1. What is the best frontline regimen for CLL patients <65 years of age who meet treatment criteria? FCR
Michael J. Keating, M.B., B.S.
 Department of Leukemia
The University of Texas MD Anderson Cancer Center

2. FC + Rituximab Schedule In CLL
(Allopurinol 300mg/day)

3. FCR300: Progression-free & Overall Survival
Proportion Surviving
Events Total
Months

4. Survival by Age FCR 300 ( )
Proportion

5. FCR300: PFS by IGHV Mutation Status
Group Events Total
IGHV-M
IGHV-UM
Unknown
Proportion Progression-free
P<.0001
MONTHS

6. FCR Based regimens (2004-2008) FCR3 -- 3 DOSES OF RITUXIMAB / COURSE
FCMR – ADD MITOXANTRONE
(Beta-2-M < mg/l)
CFAR –ADD ALEMTUZUMAB
(Beta-2-M >4mg/l)
FCR +GMCSF --MOSTLY <65 YEARS OF AGE
(FISH & MUTATION STATUS IN MOST PTS)

7. Time to Failure of Risk Groups FCR-based 2004-11: Opportunities to Improve Cure
Proportion
Mutated
17p-
11q-, UM
Non 11q-, UM
IGVH Mutated

8. 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.

9. 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.

10. 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.

11. CLL10 Study: FCR VS BR in Front-Line
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.

12. CLL10 Study: FCR VS BR in Front-Line
Progression-free survival = Primary endpoint
Median PFS
FCR not reached
BR months
P = 0.041
Currently no difference in overall survival
Eichhorst et al. ASH 2013, Abstract 526.

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

14. CLL10 Study: FCR VS BR in Front-Line
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.

15. CLL10 Study: FCR VS BR in Front-Line
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 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 et al. ASH 2013, Abstract 526.

16. ISSUES WITH CLL 10
IMBALANCE OF PROGNOSTIC FACTORS MORE NEUTROPENIAAND INFECTION SHORT FOLLOW UP How important is MRD negativity ?

17. First-line FCR: NCI-WG Response & Bone Marrow MRD-free Status
% of Patients
% MRD- Negative* CR
153 65 75
nPR 29 12 4 PR 48 20 44 NR 7 3
Overall MRD
220 93 59
* Bone marrow evaluation by 4-color flow cytometry (sensitivity .01%)

18. First-line FCR: Prospective Evaluation of Prognostic Factors and MRD
Pretreatment Characteristic n
% MRD- Negative
p-value
IGHV Unmutated
Mutated
115 78 47 71
.006
ZAP70 IHC Positive
Negative
129 55 63
.252
CD  7%
< 7%
134 74 57 62
.51
FISH p del
11q del
+12
None
13q del 15 44 38 41 68 27 52 76 70 56
.04
.70
.12
Ref

19. First-line FCR: PFS & OS by IGHV Mutation Status
Progression-free Survival
Overall Survival
Proportion of Patients
p=.008
p=.17
Months

20. First-line FCR: Multivariable Model for BM MRD-free Status (N=181)
Pretreatment
Characteristic
p-value
IGHV - Unmutated
.003
Rai Stage - III-IV
.016
Trisomy 12
.02
17p del
.04

21. Should we Replace Cytotoxic Chemotherapy as Frontline Treatment?
40% of deaths of CLL patients are associated with second solid tumors, Acute Leukemia/MDS or Richter’s. This includes 71% of deaths in first remission!

22. Risk of 2nd malignancies for fcr-based vs non-genotoxic regimens as initial therapy for CLL in patients >65 years
Malignancy
FCR-based (n=120)
Non-genotoxic* (n=170)
Solid tumors
13 (11%)
18 (11%)
Richter’s transformation
8 (7%)
2 (1%) p=.02
AL/MDS
10 (8%)
7 (4%)
Antibody regimens(n=53), Lenalidomide regimens (n=68), BCR antagonist regimens (n=49)

23. Patients Age >65: Survival by Treatment > 2004
Proportion

24. initial therapy of CLL (2014)
PRIORITIES
Lenalidomide + Rituximab: All ages
(Till new Targeted studies developed)
FCR only if Lenalidomide+Rituximab not approved or inconvenient
2. Ibrutinib + Rituximab: 17p del (p53 mutated)
Eradication initiative: CAR+ T cell (ROR1)
Timing to be determined
Immunorestoration with lenalidomide and/or expanded autologous t cells

25. FCR STILL STANDARD
HOW DO WE MAKE IT BETTER?