1. 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

2. FIT Study Schema 90Y-ibritumomab (n = 207)
Rituximab 250 mg/m2 IV on day −7 and day Y-ibritumomab 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:

3. 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

4. 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

5. 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

6. 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% %
0.4% - 1.7%
0.96% %
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:
3. Morton et al. J Clin Oncol. 2010;28:
2. Czuczman et al. J Clin Oncol. 2007;25:

7. 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.

8. 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?

9. 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.

10. 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.

11. 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.

12. 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

13. 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: NCT
*Stratification by response (CR / PR)
Lopez-Guillermo et al. ASH 2013, abstract

14. 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)

15. 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

16. 90Y Ibritumomab Tiuxetan
Overall survival (OS)
90Y Ibritumomab Tiuxetan
Rituximab
Causes of death: progression (6), GVHD (1)

17. 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

18. 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

19. 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.

20. 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% ( %)
Ref group
420
100%
95% ( %)
Casulo et al., ASH 2013, abstract 510

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

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

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

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

25. 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

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