CLL: FCR vs. FR - ASH abstract

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Immunochemotherapy with Fludarabine (F), Cyclophosphamide ©, and Rituximab ®

(FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and

Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with

Advanced Chronic Lymphocytic Leukemia (CLL)

n = 817 pts with good physical fitness - median CIRS score was 1 (range 0-8),

median age was 61 years (range 30 to 81), The overall incidences of trisomy 12

and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%,

and 8%, respectively, with no statistically significant differences between

treatment arms.

http://ash.confex.com/ash/2008/webprogram/Paper9237.html

Monday, December 8, 2008: 11:00 AM

Introduction: Previous phase II studies have suggested that a combination of FCR

may increase the outcome of both untreated and relapsed CLL pts. In order to

validate this concept the German CLL study group (GCLLSG) initiated a

multicentre, multinational phase III trial, CLL8, to evaluate the efficacy and

tolerability of FCR versus FC for the first-line treatment of pts with advanced

CLL.

Methods and Patients:

817 pts with good physical fitness as defined by a cumulative illness rating

scale (CIRS) score (Extermann et al., JCO 1998) of up to 6 and a creatinine

clearance (cr cl) ³ 70 ml/min were enrolled between July 2003 and March 2006.

Pts were randomly assigned to receive 6 courses of either FC (N=409; F 25mg/m2

i.v. d1-3 and C 250 mg/m2 i.v. d1-3; q 28 days) or FC plus R (N=408; 375 mg/m2

i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days).

Both treatment arms were well balanced with regard to age, stage, genomic

aberrations and VH status. 64% were Binet B, 32% Binet C and 5% Binet A. The

median age was 61 years (range 30 to 81), the median CIRS score was 1 (range

0-8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and

17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no

statistically significant differences between treatment arms.

A mean number of 5.2 courses was given in the FCR arm versus 4.8 courses in the

FC arm (p=0.006). 74% (FCR) and 67% (FC) of pts received 6 cycles. Dose was

reduced by more than 10% in at least one treatment course in 43% (FCR) and 30%

(FC) of pts, and in 21% (FCR) and 17% (FC) of all treatment courses given. 17

pts did not receive any study medication, 10 due to violation of enrolment

criteria (4 decreased renal function, 2 active secondary malignancies, 2 active

infections, 1 autoimmune thrombocytopenia, 1 pt not requiring treatment), 3 due

to withdrawal of consent, 2 due to worsened concomitant diseases. 2 pts were

lost before start of treatment. 56 pts were not evaluable for response: 17 did

not receive any study medication, 16 withdrew consent before interim staging, 7

due to violation of enrolment criteria, 4 discontinued treatment due to toxicity

and 12 due to early death (caused by toxicity, progression or secondary

malignancy). Prophylactic use of antibiotics or growth factors was not generally

recommended in the protocol.

Results: At the time of analysis, June 2008, the median observation time was

25.5 months (mo). 761 pts (FCR 390; FC 371) were evaluable for response, 787 pts

(FCR 400; FC 387) for PFS and all for OS. The overall response rate (ORR) was

significantly higher in the FCR arm (95%; 370/390) compared to FC (88%; 328/371

(p=0.001).

The complete response rate of the FCR arm was 52% as compared to 27.0% in the FC

arm (p<0.0001).

PFS was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm (p<0.0001).

There was a trend for an increased OS rate in the FCR arm (91% vs 88% at 2 years

p=0.18).

Hazard Ratio for PFS was 0.59, for OS 0.76. The largest benefit for FCR was

observed in Binet stage A and B with regard to CR, ORR and PFS (A: p=0.01, B:

p<0.0001).

[Comment: Suggesting that lower disease burden (Binet A and was associated

with higher CR rate, overall response rate, and longer progression free

survival. ]

FCR treatment was more frequently associated with CTC grade 3 and 4 adverse

events (47% of FC vs 62% of FCR treated pts).

