1. WHAT IS THE BEST Front-Line REGIMEN for Patients With CLL <60 YEARS OF AGE WHO MEET TREATMENT CRITERIA? Bendamustine and Rituximab (BR)
Alessandra Ferrajoli, M.D.
Department of Leukemia
The University of Texas MD Anderson Cancer Center

2. Bendamustine Hydrochloride (Synthesized in East Germany in 1963)
Alkylating group
Benzimidazole ring (shares the antimetabolic properties of purine analogues)
Butyric acid side-chain
single agent (Knauf WU , J Clin Oncol, 2009)
in combination with anthracyclines (Weide R, Leuk Lymph, 2002)
in combination with rituximab (Fischer K, J Clin Oncol, 2011)
Ferrajoli A. Haematologica 10:1300, 2005

3. Bendamustine Bifunctional Antineoplastic Agent
CH3 N
ClH2C N N
CO2H
Purine-like Benzimidazole Ring
ClH2C
Alkylating Group
Available in Germany,
Unique in vitro anti-tumor profile
Rummel M, et al. J Clin Oncol. 2005;23: 3

4. BENDAMUSTINE COMBINED WITH RITUXIMAB IN FIRST-LINE THERAPY OF CLL: TREATMENT SCHEDULE
R = Rituximab mg/m2 day 0, cycle 1, 500 mg/m2 cycle 2-6, q4wks
B = Bendamustine mg/m2 day 1-2, cycle 1-6, q4wks
Fischer et al. J Clin Oncol 30: , 2012 4

5. BENDAMUSTINE COMBINED WITH RITUXIMAB IN FIRST-LINE THERAPY OF CLL: RESPONSE RATE%
ORR
103 88 CR 27
23.1 PR 74
64.9 SD 11
9.4
Fischer et al. J Clin Oncol 30: , 2012

6. CLL10 Study: FCR VS BR in Front-line
Design
Patients with untreated, active CLL without del(17p) and good physical fitness
(CIRS ≤ 6, creatinine clearance ≥ 70 ml/min)
Randomization
FCR
Fludarabine 25 mg/m² i.v., days 1-3
Cyclophosphamide 250 mg/m², days 1-3,
Rituximab 375 mg/ m2 i.v. day 0, cycle 1
Rituximab 500 mg/m² i.v. day 1, cycle 2-6 BR
Bendamustine 90mg/m² day 1-2
Rituximab 375 mg/m² day 0, cycle 1
Rituximab 500 mg/m² day 1, cycle 2-6
Non-Inferiority of BR in comparison to FCR for PFS:
HR (λ BR/FCR) less than 1.388
Eichhorst et al. ASH 2013, Abstract 526.

7. CLL10 Study: FCR VS BR in Front-line
Consort Diagram
688 CLL patients screened centrally for:
immunophenotype
CIRS
genomic aberrations (FISH)
GFR
IGHV sequencing
564 underwent 1:1 randomization
FCR n = 284
BR n = 280
1 treatment before randomization
1 patient decision
1 misdiagnosis (MCL)
ITT: FCR n = 282
ITT: BR n = 279
Median observation time: 27.5 months
Eichhorst B. et al, ASH 2013

8. CLL10 Study: FCR VS BR in Front-line
Patients´ characteristics
Baseline characteristics
FCR
n=282 BR
n=279
p value
Median age (y)
61.0
62.1
0.131
Age ≥ 65
33.7%
40.5%
0.098
Age ≥ 70
13.8%
21.5%
0.020
Male
71.3%
74.2%
0.450
Median time since diagnosis (months)
21.2
24.4
0.811
ECOG = 0
63.2%
64.1%
0.207
CIRS, median 2
0.689
Mean number of cycles
5.27
5.41
0.022
Eichhorst et al. ASH 2013, Abstract 526.

9. CLL10 Study: FCR VS BR in Front-Line
Patients´ characteristics: prognostic factors
Baseline prognostic factors
FCR
n=282 BR
n=279
p value
Binet stage A
22.4%
22.2%
0.970
Binet stage B
37.4%
38.4%
Binet stage C
40.2%
39.4%
IGHV Unmutated
55.3%
67.8%
0.003
11q deletion
24.1%
22.6%
0.691
Trisomy 12
12.4%
12.2%
1.000
13q deletion
55.0%
52.7%
0.612
s- TK (U/L) ≥ 10.0
73.9%
74.3%
0.921
s- β2m (mg/l) ≥ 3.5
31.6%
39.5%
0.059
Eichhorst et al. ASH 2013, Abstract 526.

