What is the optimal management of a 43-year-old man with high-risk FL not in CR after R-chemo? Answer: Radioimmunotherapy Peter Martin, M.D. The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology Director of Lymphoma Clinical Research Assistant Professor of Medicine

FIT Study Schema 90Y-ibritumomab (n = 207) Rituximab 250 mg/m2 IV on day −7 and day 0 + 90Y-ibritumomab 14.8 MBq/kg (0.4 mCi/kg) [max 1184 MBq (32 mCi)] on day 0 CONSOLIDATION Start of study R ANDOMI ZAT I ON Patients with previously untreated FL First-line therapy with chlorambucil, CVP, CHOP, CHOP-like, fludarabine combination, or rituximab combination 6-12 weeks after last dose of induction CR/CRu or PR INDUCTION No further treatment (n = 202) CONTROL NR PD Not Eligible CVP = cyclophosphamide, vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CR = complete response; CR/u = unconfirmed CR; PR = partial response; NR = no response; PD = progressive disease. Morschhauser et al. J Clin Oncol. 2008;26:5156-5164.

Overall CR Rates After Randomization According to First-line Induction Regimen First-line Regimen Control, % 90Y-Ibritumomab, % CR/CRu All patients 53.3 87.4 Chlorambucil 31.6 85.0 CVP / COP 39.6 86.8 CHOP 56.1 84.6 CHOP-like 67.7 86.7 Fludarabine comb. 50.0 100.0 Rituximab comb. 71.0 92.9

PFS for Patients in CR/CRu After Induction The 5-year PFS among patients with a CR/CRu after induction was 43% in the control arm compared with 57% in the 90Y-ibritumomab arm HR = 1.64 (95% CI: 1.12 – 2.40); P = 0.011 100 75 90Y-ibritumomab: n = 107 Median PFS: > 92 mo Cumulative Percentage 50 Control: n = 108 Median PFS: 32 mo 25 90Y-ibritumomab Control 107 108 46 63 N F 12 24 36 48 60 PFS From Time of Randomization (months) At risk: 90Y-ibritumomab 107 92 75 66 56 46 Control 108 75 63 49 48 35

PFS for Patients in PR After Induction The 5-year PFS among patients with a PR after induction was 14% in the control arm compared with 38% in the 90Y-ibritumomab arm HR = 2.62 (95% CI: 1.88 – 3.66); P < 0.001 100 75 90Y-ibritumomab: n = 100 Median PFS: 30 mo Cumulative Percentage 50 Control: n = 94 Median PFS: 6 mo 25 N F 90Y-ibritumomab 100 62 Control 94 81 12 24 36 48 60 PFS From Time of Randomization (months) At risk: 90Y-ibritumomab 100 82 58 47 42 34 Control 94 42 20 18 17 11

MDS/AML: Annualized Rates in 90Y-Ibritumomab Studies Compared With FL Patients Generally (SEER Data) FIT Study,1 90Y-ibritumomab group Witzig Studies2 SEER data3 (R)-Chemo Annualized rate 0.55% 1.0% 1.03% 95% CI 0.25% - 1.23% 0.4% - 1.7% 0.96% - 1.11% The annualized rate of secondary MDS/AML in patients treated with 90Y-ibritumomab does not appear higher than the annualized rate of MDS/AML observed in patients treated for FL generally. 1. Morschhauser et al. J Clin Oncol. 2008;26:5156-5164. 3. Morton et al. J Clin Oncol. 2010;28:4935-4944. 2. Czuczman et al. J Clin Oncol. 2007;25:4285-4292.

Patients in Control and 90Y-Ibritumomab Arms Achieved Comparable Responses to Second-Line Therapy Response to Second-Line Therapy After Progressive Disease, % Control (n = 122*) 90Y-Ibritumomab (n = 82*) ORR 78% 79% CR/CRu 59% 57% PR 19% 22% SD 5% 1% *Number of patients who received treatment after progressive disease. ORR = overall response rate; CR = complete response; CRu = unconfirmed CR; PR = partial response; SD = stable disease.

Radioimmunotherapy is FDA approved for patients with previously untreated follicular lymphoma that achieve a CR or PR to first-line chemotherapy BUT … What about comparison to R-chemo? What about comparison to R-maintenance?

Stratified by IWF groups A to D or transformed 90Y Ibritumomab Tiuxetan Regimen Versus Rituximab Therapy: Study Design Objective Compare the 90Y ibritumomab tiuxetan regimen versus rituximab alone in rituximab-naïve patients with relapsed or refractory low‑grade, follicular, or CD20+ transformed NHL Rituximab (375 mg/m2 weekly  4) Stratified by IWF groups A to D or transformed N=143 Randomized 90Y ibritumomab tiuxetan and rituximab: Day 0: Rituximab (250 mg/m2) 111In ibritumomab tiuxetan (5 mCi/kg) Day 7: Rituximab (250 mg/m2) 90Y ibritumomab tiuxetan (0.4 mCi/kg) Witzig et al. J Clin Oncol. 2002;20(10):2453.

