The Argument Why This Patient SHOULD Receive “Maintenance” Rituximab Morton Coleman, M.D. Director, Center for Lymphoma and Myeloma Weill Cornell Medical College New York-Presbyterian Weill Cornell Medical Center

Current Treatment of Follicular NHL Overall survival of FL patients is improving SWOG trials, SEER data etc Rituximab + Chemotherapy is superior to Chemotherapy alone (multiple trials) Higher response rates/ CR Longer PFS Some trials with better OS The fact that OS is improved in some trials demonstrates that the choice of front-line therapy is critical. ChemoRx+R is optimal.

Phase III Frontline Trials of R-Chemo Regimen N RR TTF/PFS (months) CHOP 205 90% 31 Rituximab + CHOP (R-CHOP) 223 96% Not reached (18+) CVP 159 57% 15 Rituximab + CVP (R-CVP) 162 81% 34 Mitoxantrone, chlorambucil, prednisolone 96 75% 29 Rituximab + mitoxantrone, chlorambucil, prednisolone 105 92% Not reached (47+) CHVP/IFN-α 182 86% 36 Rituximab + CHVP (R-CHVP)/IFN-α 175 94% Not reached (42+) Hiddemann. Blood. 2005;106:3725; Hiddemann. ASH 2004 (abstr 161); Foussard. ASCO 2006 (abstr 7508); Marcus. Blood. 2005;105:1417; Marcus. ASH 2006 (abstr 481); Herold. ASH 2006 (abstr 484).

Principles of Maintenance Therapy Not needed following a curative therapy Not useful in patients resistant or refractory to the maintenance therapy May be easiest to demonstrate a benefit in patients with high risk of early relapse Following less effective therapy (R alone, CVP versus CHOP, Bendamustine) Relapsed patients (shorter remissions) High risk patients (high tumor burden, high FLIPI) Hardest to demonstrate a benefit following more effective therapies Treatment naïve pts (higher OR, longer PFS) More effective therapy (R-CHOP, R-Bendamustine)

Maintenance Rituximab Prolongs PFS in Most Trials and OS in Some Following Rituximab: SAKK trial of standard vs extended rituximab (initial therapy and relapsed disease) RESORT study following rituximab induction Following Chemotherapy: ECOG 1496 trial of CVP +/- extended Rituximab (initial therapy) Following R-Chemotherapy: FCM vs R-FCM +/- extended Rituximab (relapsed patients) EORTC trial of CHOP vs R-CHOP +/- extended Rituximab (relapsed patients) PRIMA study

Rituximab Maintenance Therapy in FL (SAKK Trial) 375 mg/m2 q8w  4 (n=73) R A N D O M I Z E Untreated or relapsed/ refractory FL grade I-III (N=202) ASSESS Rituximab 375 mg/m2 qw × 4 CR, PR, SD A total of 202 patients with newly diagnosed or chemotherapy-resistant/relapsed FL or SLL were enrolled in the Swiss Group for Clinical Cancer Research (SAKK) trial of maintenance rituximab following rituximab induction therapy. All patients received the standard induction regimen of rituximab 375 mg/m2 weekly for 4 cycles. At week 12, patients with CR, PR, or SD were randomized to observation or maintenance treatment with rituximab (375 mg/m2 every 8 weeks) at months 3, 5, 7, and 9. Observation (n=78) Ghielmini et al. Blood. 2004;103:4416. Ghielmini et al. Blood. 2004;103:4416.

Rituximab Maintenance Therapy in FL (SAKK Trial): Efficacy 46% response rate to initial treatment with rituximab (relapsed pts) CR rate identical in both arms 151 patients randomized No differences in toxicity Observation Maintenance Median EFS All patients 13.4 22.4 Previously untreated 18.3 35.6 In remission at 1 year 57% 80% Ghielmini et al. Blood. 2004;103:4416.

Rituximab Maintenance Therapy in FL (SAKK Trial): EFS Prolonged: median 23.2 months 6 12 18 24 30 36 42 48 0.2 0.4 1.0 0.6 0.8 P=0.024 Standard: median 11.8 months Probability EFS defined as the time from first induction infusion to progression, relapse, second tumor, or death from any cause. EFS curves for patients receiving prolonged treatment or standard observation. The median EFS for patients receiving prolonged treatment was 23.2 months vs 11.8 months for the standard observation group, P=0.024. Months Ghielmini et al. Blood. 2004;103:4416. Ghielmini et al. Blood. 2004;103:4416.

