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E1496: ECOG and CALGB

E1496: ECOG and CALGB. Cyclophosphamide/Fludarabine (CF) with or without Maintenance Rituximab (MR) in Advanced Indolent Lymphoma Patients: Results from the E1496 Trial Howard S. Hochster Edie Weller Randy D. Gascoyne Theresa S. Ryan Thomas M. Habermann Leo I. Gordon Stanley R. Frankel

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E1496: ECOG and CALGB

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  1. E1496: ECOG and CALGB Cyclophosphamide/Fludarabine (CF) with or without Maintenance Rituximab (MR) in Advanced Indolent Lymphoma Patients: Results from the E1496 Trial Howard S. Hochster Edie Weller Randy D. Gascoyne Theresa S. Ryan Thomas M. Habermann Leo I. Gordon Stanley R. Frankel Sandra J. Horning

  2. E1496: Rationale and Objectives • Indolent Lymphoma – responsive to chemotherapy with long survival • Therapy is rarely curative with continuous relapse pattern • Hypothesis: Chemotherapy induction to maximal benefit followed by therapy with anti-CD20 antibody will improve progression free survival • To compare the response rate, PFS, and OS for treatment with CF (cyclophosphamide ‑ fludarabine) to a control arm consisting of standard treatment with CVP • To determine the effect of maintenance with anti‑CD20 (rituximab) on time to progression, time to treatment failure, and survival for CF and CVP

  3. E1496 Study History • Accrual 3/98 - 2/00 • Suspended with 115 CF and 119 CVPR patients • 32 CF deaths vs 8 CVP deaths (ASCO 2001) • Reopened 11/00: CVP induction (CVPT) +/- maintenance rituximab • Terminated at 2nd interim analysis Prolonged PFS with MR (ASCO 2004) • This Analysis • Examine Effect of maintenance rituximab on CF and randomized CVP (CVPR) patients

  4. E1496 Eligibility • Stage III-IV • Low-grade (WF) histology: A,B,C • Untreated, measurable disease • Age > 18 years, ECOG 0-1 • Adequate organ function • Prospective assessment of tumor burden

  5. E 1496 Study Design CFCyclophosphamide 1000 mg/m2 IV d 1, Fludarabine 20 mg/m2 iv d 1-5 Repeat q 28 d; best response + 2 cycles (6- 8) MRRituximab 375 mg/m2 wkly x 4 Start 4 wk after chemotherapy, every 6 m for 2 yr RANDOMIZE RANDOMIZE RESTAGE MR CF (n=115) CF (n=69) Advanced Indolent NHL CR, PR, SD Observation CVP n=95 CVP n=119 Stratify: Histology, age, Tumor burden Stratify: Histology, Residual Disease* *Minimal residual disease = <10% marrow, nodes < 2 cm, >75% reduction in large mass

  6. E1496 Study Treatment (revised) RANDOMIZE RESTAGE Maintenance Rituximab (MR) Stratify: Histology, Residual disease CVP CR, PR, SD Observation (OBS) N=282 C• Cyclophosphamide 1000 mg/m2 IV d 1 V• Vincristine 1.4 mg /m2 (max = 2) IV d 1 P• Prednisone 100 mg/m2 PO d 1-5 Repeat q 21 d; best response + 2 cycles (6- 8) MR• Rituximab 375 mg/m2 wkly x 4 Start 4 wk after CVP; every 6 m for 2 y

  7. E1496 Study Population * All path exclusions

  8. E1496 Induction Patient Characteristics (%)

  9. E1496 Induction Toxicity (%)

  10. E1496 Grade 5 Toxicity (n) *1 = OBS; 3 MR

  11. E1496: Response to Induction chemotherapy

  12. E1496 Maintenance Randomization Induction Patients Not Proceeding to 2nd Randomization

  13. E1496 Maintenance Patient Characteristics(%)

  14. E1496 Maintenance Toxicity (%)

  15. E1496: Response to Maintenance Therapy

  16. 1.0 0.8 0.6 Probability 0.4 CF (110) CVP (112) 0.2 0.0 0 2 4 6 8 Years from Induction Randomization Progression Free Survival CF vs CVP Patients Median 3.8 vs. 3.3 y Logrank p=0.19 HR=0.8 (0.6,1.1)

  17. 1.0 0.8 0.6 Probability 0.4 Median NR vs. NR y Logrank p=0.12 0.2 HR=1.4 (0.9,2.2) 0.0 0 2 4 6 8 Overall Survival CF vs CVP Patients CVP (112) CF (110) Years from Induction Randomization

  18. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 Progression Free Survival MR vs OBS for Induction CVP Probability MR (48) Median 4.9 vs. 1.3 y Logrank p=0.004 OBS (41) HR=0.5 (0.3,0.8) Years from Maintenance Randomization

  19. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 Progression Free Survival MR vs OBS for Induction CF MR (34) Probability Median NR vs. 5.0 y OBS (33) Logrank p=0.19 HR=0.7 (0.4,1.5) Years from Maintenance

  20. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 Progression Free Survival CF vs. CVP +/- maintenance rituximab CF-MR (34) CF-OBS (33) CVP-MR (48) CVP-OBS (41) Probability Years from Maintenance Randomization

  21. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 Overall Survival MR vs OBS for Induction CVP MR (48) OBS (41) Probability Median NR vs. NR Logrank p=0.21 HR = 0.7 (0.3,1.6) Years from Maintenance Randomization

  22. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 8 6 Overall Survival MR vs OBS for Induction CF OBS (33) MR (34) Probability Median NR vs. NR Logrank p=0.42 HR = 1.1 (0.4,2.9) Years from Maintenance Randomization

  23. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 Overall Survival CF vs. CVP +/- maintenance rituximab Probability CF-MR (34) CF-OBS (33) CVP-MR (48) CVP-OBS (41) Years from Maintenance Randomization

  24. E1496: CONCLUSIONS • Induction CF (E1496 dose & schedule), compared to CVP, resulted in: • Higher CR and OR rates (56 vs 25%; 94 vs 77%) • Higher minimal disease rates (95 vs 65%) • Increased induction toxicity and mortality (gr 3-5 hematologic toxicity = 96 vs 59% ) • Maintenance rituximab after induction: • Was given to fewer CF patients due to induction toxicity • Was associated with greater toxicity after CF. • Prolonged PFS after CVP but not after CF.

  25. E1496: CONCLUSIONS • CF followed by observation resulted in longer PFS (median 5 y) than the CVP-observation arm (median 1.3 y, p= 0.02) • Similar to CVP-MR arm (median 4.9 yrs) • No differences in OS observed to date. • CF in E1496 dose and schedule cannot be recommended due to toxicity. • Results suggest that a more effective induction regimen can translate into longer PFS and that the benefit of MR may be more difficult to demonstrate in that setting.

  26. With our Thanks: • Co-investigators • Institutional investigators • Data Management staff • ECOG Operations Office and Statistical Center staffs • Patients

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