eastern cooperative oncology group eastern cooperative oncology group E1496: ECOG and CALGB E1496: ECOG and CALGB Cyclophosphamide/Fludarabine (CF) with Cyclophosphamide/Fludarabine (CF) with or without Maintenance Rituximab (MR) or without Maintenance Rituximab (MR) in Advanced Indolent Lymphoma in Advanced Indolent Lymphoma Patients: Results from the E1496 Patients: Results from the E1496 Trial Trial Howard S. Hochster Edie Weller Randy D. Gascoyne Theresa S. Ryan Thomas M. Habermann Leo I. Gordon Stanley R. Frankel Sandra J. Horning
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 - PowerPoint PPT Presentation
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eastern cooperative oncology groupeastern cooperative oncology group
E1496: ECOG and CALGBE1496: ECOG and CALGB
Cyclophosphamide/Fludarabine (CF) with or Cyclophosphamide/Fludarabine (CF) with or without Maintenance Rituximab (MR) in without Maintenance Rituximab (MR) in
Advanced Indolent Lymphoma Patients: Advanced Indolent Lymphoma Patients: Results from the E1496 TrialResults 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
eastern cooperative oncology groupeastern cooperative oncology group
E1496: Rationale and ObjectivesE1496: Rationale and Objectives
Indolent Lymphoma – responsive to chemotherapy with Indolent Lymphoma – responsive to chemotherapy with long survivallong survival
Therapy is rarely curative Therapy is rarely curative with continuous relapse patternwith continuous relapse pattern
HypothesisHypothesis: Chemotherapy induction to maximal benefit : Chemotherapy induction to maximal benefit followed by therapy with anti-CD20 antibody will improve followed by therapy with anti-CD20 antibody will improve progression free survivalprogression free survival
To compare the response rate, PFS, and OS for treatment To compare the response rate, PFS, and OS for treatment with CF (cyclophosphamide ‑ fludarabine) to a control arm with CF (cyclophosphamide ‑ fludarabine) to a control arm consisting of standard treatment with CVPconsisting of standard treatment with CVP
To determine the effect of maintenance with anti‑CD20 To determine the effect of maintenance with anti‑CD20 (rituximab) on time to progression, time to treatment failure, (rituximab) on time to progression, time to treatment failure, and survival for CF and CVPand survival for CF and CVP
Indolent Lymphoma – responsive to chemotherapy with Indolent Lymphoma – responsive to chemotherapy with long survivallong survival
Therapy is rarely curative Therapy is rarely curative with continuous relapse patternwith continuous relapse pattern
HypothesisHypothesis: Chemotherapy induction to maximal benefit : Chemotherapy induction to maximal benefit followed by therapy with anti-CD20 antibody will improve followed by therapy with anti-CD20 antibody will improve progression free survivalprogression free survival
To compare the response rate, PFS, and OS for treatment To compare the response rate, PFS, and OS for treatment with CF (cyclophosphamide ‑ fludarabine) to a control arm with CF (cyclophosphamide ‑ fludarabine) to a control arm consisting of standard treatment with CVPconsisting of standard treatment with CVP
To determine the effect of maintenance with anti‑CD20 To determine the effect of maintenance with anti‑CD20 (rituximab) on time to progression, time to treatment failure, (rituximab) on time to progression, time to treatment failure, and survival for CF and CVPand survival for CF and CVP
eastern cooperative oncology groupeastern cooperative oncology group
E1496 Study HistoryE1496 Study History
Accrual 3/98 - 2/00Accrual 3/98 - 2/00
Suspended with 115 CF and 119 CVPSuspended with 115 CF and 119 CVPRR patients patients
32 CF deaths vs 8 CVP deaths (ASCO 2001)32 CF deaths vs 8 CVP deaths (ASCO 2001)
Terminated at 2nd interim analysisTerminated at 2nd interim analysis
Prolonged PFS with MR (ASCO 2004)Prolonged PFS with MR (ASCO 2004)
This AnalysisThis Analysis
Examine Effect of maintenance rituximab on CF and Examine Effect of maintenance rituximab on CF and randomized CVP (CVPrandomized CVP (CVPRR) patients) patients
eastern cooperative oncology groupeastern cooperative oncology group
MRMR Rituximab 375 mg/m2 wkly x 4Rituximab 375 mg/m2 wkly x 4
Start 4 wk after chemotherapy, every 6 m for 2 yrStart 4 wk after chemotherapy, every 6 m for 2 yr
ObservationObservation
MRMR
CVPCVPn=119n=119
CF CF (n=115)(n=115)
RANDOMIZE
RANDOMIZE
RESTAGE
Advanced Advanced Indolent Indolent
NHLNHLCR, PR, SD
Stratify: Histology, age,Tumor burden
Stratify: Histology,
Residual Disease*
CF CF (n=69)(n=69)
CVPCVPn=95n=95
*Minimal residual disease = <10% marrow, nodes < 2 cm, >75% reduction in large mass
eastern cooperative oncology groupeastern cooperative oncology group
E1496 Study Treatment (revised)E1496 Study Treatment (revised)
CC •• Cyclophosphamide 1000 mg/m Cyclophosphamide 1000 mg/m22 IV d 1 IV d 1VV •• Vincristine 1.4 mg /m Vincristine 1.4 mg /m22 (max = 2) IV d 1 (max = 2) IV d 1PP •• Prednisone 100 mg/m Prednisone 100 mg/m22 PO d 1-5 PO d 1-5Repeat q 21 d; best response + 2 cycles (6- 8)Repeat q 21 d; best response + 2 cycles (6- 8)
MRMR •• Rituximab 375 mg/m Rituximab 375 mg/m22 wkly x 4 wkly x 4 Start 4 wk after CVP; every 6 m for 2 yStart 4 wk after CVP; every 6 m for 2 y
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.
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.
eastern cooperative oncology groupeastern cooperative oncology group
E1496: CONCLUSIONSE1496: 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.
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.
eastern cooperative oncology groupeastern cooperative oncology group