E4402 (RESORT) Schema R Rituximab A Maintenance* N D O M Rituximab I Z 375 mg/m2 q 3 months Rituximab 375 mg/m2 qw × 4 CR or PR Rituximab re-treatment at progression* 375 mg/m2 qw × 4 ECOG 4402 (RESORT) is a phase III randomized trial of rituximab in patients with low-tumor-burden indolent NHL. Induction rituximab: Patients receive rituximab IV once a week for 4 weeks. Patients are re-evaluated 8 weeks after the completion of induction rituximab. Patients with a PR or CR to induction rituximab are randomized to 1 of 2 treatment arms. Arm I (scheduled rituximab): Patients receive a single dose of rituximab IV once every 12 weeks until disease progression and in the absence of unacceptable toxicity. Patients are followed at least annually for 15 years from study entry. Arm II (re-treatment rituximab): Patients receive rituximab IV once a week for 4 weeks upon disease progression, provided TTP is more than 6 months. *Continue until treatment failure No response to retreatment or PD within 6 months of R Initiation of cytotoxic therapy or Inability to complete rx 7

Time to First Cytotoxic Therapy eastern cooperative oncology group

Phase III Trial of CVP  Maintenance Rituximab in Advanced Indolent NHL (E1496) Z E Rituximab 375 mg/m2 (qw × 4) q6mo × 4 (n=157) CVP Cyclophosphamide 1000 mg/m2 d1 Vincristine 1.4 mg/m2 d1 Prednisone 100 mg/m2 d1-5 6-8 cycles R ESTAGE CR, PR, SD R A N D O M I Z E Observation (n=148) Untreated stage III/IV grade 1/2 FL or SLL (N=401) This phase III trial (E1496) conducted by the Eastern Cooperative Oncology Group (ECOG) and Cancer and Leukemia Group B (CALGB) evaluated cyclophosphamide, vincristine, and prednisone (CVP) with or without maintenance rituximab therapy in advanced indolent NHL. Eligible patients included stage III/IV FL grade 1 and 2 (small cleaved, mixed) and SLL histologies. A total of 401 patients were enrolled in the study. Of those, 115 patients were enrolled in the cyclophosphamide + fludarabine arm, with that arm being discontinued due to toxicity. The remaining patients were treated with CVP (cyclophosphamide 1000 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1; and prednisone 100 mg/m2 on days 1 through 5). Out of 401 patients, 9% progressed. Of stable/responding patients, 322 were randomized to rituximab (375 mg/m2 weekly for 4 weeks every 6 months for 4 cycles) or observation, stratified by residual disease (minimal vs greater) and histology. (n=322) CF Cyclophosphamide Fludarabine (n=115) DISCONTINUED Primary end point: PFS from time of randomization post-CVP Hochster et al. Blood. 2005;106:106a. Abstract 349. Hochster et al. Blood. 2005;106:106a. Abstract 349.

CVP  Maintenance Rituximab in Advanced Indolent NHL (E1496): Results P Value After median follow-up of 3 y, estimated median PFS favored rituximab maintenance 0.000000003 After median follow-up of 3 y, median OS not significantly different 0.09 % of Patients Follicular Histology (n=238) Rituximab Observation P Value Estimated 4-y PFS (%) 56 33 0.0000003 Estimated 4-y OS (%) 88 72 0.03 This trial was terminated early because at the time of the planned second interim analysis, the O’Brien-Fleming boundary for PFS was crossed with 305 of 322 randomized evaluable patients (one-sided P=0.00008). The rituximab (n=157) vs observation (n=148) patients were balanced with respect to median age (58 vs 56 years), histology (77% vs 79% FL), tumor burden (62% vs 68% high), gender (55 vs 57 male), stage (77 vs 74 IV), and marrow involvement (69% vs 71%). For randomized patients Improved response rate post–CVP therapy was seen in 22% of patients receiving maintenance rituximab vs 8% after observation (P=0.002). PFS at a median of 3 years of follow-up favored the rituximab maintenance arm vs the observation arm (P=0.000000003). The median OS at a median of 3 years was not significantly different (P=0.09). In the 238 patients evaluable with follicular histology, the estimated 4-year PFS was significantly improved for patients in the rituximab maintenance arm compared with observation (56% vs 33%, respectively; P=0.0000003). Hochster et al. Blood. 2005;106:106a. Abstract 349. Hochster et al. Blood. 2005;106:106a. Abstract 349.

