Triple Therapy: New Standard for CLL

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Supplemental to earlier posting, below is their abstract, No. 325 at

50th ASH Annual Meeting & Exposition. Also, to my mind ZAP-70 (a

substitute for IgVH), IgVH, CD38, CD49, and other such markers of

like import, may be rather moot as they're prognostic indicators for

expected values as to pathology. However, specific karyotype &

chromosomal genetics, which are more than just prognostic indicators,

id est, severity, response, overall survival, et cetera, would not be

moot. In this regard, I agree that specifics prior to & similarly

during and after are desirable to know. I would like to see a

complete set of all the stats. With that having been stated, here's

their abstract.

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). 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.