10. CLL10 Study: FCR VS BR in FrontLine
Response to therapy (Best response)
Response
FCR
n=274 BR
n=273
p value
CR (CR + CRi)
47.4%
38.1%
0.031 CR
40.1%
36.3%
CRi
7.3%
1.8% PR
50.4%
59.7%
ORR
97.8%
1.0
Eichhorst et al. ASH 2013, Abstract 526.

11. CLL10 Study: FCR VS BR in FrontLine
Minimal residual disease (MRD)
p=0.024
No. of patients: 72/ / / / / /98
Eichhorst et al. ASH 2013, Abstract 526.

12. CLL10 Study: FCR VS BR in Front-Line
Progression-free survival = Primary endpoint
Median PFS
FCR not reached
BR months
P = 0.041
Eichhorst B. et al, ASH 2013

13. CLL10 Study: FCR VS BR in FrontLine
Multivariate Analysis
Prognostic factor
Overall Survival
Progression-free Survival HR CI
p-value
Treatment arm
1.649
0.153
0.704
0.038
No del(11q)
0.551
0.189
0.447
<0.001
Age ≥ 65
2.095
0.034
0.800
0.204
CIRS item score >1
2.267
0.019
1.256
0.210
Beta2-MG
2.546
0.007
1.425
IGHV unmutated
4.017
0.004
2.645
Eichhorst B. et al, ASH 2013

14. WHAT IS THE BEST Front-Line REGIMEN for Patients With CLL <60 YEARS OF AGE WHO MEET TREATMENT CRITERIA? FCR: End of the debate not quite, let’s look at details

15. CLL10 Study: FCR VS BR in Front-line
Overall survival
OS at 24 months:
FCR 94.2%
BR 95.8%
P = 0.593
Eichhorst B. et al, ASH 2013

16. CLL10 Study: FCR VS BR in FrontLine
Adverse Events CTC °3-5 (Interval 1st cycle until 3 months after Final staging)
Adverse event
FCR
(% of pt) BR
p value
All
90.8
78.5
<0.001
Hematological AEs
90.0
66.9
Neutropenia
81.7
56.8
Anemia
12.9
9.7
0.28
Thrombocytopenia
21.5
14.4
0.036
Infection
39.0
25.4
0.001
TRM
3.9
2.1
0.23
Eichhorst et al. ASH 2013, Abstract 526.

22. WHAT IS THE BEST Front-Line REGIMEN for Patients With CLL <60 YEARS OF AGE WHO MEET TREATMENT CRITERIA?
BR: older patients no difference in PFS and OS has less infection less mylosuppressive easier to administer easier to add new agents

23. GA101 + Bendamustine x 6 cycles
GALTON: Study Design
GA101 + FC x 6 cycles
n=21
Previously
untreated
CLL
(N=41)
Non-randomized
US, multicenter
Each center selects one arm
GA101 + Bendamustine x 6 cycles
n=20
Cycle 1, Day
Cycles 2–6, Day
GA101 + FC
GA mg IV
1 (100 mg), 2 (900 mg) 8 (1000 mg), 15 (1000 mg) 1
Fludarabine 25 mg/m2 IV
2, 3, 4
1, 2, 3
Cyclophosphamide 250 mg/m2 IV
GA101 + Bendamustine
Bendamustine 90 mg/m2
2, 3
1, 2
Brown et al. ASH 2013, Abstract 523.

24. PCYC 1108 A Phase 1b Study of Ibrutinib With BR or FCR in Patients With Relapsed/Refractory CLL/SLL
Ibrutinib 420 mg orally, once daily in 28d cycles +
BR (70 mg/m2 d1-d2 [B]; 375 mg/m2 cycle 1, mg/m2 cycles 2-6 [R]) for 6 cycles
N = 30
Ibrutinib 420 mg orally, once daily in 28d cycles +
FCR (25 mg/m2 d1-3 [F]; 250 mg/m2 d1-3 [C]; mg/m2 cycle 1, 500 mg/m2 cycles 2-6 [R]) for 6 cycles
N = 3
Investigator Choice
Primary endpoint
Safety
Secondary endpoints
ORR
PFS
12/11/ :47

25. PCYC 1108 Overall Response Rate (ORR)
Median treatment duration on this study was 16 months, with an ORR of 93.4% (28 responding patients [5 CR, 3 nPR])
1 patient achieved a PR with lymphocytosis (not included in ORR)

26. PCYC 1108 Progression-Free Survival
18/21 patients who continued on ibrutinib within the extension study are still on treatment ~1 year after the data-cut off without evidence of progression
12/11/ :47

27. PCYC 1108 TEAEs Grade ≥ 3 Occurring in ≥ 2 Patients
40% 7%
10%