Induction R-CHOP vs CHOP and Maintenance Rituximab vs Observation in Relapsed FL (Intergroup EORTC 20981) Rituximab 375 mg/m2 q3mo until relapse or a maximum of 2 y Observation R-CHOP 6 cycles CHOP 6 cycles CR or PR (n=319) R A N D O M I Z E Relapsed/ refractory patients with FL (N=474) A total of 474 patients with stage III or IV FL at initial diagnosis and relapsed after or resistant to a maximum of 2 non–anthracycline-containing systemic chemotherapy regimens, were randomized to 1 of 2 arms for 6 cycles of treatment to induce remission. Standard CHOP (once every 3 weeks) CHOP + rituximab (375 mg/m2 at day 1 of each cycle of CHOP) Patients with CR or PR after 6 cycles of therapy underwent a second randomization to observation or maintenance treatment with rituximab (375 mg/m2 once every 3 months until relapse or for a maximum period of 2 years). Primary end points Induction phase: rate and quality of response Maintenance phase: PFS Van Oers et al. Blood. 2005;106:107a. Abstract 353; Blood online 2006. Van Oers et al. Blood. 2005;106:107a. Abstract 353.

Induction R-CHOP vs CHOP and Maintenance Rituximab vs Observation in Relapsed FL: Results % of Patients R-CHOP CHOP P Value ORR 85 73 <0.0001 CR 29 16 PR 56 57 NS Maintenance Rituximab Observation Median PFS (mo) 51.6 15 In February 2004, a preplanned second interim analysis by the IDMC was performed. At that time, 461 patients had been included. Of these, 369 could be evaluated for response (188 CHOP; 181 R-CHOP). No significant differences existed between groups with regard to age, sex, performance status (PS), time from initial diagnosis, number and type of prior chemotherapy regimens, and best overall response to prior chemotherapy. Both treatment arms yielded similar PR rates: CHOP 57% vs R-CHOP 56%. There was a highly significant difference in CR rates: CHOP 16% vs R-CHOP 29% (P=0.0004). A total of 319 patients have been randomized for maintenance treatment. Of these, 268 were evaluable (132 observation; 136 rituximab maintenance). One-year and 3-year PFS were 55% and 31%, respectively, in the observation arm, and 80% and 68% in the rituximab maintenance treatment arm (P<0.0001 at both time points). There is as yet no impact on OS; the observed difference (in favor of rituximab maintenance) was not significant for an interim analysis (P=0.03). There were no differences in toxicity between CHOP and R-CHOP induction treatments. Van Oers et al. Blood. 2005;106:107a. Abstract 353; Blood online 2006. Van Oers et al. Blood. 2005;106:107a. Abstract 353.

EORTC 20981 Update: Effect of Rituximab Maintenance Treatment on PFS Effect of rituximab maintenance treatment on progression-free survival (PFS). Kaplan-Meier plot of PFS from second random assignment after rituximab maintenance therapy (n = 167) and observation (n = 167). Rituximab maintenance, median 3.7 years; observation, median 1.3 years. HR, hazard ratio. van Oers M H et al. JCO 2010;28:2853-2858 ©2010 by American Society of Clinical Oncology

EORTC 20981 Update: Effect of Rituximab Maintenance Treatment on PFS after Remission Induction with either CHOP or R-CHOP Effect of rituximab maintenance treatment on progression-free survival (PFS) after remission induction with either cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Kaplan-Meier plots of PFS and overall survival from second random assignment. (A) PFS after CHOP remission induction (n = 145). Rituximab maintenance, median 3.1 years; observation, median 1.0 year. (B) PFS after R-CHOP remission induction (n = 189). Rituximab maintenance, median 4.4 years; observation, median 1.9 years. HR, hazard ratio; O, observed; N, number. van Oers M H et al. JCO 2010;28:2853-2858 ©2010 by American Society of Clinical Oncology

