What is the Optimal Approach to CLL, BR vs. FCR/FR?

Michael J. KeatingMD Anderson Cancer Center

Presented by:Richard R. Furman

Weill Cornell Medical College

BendamustineBifunctional Antineoplastic Agent

Rummel M, J Clin Oncol. 2005;23:3383.

ClH2CN

N

N

CH3

CO2H

Purine-like Benzimidazole RingAlkylating Group

ClH2C

Available in Germany, 1971-1992Unique in vitro anti-tumor profile

Prop

ortio

n

Fludarabine + Prednisone (1983 – 1993)Progression Free Survival

0 6 12 18 24 30 36 42 48 54 60Months

0.0

0.2

0.4

0.6

0.8

1.0

Median PFS: 26 months

Long Term Outcomes for FR:CALGB 9712

Months

Surv

ival

Chlorambucil vs. Bendamustine in Untreated CLL:

Progression-Free Survival

Knauf WU. JCO. 2009; 27:4378

GCLLSG CLL2M:BR in Untreated CLL

Treatment:• Bendamustine 90 mg/m2 days 1,2 (cycles 1-6)• Rituximab: 375 mg/m2 (cycle 1)

500 mg/m2 (cycles 2-6)

Study Characteristics:• 117 patients• No age limit (median=64; range 34-78)• 73.5% received all 6 cycles

Fischer K. JCO 2012; 30:3209.

Fischer K. JCO 2012; 30:3209.

CLL2M: BR in Untreated CLL:Event Free Survival

median EFS = 33.9 months

CLL2M: BR in Untreated CLL:Response Rates

Response N=124 %ORR 103 88.0 CR 27 23.1 nPR 2 1.7 PR 74 63.2SD 11 9.4PD - -

Fischer K. JCO 2012; 30:3209.

BR: Adverse Events, Grades 3+4 (pts)

Adverse Event Grade 3 (%) Grade 4 (%)

Hematologic Toxicities: 26.5 25.6

Leucopenia 15.4 14.5

Neutropenia 10.3 9.4

Thrombocytopenia 14.5 7.7

Anemia 15.4 4.3

Tumor lysis syndrome 2.6 0

Allergic reaction 8.5 0.9

Infectious 6.8 0.9

Other non-hematologic 18.8 0.9

Phase III Trial of FC + / - Rituximab in Untreated CLL: GCLLSG CLL8 Trial

•Untreated•No age restriction•Active CLL requiring therapy

• Primary endpoint: PFS• No age limit• 74% of patients received all 6 courses of FCR

Fludarabine 25 mg/m2, d1-3Cyclophosphamide 250 mg/m2, d1-3

(n = 817)

RANDOMIZE

Fludarabine 25 mg/m2, d1-3Cyclophosphamide 250 mg/m2, d1-3Rituximab 500 mg/m2, d1 (375 mg/m2 initial dose)

x 6 cycles

FOLLOW

UP

Hallek M. Lancet 2010; 376:1164

FCR vs. FC in Untreated CLL:GCLLSG CLL8 Trial

FCR FC p

PFS 51.8 m 32.8 m < .001

ORR 95.1% 88.4% .001

CR 44.1% 21.8% < .001

PR 51% 66.6% < .01

OS (3yr) 87% 83% .01

Hallek M. Lancet 2010; 376:1164

GCLLSG CLL8: FCR vs. FCProgression Free Survival

0.0

0.2

0.6

0.8

1.0

0.4

Cum

ulat

ive

Surv

ival

Fischer K. ASH 2012.

Median PFS: FCR 57 monthsFC 33 months

Median follow-up: 5.9 years

CLL8: Adverse Events (pts)

Hallek M. Lancet 2010; 376:1164

Response Comparison

Response BR (%) FCR (%)ORR 88.0 95.1

CR 23.1 44.1PR 64.9 51.0

Median PFS 33.9 mo 57.0 mo

AE Comparison

Adverse Event BR (%) FCR (%)Hematologic Toxicity 52.1 96Neutropenia 19.7 55Thrombocytopenia 22.2 18Anemia 19.7 12Infections 7.7 46Tumor Lysis Syndrome 2.6 1

Patient Comparison

Characteristic BR (%) FCR (%)Age > 65 48.7 31Binet Stage C 46.2 31IgVH unmutated 61.8 63Del 11q / 17p 26.4 34Zap-70+ 15.7 42

Patient Comparison

Characteristic BR (%) FCR (%)Age > 65 48.7 31Binet Stage C 46.2 31IgVH unmutated 61.8 63Del 11q / 17p 26.4 34Zap-70+ 15.7 42

FCR300:First-line Outcomes

Department of LeukemiaUT MD Anderson Cancer Center

Houston, TX

Response to FCR(NCI-WG: 300 Patients)

Response # of Pts (%)ORR 285 95CR 217 72nPR 31 10PR 37 12No response 13 4Early death 2 1

FCR300: PFS and OS

Months

Prop

ortio

n Su

rviv

ing P<.0001

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PFS

OS

PFSOS

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

FCR300: PFS by IGHV Mutation Status

Months

Prop

ortio

n Pr

ogre

ssio

n-fr

ee

IGHV-M 33 82

IGHV-UM 114 131

Group Events Total

P<.0001

Unknown 39 87

FCR vs. BR: The Tally

FCR BR

Duration of follow up

ORR

CR

PFS

Toxicity Profile

CLL10 GCLLSG:Randomized Trial of FCR vs. BR

ASH 2013?

fludarabine 25 mg/m2 d1-3cyclophosphamide 250 mg/m2 d1-3rituximab 375 mg/m2 C1, d1

500 mg/m2 C2-6, d1

Untreated CLL (N = 564)Randomize

bendamustine 90 mg/m2 d1,2 rituximab 375 mg/m2 C1, d1

500 mg/m2 C2-6, d1

Primary Endpoint:PFS @ 2 yr