What is the Optimal A pproach to CLL, BR vs. FCR/FR?
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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
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n
Fludarabine + Prednisone (1983 – 1993)Progression Free Survival
0 6 12 18 24 30 36 42 48 54 60Months
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Median PFS: 26 months
Long Term Outcomes for FR:CALGB 9712
Months
Surv
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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
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ive
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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
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n Su
rviv
ing P<.0001
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
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PFS
OS
PFSOS
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
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FCR300: PFS by IGHV Mutation Status
Months
Prop
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ogre
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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