1. eastern cooperative oncology group 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. eastern cooperative oncology group 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  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. eastern cooperative oncology group E1496 Study History  Accrual 3/98 - 2/00  Suspended with 115 CF and 119 CVP R patients  32 CF deaths vs 8 CVP deaths (ASCO 2001)  Reopened 11/00: CVP induction (CVP T ) +/- 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 (CVP R ) patients

4. eastern cooperative oncology group 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  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. eastern cooperative oncology group E 1496 Study Design CF Cyclophosphamide 1000 mg/m 2 IV d 1, Fludarabine 20 mg/m 2 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 CF Cyclophosphamide 1000 mg/m 2 IV d 1, Fludarabine 20 mg/m 2 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 Observation MR CVPn=119 CF(n=115) RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE RESTAGERESTAGE Advanced Indolent NHL CR, PR, SD Stratify: Histology, age, Tumor burden Stratify: Histology, Residual Disease* CF CF(n=69) CVPn=95 *Minimal residual disease = 75% reduction in large mass

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

7. eastern cooperative oncology group E1496 Study Population CFCVP R CVP CVP T Total Patients115119401 Path exclusion 4 6 18 Other Ineligible 1 1 4 Eligible110112379 Maintenance Randomization6995322 Eligible and randomized67*89*304 * All path exclusions

8. eastern cooperative oncology group E1496 Induction Patient Characteristics (%) CF (n = 110) CVP R (n =112) CVP CVP T(n=379) Age > 60394643 Median age (years)575858 Male515956 Follicular histology747376 Stage IV727970 PS 0757064 High tumor burden656665 LDH elevated161928 B symptoms present252325 Bone marrow involved737970

9. eastern cooperative oncology group E1496 Induction Toxicity (%) Grade 3-5 toxicity CF(n=115) CVP R (n =119) CVP T (n =401) p value Neutropenia82% 37% 37%30%<0.0001 Thrombopenia29%4%3%<0.0001 Febrile neutropenia 3%0%1%0.12 Infection17%5%7%0.003 Pulmonary7%3%3%0.25 N, V 10%2%2%0.01

10. eastern cooperative oncology group E1496 Grade 5 Toxicity (n) TOXICITYCF(n=115) CVP R (n=119) p value Infection/sepsis5 00.03 Liver20NS CNS10NS Cardiac01NS MAINTENANCE Infection4*00.03 *1 = OBS; 3 MR

11. eastern cooperative oncology group E1496: Response to Induction chemotherapy CF (n=110) CVP R (n=112) p value p value CR 56 (51%) 25 (22%) <0.0001 PR 38 (35%) 61 (55%) NS SD 5 (5%) 16 (14%) NS RR 94 (86%) 77 (77%) NS

12. eastern cooperative oncology group E1496 Maintenance Randomization Reason Reason CF (n=46) CVP R (n=24) p value p value Central pathology review 3 (6%) 2 (8%) 0.66 Progressive disease 11 (24%) 11 (46%) 0.10 Induction toxicity 19 (41%) 1 (4%) 0.0008 Pt refusal or withdrawal 6 (13%) 4 (17%) 0.73 Other/unknown 7 (15%) 6 (25%) 0.22 Induction Patients Not Proceeding to 2nd Randomization

13. eastern cooperative oncology group E1496 Maintenance Patient Characteristics (%) CF(n=67) CVP R CVP R(n=89) MR (n = 34) OBS (n =33) MR (n = 48) OBS (n =41) Age > 6029304037 Median age (years)53505557 Male53395671 Follicular histology74737176 Stage IV74708176 PS 079888163 High tumor burden74556763 LDH elevated12152214 B symptoms present27211039 Bone marrow involved79677976 Minimal Residual Disease (p<0.0001)94976763

14. eastern cooperative oncology group E1496 Maintenance Toxicity (%) CF(n=69) CVP R (n=95) Grade 3-5 toxicity MR (n = 35) OBS (n =34) MR (n = 49) OBS (n =46) Neutropenia252700 Thrombopenia121800 Febrile neutropenia 3000 Infection251522 Pulmonary12300 Diarrhea9300

15. eastern cooperative oncology group E1496: Response to Maintenance Therapy CF(n=67) CVP R (n=89) p-value p-value CR 41 (61%) 24 (27%) 0.00002 PR 22 (33%) 53 (60%) 0.002 SD 3 (5%) 11 (12%) 0.10 RR 63 (94%) 9 (87%) 0.18 Improved Response after randomization 9/25 (36%) 20/64 (31%) 0.81

16. eastern cooperative oncology group 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. eastern cooperative oncology group Overall Survival CF vs CVP Patients Years from Induction Randomization CF (110) CVP (112)

18. eastern cooperative oncology group Progression Free Survival MR vs OBS for Induction CVP Years from Maintenance Randomization Probability 02468 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)

19. eastern cooperative oncology group Progression Free Survival MR vs OBS for Induction CF Years from Maintenance Probability 0246 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)

20. eastern cooperative oncology group Progression Free Survival CF vs. CVP +/- maintenance rituximab Years from Maintenance Randomization Probability CF-MR (34) CF-OBS (33) CVP-MR (48) CVP-OBS (41)

21. eastern cooperative oncology group Overall Survival MR vs OBS for Induction CVP Years from Maintenance Randomization Probability MR (48) OBS (41) Median NR vs. NR Logrank p=0.21 HR = 0.7 (0.3,1.6)

22. eastern cooperative oncology group Overall Survival MR vs OBS for Induction CF Years from Maintenance Randomization Probability MR (34) OBS (33) Median NR vs. NR Logrank p=0.42 HR = 1.1 (0.4,2.9)

23. eastern cooperative oncology group Overall Survival CF vs. CVP +/- maintenance rituximab Years from Maintenance Randomization Probability CF-MR (34) CF-OBS (33) CVP-MR (48) CVP-OBS (41) 02468 0.0 0.2 0.4 0.6 0.8 1.0

24. eastern cooperative oncology group 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.   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. eastern cooperative oncology group 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.   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. eastern cooperative oncology group With our Thanks:  Co-investigators  Institutional investigators  Data Management staff  ECOG Operations Office and Statistical Center staffs  Patients  Co-investigators  Institutional investigators  Data Management staff  ECOG Operations Office and Statistical Center staffs  Patients