what is the best approach for a follicular lymphoma patient who achieves cr after frontline ...

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