months FAIL Induction Treatment MEDIAN TOTAL CNSR 45 mg/m2/day 59 46 13 10.2 63 18 10.4 90 mg/m2/day 45 OS by Induction: Unfavorable

  16. Response by Mutational Analysis

  17. Overall Survival by Induction Treatment--FLT3 Positive Patients 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.091 0.0 0 10 20 30 40 50 60 70 Months Induction Treatment TOTAL FAIL CNSR MEDIAN 45 mg/m2/day 83 65 18 10.2 90 mg/m2/day 64 39 25 15.2 OS by Induction: FLT3 Positive

  18. Overall Survival by Induction Treatment--FLT3 Negative Patients 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.014 0.0 0 10 20 30 40 50 60 70 Months Induction Treatment TOTAL FAIL CNSR MEDIAN 45 mg/m2/day 215 119 96 18.9 90 mg/m2/day 241 116 125 28.6 OS by Induction: FLT3 Negative

  19. Overall Survival by FLT3 at the high dose 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.009 0.0 20 40 60 0 10 30 50 70 Months FLT3 ITD TOTAL FAIL CNSR MEDIAN Negative 241 116 125 28.6 Positive 64 39 25 15.2 OS Daunorubicin 90mg/m2/d: FLT3 Status

  20. Overall Survival by Induction Treatment--MLL-PTD Positive Patients 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.30 0.0 0 10 20 30 40 50 Months Induction Treatment TOTAL FAIL CNSR MEDIAN 45 mg/m2/day 16 15 1 16.2 90 mg/m2/day 15 10 5 19.0 OS by Induction: MLL Positive

  21. Overall Survival by Induction Treatment--MLL-PTD Negative Patients 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 0.1 Log Rank Test p=0.002 0.0 0 10 20 30 40 50 60 70 80 Month Induction Treatment TOTAL FAIL CNSR MEDIAN 45 mg/m2/day 290 175 115 15.1 90 mg/m2/day 296 149 147 25.0 OS by Induction: MLL Negative

  22. Conclusions • In AML patients <60 years, induction therapy with daunorubicin 90mg/m2/d: • Is safe • Improves CR rates: 70.6% vs. 57.3% • Improves OS: 23.7 vs. 15.7 mo. • 45mg/m2/d is no longer the standard dose

  23. Future Directions • Randomized trial of other anthracycline doses • Daunorubicin 60 mg vs. 90 mg/m2/day • Idarubicin 12 mg/m2/day vs. 90 mg/m2/day • Focus on shortcomings • Patients older than 55 years- P-gp inhibitors- Zosuquidar • Unfavorable cytogenetics • Mutation abnormalities • FLT3 positive- CALGB 10603- RATIFY trial • MLL

  24. Acknowledgements Investigators Laboratory Elisabeth Paietta Janis Racevskis Rhett Ketterling Gordon DeWald Gary Hicks John Bennett Data/ Statistics Zhuoxin Sun Julie Mann Xiaopan Yao • Martin Tallman • Hillard Lazarus • Mark Litzow • Selina Luger • Jacob Rowe • ECOG E1900 PIs

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