EORTC 20981 Update: Effect of Rituximab Maintenance Treatment on Overall Survival. Effect of rituximab maintenance treatment on overall survival. Kaplan-Meier plot of overall survival from second random assignment after rituximab maintenance therapy (n = 167) and observation (n = 167). Rituximab maintenance, 74.3% at 5 years; observation, 64.7% at 5 years. HR, hazard ratio. van Oers M H et al. JCO 2010;28:2853-2858 ©2010 by American Society of Clinical Oncology

Rituximab maintenance European PRIMA Study for Follicular NHL: Rituximab Maintenance Therapy following R-Chemotherapy R-CVP n=272 R-CHOP n=885 R-FCM n=45 CR PR R Rituximab maintenance 375 mg/m2 q 8 wk x 2 years Observation

PRIMA Study: ASCO 2010 (n=1202) Primary therapy R-CVP, R-CHOP, R-FCM Rituximab every 2 months x 2 yr vs. observation At 24 months PFS 82% vs 66% (p<0.0001) HR 0.49 Benefits in all subgroups Similar benefits in CR and PR patients No current difference in OS Likely the new standard for all initial trials Salles G, ASCO 2010

PRIMA: Primary Endpoint PFS 36 60 Salles, G et al Lancet 2010; 377: 42–51

PRIMA: Time to Next Lymphoma Therapy Rituximab Observation 36 60 Salles, G et al Lancet 2010; 377: 42–51

PRIMA: Overall Survival Salles, G et al Lancet 2010; 377: 42–51

META Analysis: Pooled estimates of OS with Rituximab Maintenance Therapy for Patients with FL compared with Observation and Rituximab at Disease Progression. Pooled estimates of overall survival with rituximab maintenance therapy for patients with follicular lymphoma compared with observation and rituximab at disease progression. Black squares represent the point estimate, their sizes represent their weight in the pooled analysis, and the horizontal bars represent the 95% CI. The black diamond at the bottom represents the pooled point estimate. HR = hazard ratio for death; CI = confidence interval; MR = maintenance therapy with rituximab. Vidal L et al. JNCI J Natl Cancer Inst 2009;101:248-255 © The Author 2009. Published by Oxford University Press.

META Analysis: Pooled HRs of OS of Patients with Refractory or Relapsed FL and of Untreated Patients with FL Pooled HRs of overall survival of patients with refractory or relapsed follicular lymphoma and of untreated patients with follicular lymphoma. Black squares represent the point estimate, their sizes represent their weight in the pooled analysis, and the horizontal bars represent the 95% CI. The black diamond at the bottom represents the pooled point estimate. HR = hazard ratio for death; CI = confidence interval; MR = maintenance therapy with rituximab. Vidal L et al. JNCI J Natl Cancer Inst 2009;101:248-255 © The Author 2009. Published by Oxford University Press.

Updated METAnalysis

Potential Toxicity of Maintenance Infusion related symptoms generally mild Slightly greater neutropenia Prolonged B cell depletion There may be decreases in Ig subsets after fludarabine + R regimens Infections Small increase in treatable infections Reactivation of viral infections Cost: but several analysis suggest benefit

“No Argument About Maintenance” When relapse would be acutely harmful Associated adverse complications of disease Autoimmune hemolysis or thrombocytopenia Cryoglobulins, cold agglutinins Hyperviscosity Hypersplenism Kidney disease

Should most high IPI FL Patients Receive “Maintenance” Rituximab? YES Although the PRIMA study and meta-analysis do not show a survival advantage for naïve rx’ed patients receiving Chemoimmunotherapy followed by Rituximab, are the data sufficiently mature and powered to exclude a survival advantage? Patients are indeed surviving longer than ever and enormous patients and patience (time) may be necessary to show the full impact on survival of maintenance in this setting.

What about radioimmunotherapy as consolidation after chemorx-rituximab There has been only one study comparing radioimmunotherapy consolidation after CHOP versus R-CHOP(chemoimmunoRx): NO BENEFIT (Press, O., et al; JCO 31:4 (2013) Almost all studies showing any benefit from radioimmunotherapy after induction were with chemorx alone Radioimmunotherapy has leukemogenic potential following chemotherapy.

THANK YOU FOR YOUR ATTENTION, AND, IN ADVANCE, FOR YOUR MOST THOUGHTFUL AND INTELLIGENT VOTE SUPPORTING MY PRESENTATION