what is the best approach for a follicular lymphoma patient who achieves cr after frontline ...
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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. - PowerPoint PPT PresentationTRANSCRIPT
What is the best approach for a follicular lymphoma patient who achieves CR after
frontline chemoimmunotherapy? Radioimmunotherapy!
Matthew Matasar, MD MSAssistant Member, Lymphoma and Adult BMT Services
Memorial Sloan-Kettering Cancer CenterNew York, NY
Radioimmunotherapy consolidation of CR1 for FL
• Observation• Rituximab maintenance• Radioimmunotherapy (RIT)
Radioimmunotherapy consolidation of CR1 for FL
• Observation• Rituximab maintenance• Radioimmunotherapy (RIT)
RIT Background
90Y Ibritumomab tiuxetan 131I Tositumomab
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)
Crossfire Effect of Radiolabeled Antibodies
Unlabeled “Cold” Antibody Radiolabeled “Hot” Antibody(cause damage to tumor cells as well
as adjacent normal tissues)Courtesy of Andrew Zelenetz, MD
Weaknesses of alternative strategies
Observation• Loss of opportunity to
prolong PFS• Prolonging TTNT is a valid
goal
Rituximab maintenance• 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
RIT consolidation of first remission
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-
tositumomabAwaiting data:• SWOG 0801: RCHOP 131I-tositumomab R-
maintenance q3m x 4y• Fol-BRITe: BR 90Y-ibritumomab
RIT consolidation: SWOG 9911
Cyclophosphamide 750 mg/m2 I.V.Doxorubicin 50 mg/m2 I.V.Vincristine 1.4 mg/m2 I.V.Prednisone 100 mg PO qd x 5d
Day
CH
OP
#1
CH
OP
#2
CH
OP
#3
CH
OP
#4
CH
OP
#5
CH
OP
#6
1 22 43 64 85 106 134 141
If PR or CR
BE
XX
AR
D
osim
etric
D
ose
BE
XX
AR
Th
erap
eutic
D
ose
RIT consolidation: SWOG 9911
* 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.
66%
39%
23%
49%
2%2%10% 8%
0102030405060708090
100
After CHOP After BEXXAR
CR/ CRu
PR
SD NE*
RIT consolidation: SWOG 9911
0%0%
20%20%
40%40%
60%60%
80%80%
100%100%
00 11 22 33
Years from Registration
At Risk90
Relapseor Death18
2-yr PFSEstimate81%
Median FU = 2.3 yr.
RIT consolidation: FIT
RIT consolidation: FIT
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
RANDOMIZATION
Start of study6-12 weeks after last
dose of induction
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.
INDUCTIONPatients with previously untreated FLFirst-line therapy with CVP, CHOP, CHOP-like, chlorambucil, fludarabine combination, or rituximab combination
NRPD
CR/CRu or PR
Not Eligible
Response
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
Hagenbeek, et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 594
25
50
75
100
0 12 24 36 48 60
Prop
ortio
n Pr
ogre
ssio
n Fr
ee
PFS From Time of Randomization (months)90Y-ibritumomab
Control207 174
11713383
11367
9865
8046
At risk:
202
90Y-ibritumomab: n = 207Median PFS: 49 mo
Control: n = 202 Median PFS: 15 mo
0
N F
Control 202 14490Y-ibritumomab 207 108
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
Hagenbeek, et al. Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 594
90Y-ibritumomab
Control
At risk:207202
202194
195192
185182
172171
146135
0
25
50
75
100
0 12 24 36 48 60
Prop
ortio
n A
live
OS From Time of Randomization (months)
90Y-ibritumomabControl
207202
1822
N F
90Y-ibritumomab: n = 207 Median PFS: > 98 mo
Control: n = 202 Median PFS: > 101 mo
RIT consolidation: FIT
RIT consolidation: SWOG 0016
• Untreated follicular lymphoma
• PS 0-2• Stage III-IV
RANDOMIZE
CHOP21 x 6
CHOP21 x 6 +R x 6 (4 pre, 2 post)
CHOP21 x 6 + 131I tositumomab post
RIT consolidation: SWOG 0016
• Untreated follicular lymphoma
• PS 0-2• Stage III-IV
RANDOMIZE
CHOP21 x 6
CHOP21 x 6 +R x 6 (4 pre, 2 post)
CHOP21 x 6 + 131I tositumomab post
N=27
N=279
N=276
RIT consolidation: SWOG 0016 (PFS)
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10
Years from Registration
CHOP I-131CHOP-R
At Risk265267
Relapseor Death
86106
2-YearEstimate
80%76%
2-sided, multivariate p = .11
S0016
CHOP-RIT
CHOP-RMedian FU 4.9y
Overall Survival: S0016
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10
CHOP I-131CHOP-R
At Risk265267
Deaths4026
2-YearEstimate
93%97%
2-sided, multivariate p = .08
Years from Registration
CHOP-R
CHOP-RITMedian FU 4.9y
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% - 1.23% 0.4% - 1.7% 0.96% - 1.11%
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
What is the best approach for a follicular lymphoma patient who achieves CR after
frontline chemoimmunotherapy? Radioimmunotherapy!
Matthew Matasar, MD MSAssistant Member, Lymphoma and Adult BMT Services
Memorial Sloan-Kettering Cancer CenterNew York, NY