Early versus deferred treatment

with combined
fludarabine, cyclophosphamide and rituximab
(FCR) improves event-free survival
in patients with high-risk Binet stage A CLL
********
First results of a randomized German-French
cooperative phase III trial
(GCLLSG & FCGCLL)

Carmen D Schweighofer, Florence Cymbalista, Carolin Muller, Raymonde Busch,

Raphael Porcher, Petra Langerbeins, Bruno Cazin, Anna-Maria Fink, Brigitte Dreyfus,
Stefan Ibach, Stephane Lepretre, Kirsten Fischer, Ursula Vehling-Kaiser, Barbara
Eichhorst, Manuela A. Bergmann, Stephan Stilgenbauer, Hartmut Dohner, Veronique
Leblond, Michael Hallek, and Vincent Levy

55th ASH Annual Meeting in New Orleans, Dec 9 2013, abstr #524
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Study Design
Binet A stage CLL
1 Registration 1st dx 12 months, GFR 70 ml/min, untreated

Assessment of 4 defined risk factors:

Central Unfavorable cytogenetics (del17p, del11q, tri12)
2
diagnostics Unmutated IGHV status
Thymidine kinase > 10 U/L
Lymphocyte doubling time 12 months

3 Risk
Risk stratification
stratification
High risk Low risk
2 risk factors < 2 risk factors
Randomization
4
(high risk)
6 cycles FCR * watch & wait watch & wait

* FCR dosing: q28d

Rituximab 375 mg/ m2 iv, d0, #1,
Rituximab 500 mg/m iv, d1, #2-6
Fludarabine 25 mg/m iv, d1-3, #1-6
Cyclophosphamide 250 mg/m iv, d1-3, #1-6
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Study Population

n = 824 patients registered

( 401pts, 423 pts)

24 patients w/ premature end of study:

PD, withdrawal, mis-diagnosis, 2nd malignancy

n = 800 patients available for risk stratification

High risk Low risk

n = 201 (25.1%) n= 599 (74.9%)

FCR w&w w&w

n = 100 (ITT) n = 101 n= 599

Primary endpoint: Event-free survival (EFS)

Assumption: Improvement by FCR from 50 to 70% at month 36
Median follow up at analysis: 49 months

55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Baseline Characteristics
Stratified patients n = 800

High risk Low risk

FCR w&w w&w P value
Median (range) 57 (33-77) 60 (39-80) 58 (27-80) n. s.
70 yrs (%) 15 17 12 n. s.
Male (%) 69 77 61 0.004
CIRS: 1 comorbidity (%) 54 60 63 n. s.
ECOG 0-1 (%) 99 100 100 n. s.
B symptoms (%) 7 9 9* n. s.
Clinical lymphadenopathy (%) 58 64 6* n. s.
Median time from dx to
6* 7* 7* n. s.
stratification
* Available from German cohort only

55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Baseline Characteristics
Stratified patients n = 800

High risk Low risk

FCR w&w w&w P value
Thymidine kinase > 10 U/L (%) 62 53 7 <0.001
Lymphocyte doubling time
58 50 12 <0.001
12 months (%)
IGHV unmutated (%) 84 84 10 <0.001

del(17p) (%) 4 9 1 <0.001

Unfavorable
del(11q) (%) 17* 35* 1 <0.001
cytogenetics
trisomy12 (%) 27 27 3 <0.001
> 2 risk factors (%) 42 43 0 <0.001
* p = 0.004 comparing HR-FCR vs HR-w&w

55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
High risk: Study therapy
Reasons for no or incomplete FCR therapy % patients (n = 100)
Consent withdrawal 21 (21%)
Hematotoxicity 6 (6%)
Allergic exanthema 2 (2%)

% pts (ITT n=100)

CMV reactivation 1 (1%)
Richter transformation 1 (1%)
Thrombosis 1 (1%)
Unknown 1 (1%)
80%
67%
60%
Administered study therapy in
n pts
40%
n = 100 high risk patients
18% 15%
randomized for FCR 20%

0%
no cycle 1 to 5 6 cycles
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Adverse Events
HR-FCR, n=82, within 12 months from stratification/randomization

CTC category* N patients (%) CTC grade 3/4/5 event

All 54 (65.9%) All categories
Blood/bone marrow 49 (59.8%) Any cytopenia

49 (59.8%) Leukopenia/neutropenia

4 (4.9%) Thrombopenia
3 (3.7%) Anemia
Infections 12 (14.6%) Most common: respiratory tract, herpes zoster
Metabolic/laboratory 9 (11.0%) Elevated liver enzymes, hyperglycemia
Gastrointestinal 3 (3.7%) Nausea, anorexia, constipation, diarrhea
Thrombosis, pulmonary embolism,
Vascular 3 (3.7%)
aortic aneurysm ruptur
1 sepsis, 1 sepsis + pulmonary aspergillosis, 1
TRM 3 (3.7%)
encephalitis
* AE assessment according to NCI-CTC v3.0 criteria
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Adverse Events (German data)
HR-FCR, n=44, within 12 months from stratification/randomization