90Y Ibritumomab Tiuxetan Regimen Versus Rituximab Therapy: Response 100 ORR CR 90Y ibritumomab tiuxetan regimen (n=73) 90 80 P=0.002 80 70 56 ORR CR Rituximab (n=70) 60 Patients (%) 50 40 30 P=0.04 30 20 16 10 90Y ibritumomab tiuxetan Rituximab Witzig. J Clin Oncol. 2002;20(10):2453.

SWOG/CALGB Trial S0016 Untreated advanced stage follicular NHL CHOP  6 CHOP  6 + rituximab CHOP  6 + 131I-tositumomab N=17 N=279 N=275 Stratification factor: β2M level (elevated or not) β2M, β-2 microglobulin Press OW et al. Blood. 2011;118:Abstract 98.

Progression Free Survival 100% 80% CHOP-RIT 60% Median FU 4.9 yr CHOP-R 40% CHOP -RIT CHOP-R At Risk 265 267 Relapse or Death 86 106 2-Year Estimate 80% 76% 2-sided, multivariate p = .11 20% 0% 2 4 6 8 10 Years from Registration S0016

Rituximab Maintenance ZAR study: Design Registration Induction Consolidation / Maintenance 90Y-Ibritumomab tiuxetan 1 dose Follow-up 5 years Untreated FL stages II–IV R-CHOP x 6 R* CR/PR Rituximab Maintenance 1 dose every 8 weeks for 24 months PDs/SDs off study ClinicalTrials.gov: NCT00662948 *Stratification by response (CR / PR) Lopez-Guillermo et al. ASH 2013, abstract

ZAR: Patient disposition Patients registered N=146 R-CHOP x 6 Not randomized (N=20): - Incomplete induction treatment or Response <PR (N=8) - Low platelet or neutrophil counts (N=5) - BM infiltration>25% (N=1) - Patient decision (N=2) - Other (N=4) Patients randomized N=126 (PR 57; CR 69) 90Y-Ibritumomab Tiuxetan (N=64) Rituximab (N=62)

Status at the end of the maintenance period (24 months from randomization) CR PR Rel/Prog Patients in CR after R-CHOP Arm A (N=34) 30 (88%) - 4 (12%) Arm B (N=35) 32 (91%) 3 (9%) Patients in PR after R-CHOP Arm A (N=30) 12 (40%) 6 (20%) Arm B (N=27) * 18 (67%) 6 (22%) ** 3 (11%) CR: complete response; PR: partial response; Rel/Prog relapse/progression; Arm A: 90Y Ibritumomab Tiuxetan; Arm B: Rituximab *P=0.06; **P=0.01

90Y Ibritumomab Tiuxetan Overall survival (OS) 90Y Ibritumomab Tiuxetan Rituximab Causes of death: progression (6), GVHD (1)

90Y Ibritumomab Tiuxetan Grades 3-4 adverse events by randomization arm 90Y Ibritumomab Tiuxetan (N=64) Rituximab (N=62) Any grade 3-4 adverse event 16 (25%) 16 (26%) Hematological Neutropenia Thrombocytopenia 6 (9%) 5 (8%) 2 (3%) 0 (0%)* Infections Febrile neutropenia Pneumonia Other infections 1 (2%) 1 8 (13%)** 3 4 Thrombotic events CNS events Neoplasia In arm A, hematological toxicity occurred within 3 months from 90Y ibritumomab tiuxetan infusion Other infections included gastroenteritis, enterocolitis and appendicitis Neoplasias: Hodgkin lymphoma, colon cancer (arm A) and skin cancer (arm B) at 2.7, 2.4 and 2.1 years from randomization, respectively *P=0.055; **P=0.01

Summary RIT consolidation provides a PFS benefit over observation in patients receiving chemo (no rituximab) Chemo-RIT is not superior to R-chemo but it’s likely that R-chemo+RIT would provide longer PFS than R- chemo+observation

Summary R-chemo+R maintenance has not been adequately compared to R-chemo+RIT Hint at better PFS for R maintenance only in PR group, but requires 2 years of treatment, is associated with increased infections, and has no impact on OS.

This patient is at high risk of death within the next 5 years High FLIPI is associated with a median PFS of < 3 years following R-CHOP PR to R-CHOP is associated with a median PFS of about 30 months. Patients that progress within two years of R-CHOP have a poor prognosis. N 2-year OS (95% CI) 5-year OS (95% CI) Early progressors 120 71% (61.5–78.0%) 50% (40.3-58.8%) Ref group 420 100% 95% (92.7-97.0%) Casulo et al., ASH 2013, abstract 510

R-CHOP vs. R-HDS in FL Ladetto M et al. Blood 2008;111:4004-4013

R-CHOP vs. R-HDS in FL Ladetto M et al. Blood 2008;111:4004-4013

R-HDS is associated with a high risk of tMDS ©2008 by American Society of Hematology Ladetto M et al. Blood 2008;111:4004-4013

Second-line R-HDS is effective following R-CHOP failure ©2008 by American Society of Hematology Ladetto M et al. Blood 2008;111:4004-4013

Summary R-HDS does not improve survival compared to R-CHOP Unclear impact on PR subgroup R-HDS is associated with a high risk of tMDS R-HDS is effective second-line therapy after R-CHOP failure

My recommendation R-chemo Consider RIT consolidation Consider R maintenance following RIT Consider ASCT after relapse