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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
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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
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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)
Reopened 11/00: CVP induction (CVPReopened 11/00: CVP induction (CVPTT)) +/- +/- maintenance rituximabmaintenance rituximab
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
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E1496 EligibilityE1496 Eligibility
Stage III-IVStage III-IV
Low-grade (WF) histology: A,B,CLow-grade (WF) histology: A,B,C
Untreated, measurable diseaseUntreated, measurable disease
Age Age >> 18 years, ECOG 0-1 18 years, ECOG 0-1
Adequate organ functionAdequate organ function
Prospective assessment of tumor burdenProspective assessment of tumor burden
Stage III-IVStage III-IV
Low-grade (WF) histology: A,B,CLow-grade (WF) histology: A,B,C
Untreated, measurable diseaseUntreated, measurable disease
Age Age >> 18 years, ECOG 0-1 18 years, ECOG 0-1
Adequate organ functionAdequate organ function
Prospective assessment of tumor burdenProspective assessment of tumor burden
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E 1496 Study DesignE 1496 Study Design
CFCF Cyclophosphamide 1000 mg/mCyclophosphamide 1000 mg/m22 IV d 1, Fludarabine 20 mg/m IV d 1, Fludarabine 20 mg/m22 iv d 1-5 iv d 1-5
Repeat q 28 d; best response + 2 cycles (6- 8)Repeat q 28 d; best response + 2 cycles (6- 8)
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
CFCF Cyclophosphamide 1000 mg/mCyclophosphamide 1000 mg/m22 IV d 1, Fludarabine 20 mg/m IV d 1, Fludarabine 20 mg/m22 iv d 1-5 iv d 1-5
Repeat q 28 d; best response + 2 cycles (6- 8)Repeat q 28 d; best response + 2 cycles (6- 8)
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
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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
Observation Observation (OBS)(OBS)
Maintenance Maintenance Rituximab (MR)Rituximab (MR)
CVPCVP
RANDOMIZE
RESTAGE
CR, PR, SD
Stratify: Histology,Residual disease
N=282
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E1496 Study Population E1496 Study Population
CF CVPR CVPCVPT
Total Patients 115115 119119 401Path exclusion 4 4 66 18Other Ineligible 11 11 4Eligible 110110 112112 379Maintenance Randomization 6969 9595 322
Eligible and randomized 67*67* 89*89* 304
* All path exclusions
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E1496 Induction Patient Characteristics (%)E1496 Induction Patient Characteristics (%)
CF
(n = 110)CVPR
(n =112)CVPCVPT
(n=379)(n=379)
Age > 60 3939 4646 43
Median age (years) 5757 5858 58
Male 5151 5959 56
Follicular histology 7474 7373 76
Stage IV 7272 7979 70
PS 0 7575 7070 64
High tumor burden 6565 6666 65
LDH elevated 1616 1919 28
B symptoms present 2525 2323 25Bone marrow involved 7373 7979 70
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E1496 Induction Toxicity (%)E1496 Induction Toxicity (%)
Grade 3-5 Grade 3-5 toxicitytoxicity
CFCF
(n=115)(n=115)
CVPCVPRR
(n =119)(n =119)
CVPCVPTT
(n =401)(n =401)p valuep value
NeutropeniaNeutropenia 82%82% 37%37% 30%30% <0.0001<0.0001
ThrombopeniaThrombopenia 29%29% 4%4% 3%3% <0.0001<0.0001
Febrile Febrile neutropenianeutropenia
3%3% 0%0% 1%1% 0.120.12
InfectionInfection 17%17% 5%5% 7%7% 0.0030.003
PulmonaryPulmonary 7%7% 3%3% 3%3% 0.250.25
N, VN, V 10%10% 2%2% 2%2% 0.010.01
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E1496 Grade 5 Toxicity (n)E1496 Grade 5 Toxicity (n)
TOXICITYTOXICITY CFCF(n=115)(n=115)
CVPCVPR R
(n=119)(n=119) p valuep value
Infection/sepsis Infection/sepsis 55 00 0.030.03
LiverLiver 22 00 NSNS
CNSCNS 11 00 NSNS
CardiacCardiac 00 11 NSNS
MAINTENANCEMAINTENANCE
InfectionInfection 4*4* 00 0.030.03
*1 = OBS; 3 MR
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E1496: Response to Induction chemotherapyE1496: Response to Induction chemotherapy
CF CF (n=110)(n=110)
CVPCVPR R
(n=112)(n=112) p valuep value
CRCR 56 (51%)56 (51%) 25 (22%)25 (22%) <0.0001<0.0001
PRPR 38 (35%)38 (35%) 61 (55%)61 (55%) NSNS
SDSD 5 (5%)5 (5%) 16 (14%)16 (14%) NSNS
RRRR 94 (86%)94 (86%) 77 (77%)77 (77%) NSNS
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E1496 Maintenance RandomizationE1496 Maintenance Randomization
ReasonReason
CF CF (n=46)(n=46)
CVPCVPRR
(n=24)(n=24) p valuep value
Central pathology Central pathology reviewreview 3 (6%)3 (6%) 2 (8%)2 (8%) 0.660.66
Progressive Progressive diseasedisease 11 (24%)11 (24%) 11 (46%)11 (46%) 0.100.10
Induction toxicityInduction toxicity 19 (41%)19 (41%) 1 (4%)1 (4%) 0.00080.0008
Pt refusal or Pt refusal or withdrawalwithdrawal 6 (13%)6 (13%) 4 (17%)4 (17%) 0.730.73
