1. What is the best approach for a follicular lymphoma patient who achieves CR after frontline chemoimmunotherapy? Radioimmunotherapy!
Matthew Matasar, MD MS
Assistant Member, Lymphoma and Adult BMT Services
Memorial Sloan-Kettering Cancer Center
New York, NY

2. Radioimmunotherapy consolidation of CR1 for FL
Observation
Rituximab maintenance
Radioimmunotherapy (RIT)

3. Radioimmunotherapy consolidation of CR1 for FL
Observation
Rituximab maintenance
Radioimmunotherapy (RIT)

4. 90Y Ibritumomab tiuxetan
RIT Background
90Y Ibritumomab tiuxetan
131I Tositumomab

5. Principles of Radioimmunotherapy for Lymphoma
Highly sensitive to radiation therapy
Targeted delivery of radiation to tumor cells
Greater exposure of tumors vs surrounding normal organs
Crossfire of particle emissions
Continuous exposure of tumor cells
Retention of anti-tumor mechanisms of the antibody
Well characterized surface antigens
CD20 (CD22, CD19, CD25)

6. Crossfire Effect of Radiolabeled Antibodies
Radiolabeled “Hot” Antibody
(cause damage to tumor cells as well as adjacent normal tissues)
Unlabeled “Cold” Antibody
Courtesy of Andrew Zelenetz, MD

7. Weaknesses of alternative strategies
Observation
Rituximab maintenance
Loss of opportunity to prolong PFS
Prolonging TTNT is a valid goal
Fails to prolong OS
PRIMA dosing requires 12 treatments over 2 years
Patient time, lost productivity
At least $38,545 incremental cost increase: higher than that of single dose of RIT

8. RIT consolidation of first remission

9. RIT consolidation of first remission
Available data:
SWOG 9911: Phase II CHOPx6  131I-tositumomab
FIT: Phase III Dealer’s choice  90Y-ibritumomab vs. observation
SWOG 0016: Phase III RCHOPx6 vs. CHOPx6 131I-tositumomab
Awaiting data:
SWOG 0801: RCHOP  131I-tositumomab  R-maintenance q3m x 4y
Fol-BRITe: BR  90Y-ibritumomab

10. RIT consolidation: SWOG 9911
Cyclophosphamide 750 mg/m2 I.V.
Doxorubicin mg/m2 I.V.
Vincristine mg/m2 I.V.
Prednisone mg PO qd x 5d
Day
CHOP #1
CHOP #2
CHOP #3
CHOP #4
CHOP #5
CHOP #6 1 22 43 64 85
106
134
141
If PR or CR
BEXXAR Dosimetric Dose
BEXXAR Therapeutic Dose

11. RIT consolidation: SWOG 9911
66%
39%
23%
49% 2%
10% 8% 10 20 30 40 50 60 70 80 90
100
After CHOP
After BEXXAR
NE* SD PR
CR/
CRu
* NE = Not Evaluable. 83/90 patients were evaluable for responses.
Overall response (CR+CRu+PR) was 98% in evaluable patients including 59% CR,
13% CRu, and 25% PR.

12. RIT consolidation: SWOG 99110%
20%
40%
60%
80%
100% 1 2 3
Years from Registration
At Risk 90
Relapse
or Death 18
2-yr PFS
Estimate
81%
Median FU = 2.3 yr.

13. RIT consolidation: FIT

14. RIT consolidation: FIT
RANDOMIZATION
Start of study
6-12 weeks after last dose of induction
INDUCTION
Patients with previously untreated FL
First-line therapy with CVP, CHOP, CHOP-like, chlorambucil, fludarabine combination, or rituximab combination NR PD
CR/CRu or PR
Not Eligible
Response
90Y-ibritumomab (n = 207)
Rituximab 250 mg/m2 days −7, 0 90Y-ibritumomab (0.4 mCi/kg) [max 32 mCi] day 0
CONSOLIDATION
No further treatment (n = 202)
CONTROL
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:

15. RIT consolidation: FIT
The 5-year overall PFS was 29% in the control arm compared with 47% in the 90Y-ibritumomab arm: HR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001 25 50 75
100 12 24 36 48 60
Proportion Progression Free
PFS From Time of Randomization (months)
90Y-ibritumomab
Control
207
174
117
133 83
113 67 98 65 80 46
At risk:
202
90Y-ibritumomab: n = 207 Median PFS: 49 mo
Control: n = 202 Median PFS: 15 mo N F
144
108
Hagenbeek, et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 594

16. RIT consolidation: FIT
The 5-year OS was 89% in the control arm compared with 93% in the 90Y-ibritumomab arm: HR = 1.26 (95% CI: 0.68 – 2.35); P = 0.465
90Y-ibritumomab
Control
At risk:
207
202
194
195
192
185
182
172
171
146
135 25 50 75
100 12 24 36 48 60
Proportion Alive
OS From Time of Randomization (months) 18 22 N F
90Y-ibritumomab: n = 207 Median PFS: > 98 mo
Control: n = 202 Median PFS: > 101 mo
Hagenbeek, et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 594

17. RIT consolidation: SWOG 0016
CHOP21 x 6
RANDOMIZE
Untreated follicular lymphoma
PS 0-2
Stage III-IV
CHOP21 x 6 +
R x 6 (4 pre, 2 post)
CHOP21 x 6 +
131I tositumomab post

18. RIT consolidation: SWOG 0016
CHOP21 x 6
N=27
RANDOMIZE
Untreated follicular lymphoma
PS 0-2
Stage III-IV
CHOP21 x 6 +
R x 6 (4 pre, 2 post)
N=279
CHOP21 x 6 +
131I tositumomab post
N=276

19. RIT consolidation: SWOG 0016 (PFS)
100%
80%
CHOP-RIT
60%
Median FU 4.9y
CHOP-R
40%
CHOP I-131
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

20. Overall Survival: S0016 Median FU 4.9y 0% 20% 40% 60% 80% 100% 2 4 6 82 4 6 8 10
CHOP I-131
CHOP-R
At Risk
265
267
Deaths 40 26
2-Year
Estimate
93%
97%
2-sided, multivariate p = .08
Years from Registration
CHOP-R
CHOP-RIT
Median FU 4.9y

21. RIT consolidation: Safety
Toxicity: Largely hematologic
Neither FIT nor other studies of standalone RIT have shown statistically significantly increased risk of MDS
FIT
Witzig Studies
SEER data
(R-Chemo)
Annualized rate
0.55%
1.0%
1.03%
95% CI
0.25% %
0.4% - 1.7%
0.96% %

22. Conclusions RIT consolidation of first remission prolongs PFS
Favorable safety profile, less expensive than PRIMA R-maintenance
No OS benefit for any approach, including RIT
Future directions:
Clarify incremental utility of RIT consolidation after R-chemo
Clarify utility following more current induction (e.g., BR): Fol-BRITe
Compare to, or combine with, R-maintenance: SWOG 0801

23. What is the best approach for a follicular lymphoma patient who achieves CR after frontline chemoimmunotherapy? Radioimmunotherapy!
Matthew Matasar, MD MS
Assistant Member, Lymphoma and Adult BMT Services
Memorial Sloan-Kettering Cancer Center
New York, NY