E1496: ECOG and CALGB

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


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


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


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


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


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


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


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


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


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


E1496: Response to Induction chemotherapyE1496: Response to Induction chemotherapy

CF CF (n=110)(n=110)

CVPCVPR R


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


E1496 Maintenance RandomizationE1496 Maintenance Randomization

ReasonReason

CF CF (n=46)(n=46)

CVPCVPRR


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


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


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


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


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)


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)


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)


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)


Progression Free SurvivalCF vs. CVP +/- maintenance rituximab


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)


Overall Survival MR vs OBS for Induction CVP


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)


Overall Survival MR vs OBS for Induction CF


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)


Overall SurvivalCF vs. CVP +/- maintenance rituximab


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


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.


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.


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

Documents

E1496: ECOG and CALGB