Other/unknownOther/unknown 7 (15%)7 (15%) 6 (25%)6 (25%) 0.220.22
Induction Patients Not Proceeding to 2nd Randomization
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E1496 Maintenance Patient CharacteristicsE1496 Maintenance Patient Characteristics(%)(%)
CF CF (n=67)(n=67) CVPCVPRR (n=89)(n=89)
MRMR
(n = 34)(n = 34)OBS OBS
(n =33)(n =33)MRMR
(n = 48)(n = 48)OBS OBS
(n =41)(n =41)
Age > 60 2929 3030 4040 3737
Median age (years) 5353 5050 5555 5757
Male 5353 3939 5656 7171
Follicular histology 7474 7373 7171 7676
Stage IV 7474 7070 8181 7676
PS 0 7979 8888 8181 6363
High tumor burden 7474 5555 6767 6363
LDH elevated 1212 1515 2222 1414
B symptoms present 2727 2121 1010 3939
Bone marrow involved 7979 6767 7979 7676
Minimal Residual Disease
(p<0.0001)9494 9797 6767 6363
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E1496 Maintenance Toxicity E1496 Maintenance Toxicity (%)(%)
CF CF (n=69)(n=69) CVPCVPRR (n=95)(n=95)
Grade 3-5 Grade 3-5 toxicitytoxicity
MRMR
(n = 35)(n = 35)OBS OBS
(n =34)(n =34)MRMR
(n = 49)(n = 49)OBS OBS
(n =46)(n =46)
NeutropeniaNeutropenia 2525 2727 00 00
ThrombopeniaThrombopenia 1212 1818 00 00
Febrile Febrile neutropenianeutropenia
33 00 00 00
InfectionInfection 2525 1515 22 22
PulmonaryPulmonary 1212 33 00 00
DiarrheaDiarrhea 99 33 00 00
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E1496: Response to Maintenance TherapyE1496: Response to Maintenance Therapy
CFCF
(n=67)(n=67)
CVPCVPRR
(n=89)(n=89) p-valuep-value
CRCR 41 (61%)41 (61%) 24 (27%)24 (27%) 0.000020.00002
PRPR 22 (33%)22 (33%) 53 (60%)53 (60%) 0.0020.002
SDSD 3 (5%)3 (5%) 11 (12%)11 (12%) 0.100.10
RRRR63 (94%)63 (94%) 9 (87%)9 (87%) 0.180.18
Improved Improved Response after Response after randomizationrandomization
9/25 (36%)9/25 (36%) 20/64 (31%)20/64 (31%) 0.810.81
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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)
Years from Induction Randomization
Pro
bab
ilit
y
0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
CF (110)
CVP (112)
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Overall Survival CF vs CVP Patients
Years from Induction Randomization
Pro
bab
ilit
y
0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
Median NR vs. NR y
Logrank p=0.12
HR=1.4 (0.9,2.2)
CF (110)
CVP (112)
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Progression Free Survival MR vs OBS for Induction CVP
Years from Maintenance Randomization
Pro
bab
ilit
y
0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
Median 4.9 vs. 1.3 y
Logrank p=0.004
HR=0.5 (0.3,0.8)
MR (48)
OBS (41)
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Progression Free Survival MR vs OBS for Induction CF
Years from Maintenance
Pro
bab
ilit
y
0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
Median NR vs. 5.0 y
Logrank p=0.19
HR=0.7 (0.4,1.5)
MR (34)
OBS (33)
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Progression Free SurvivalCF vs. CVP +/- maintenance rituximab
Years from Maintenance Randomization
Pro
bab
ilit
y
0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
CF-MR (34)CF-OBS (33)CVP-MR (48)CVP-OBS (41)
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Overall Survival MR vs OBS for Induction CVP
Years from Maintenance Randomization
Pro
bab
ilit
y
0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
MR (48)
OBS (41)
Median NR vs. NRLogrank p=0.21HR = 0.7 (0.3,1.6)
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Overall Survival MR vs OBS for Induction CF
Years from Maintenance Randomization
Pro
bab
ilit
y
0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
MR (34)
OBS (33)
Median NR vs. NRLogrank p=0.42HR = 1.1 (0.4,2.9)
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Overall SurvivalCF vs. CVP +/- maintenance rituximab
Years from Maintenance Randomization
Pro
bab
ility
CF-MR (34)CF-OBS (33)
CVP-MR (48)CVP-OBS (41)
0 2 4 6 8
0.0
0.2
0.4
0.6
0.8
1.0
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E1496: CONCLUSIONSE1496: 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.
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.
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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.
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With our Thanks:With our Thanks:
Co-investigatorsCo-investigators
Institutional investigatorsInstitutional investigators
Data Management staffData Management staff
ECOG Operations Office and Statistical ECOG Operations Office and Statistical Center staffsCenter staffs
Patients Patients
Co-investigatorsCo-investigators
Institutional investigatorsInstitutional investigators
Data Management staffData Management staff
ECOG Operations Office and Statistical ECOG Operations Office and Statistical Center staffsCenter staffs
Patients Patients