CTC category* N patients (%) CTC grade 3/4/5 event

All 31 (70.5%) All categories
Blood/bone marrow 31 (70.5%) Any cytopenia

31 (70.5%) Leukopenia/neutropenia

4 (9.1%) Thrombopenia
3 (6.8%) Anemia
Infections 11 (25.0%) Most common: respiratory tract, herpes zoster
Thrombosis, pulmonary embolism,
Vascular 3 (6.8%)
aortic aneurysm ruptur
Metabolic/laboratory 2 (4.5%) Elevated liver enzymes, hyperglycemia
TRM 2 (4.5%) 1 sepsis, 1 encephalitis
* AE assessment according to NCI-CTC v3.0 criteria

55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Best Response until Month12
HR-FCR, n=79 with actual treatment & response available

% patients
Response
(n=79)
CR 27.8
nPR/PR * 68.4
OR 96.2
SD 2.5
PD 1.3
* Includes CRu, CRi and nPR

55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Primary Endpoint: EFS

LR-W&W

HR-FCR Log rank P < 0.001

HR-W&W

N events Median EFS 5 year EFS

HR-FCR 33 n. r. 55.3%
HR-W&W 78 n. r. 14.8%
LR-W&W 111 24.2 months 80.1%
Cox regression: Variable P Value Hazard Ratio 95% CI
Cohort assignment 3.815E-43
HR-FCR vs. LR-W&W 0.001 1.9 1.3 2.8
HR-W&W vs. LR-W&W 3.881E-44 8.2 6.1 11.0
HR-FCR vs. HR-W&W 5.846E-12 0.2 0.1 0.4
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Secondary Endpoint: PFS

LR-W&W

HR-FCR Log rank P < 0.001

HR-W&W

N events Median PFS 5 year PFS

HR-FCR 32 n. r. 57.5%
HR-W&W 71 n. r. 23.7%
LR-W&W 101 25.8 months 78.6%
Cox regression: Variable P Value Hazard Ratio 95% CI
Cohort assignment 3.823E-36
HR-FCR vs. LR-W&W 0.001 2.0 1.4 3.0
HR-W&W vs. LR-W&W 2.778E-37 7.4 5.4 10.1
HR-FCR vs. HR-W&W 3.015E-09 0.3 0.2 0.4
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Secondary Endpoint: OS
LR-W&W

HR-FCR

HR-W&W

Log rank P < 0.001

N events Median OS 5 year OS

HR-FCR 10 n. r. 87.4%
HR-W&W 10 n. r. 78.7%
LR-W&W 16 n. r. 96.4%
Cox regression: Variable P Value Hazard Ratio 95% CI
Cohort assignment 1.961E-04
HR-FCR vs. LR-W&W 0.001 3.8 1.7 8.4
HR-W&W vs. LR-W&W 3.717E-04 4.2 1.9 9.3
HR-FCR vs. HR-W&W 0.742 0.9 0.4 2.1
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Conclusions
We have prospectively validated an efficiant clinical-biological
stratification system to identify high-risk CLL at early stage w/
poor outcome

Early FCR therapy is feasible in high-risk CLL, however, it

bears a high risk of side effects, in particular hematotoxicity
and infections

Early FCR therapy improves event-free- and progression-free

survival in high-risk CLL

No benefit in overall survival for early FCR has been detected

after a median follow up of 46 months
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524
Acknowledgment
Principal Investigator Central Laboratories
Prof. M. Hallek (Cologne) Prof. H. Dhner (Ulm)
Prof. F. Cymbalista (Paris) Prof. S. Stilgenbauer (Ulm)
Prof. V. Levy (Paris) Prof. D. Seidel (Munich)
Prof. M. Kneba (Kiel)
Study Office Cologne Dr. S. Bttcher (Kiel)
Dr. C. Schweighofer Dr. M. Herling (Cologne)
Dr. C. Mller Prof. K. Kreuzer (Cologne)
Dr. P. Langerbeins
Dr. A. Fink Database & Monitoring
Dr. K. Fischer Dr. S. Ibach (WiSP)
I. Stodden Dr. A. Hinke (WiSP)
S. Schott
H. Gerwin Statistics
G. Kranz Dipl.-Math. R. Busch
Dr. R. Porcher (Paris)
Financial support: K. Klein (Munich)
German Cancer Aid
Roche
THANK YOU to all patients & investigators participating in this trial
!
55th ASH Annual Meeting in New Orleans, Dec 9 2013, Schweighofer et al., abstr #524