Severe hematologic toxicity occurred in 55% (FCR) versus 39% (FC) of all

patients. Significant differences were observed for neutropenia (FCR 33,6%; FC

20,9% p=0.0001) and leukocytopenia (FCR 24%; FC 12,1% p<0.0001) but not for

thrombocytopenia (FCR 7,4%; FC 10,8% p=0.09) and anemia (FCR: 5,4% FC 6,8%

p=0.42).

The incidence of CTC grade 3 or 4 infections was not significantly increased in

the FCR arm (18,8% versus 14,8% in the FC arm, p=0.68). Tumor lysis syndrome

(FCR 0,2% FC 0,5%) and cytokine release syndrome (FCR 0,2% FC 0,0%) were rarely

observed in both arms.

Treatment related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm.

Multivariate analyses were performed to evaluate factors predicting outcome.

Amongst these variables age, sex, Binet stage, CIRS score, renal function (cr cl

< 70 ml/min) were independent prognostic factors predicting OS or PFS.

Conclusion: Treatment with FCR chemoimmunotherapy improves response rates and

PFS when compared to the FC chemotherapy. FCR caused more neutropenia/leukopenia

without increasing the incidence of severe infections. These results suggest

that FCR chemoimmunotherapy might become the new standard first-line treatment

for physically fit CLL patients.

Halls B and C (Moscone Center)

Hallek, MD1, Guenter Fingerle-Rowson, MD, PhD1*, - Fink, MD1*,

e Busch2*, Jiri Mayer, MD3*, Manfred Hensel, MD4*, Georg Hopfinger, MD5*,

Georg Hess, MD6*, Ulrich von Gruenhagen, MD7*, a A. Bergmann, MD8,

Catalano, MD9, Pier Luigi Zinzani, MD10*, Federico Caligaris Cappio, MD11*,

Francis Seymour, MBBS12, Alain Berrebi, MD13*, Ulrich Jaeger, MD14, Bruno Cazin,

MD15*, Marek Trneny, MD, PhD16, Anne Westermann1*, Clemens- Wendtner, MD1,

Barbara F. Eichhorst, MD1, Staib, MD17*, Sebastian Boettcher, MD18*,

Matthias Ritgen, MD19*, Stephan Stilgenbauer, MD20, Myriam Mendila, MD21*,

Kneba, MD, PhD19, Hartmut Döhner, MD20* and Kirsten Fischer, MD1*

1Department I of Internal Medicine, University of Cologne, Cologne, Germany

2Technical University, Institute for Medical Statistic and Epidemiology, Munich,

Germany

3Hematology/Oncology, Masaryk University Hospital, Brno, Czech Republic

4University of Heidelberg, Mannheim, Germany

5Department of Medicine III, Hanusch Hospital, Vienna, Austria

6Johannes Gutenberg-Universität, Mainz, Germany

7Praxis für Hämatologie/Onkologie, Cottbus, Germany

8Hem./Onc., Univ. Hosp. Munich, Muenchen, Germany

9Dorevitch Pathology Laboratory, ston Hospital, ston, VIC, Australia

10Department of Hematology/Oncology, University of Bologna, Bologna, Italy

11Ospedale San Raffaele, Milano, Italy

12 MacCallum Cancer Institute, Richmond, Australia

13Kaplan Medical Center, Rehovot, Israel

14Department of Internal Medicine I, Division of Hematology and Hemostaseology,

Medical University of Vienna, Vienna, Austria

15Service des Maladies du Sang, Hopital Claude Huriez, Lille, France

16First Dept. of Medicine, Univ. General Hosp., Prague, Czech Republic

17Klinik für Hämatologie und Onkologie, St.-Antonius Hospital, Eschweiler,

Germany

18Department of Internal Medicine II, University Hospital of Schleswig-Holstein,

Campus Kiel, Kiel, Germany

19Department of Internal Medicine II, University Hospital, Kiel, Germany

20Internal Medicine III, University of Ulm, Ulm, Germany

21Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland