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Featured research from recent issues of Blood
PAPER SPOTLIGHT
FCR in Patients with IGHV-Mutated CLL
Long-Term Remissions, Long-Term Survival
Treatment with fludarabine, cyclophosphamide,
and rituximab (FCR) is
considered by many to
be the standard of care
for physically fit patients
with chronic lymphocytic
leukemia (CLL) who require
therapy. Two recent studies published in Blood
examined the efficacy of
FCR against FC alone and
identified specific patient
subgroups who are likely to
achieve long-term, diseasefree survival with FCR
treatment, such as those
with IGHV-mutated CLL.
The first study, conducted by Kirsten Fischer,
MD, from the Department of Internal Medicine
and Center of Integrated
Oncology at the University of Cologne in Cologne,
Germany, and colleagues,
included 817 treatment-naïve CLL patients who were
also CD20-positive. The
prospective, randomized,
phase III CLL8 trial was
conducted in 190 centers
across 11 countries. “To our
knowledge this randomized
trial represents the largest
cohort to evaluate the current standard treatment of
FCR chemoimmunotherapy
in patients with previously
untreated CLL,” Dr. Fischer
told ASH Clinical News.
Patients were randomized to receive six courses
of intravenous fludarabine
(25 mg/m2/day) and cyclophosphamide (250 mg/m2/
day) for the first three days
of each treatment cycle
with or without the addition of rituximab (375 mg/
m2 administered on day 0
of course 1, and 500 mg/m2
on day 1 of courses 1-6).
At a median followup of 5.9 years, median
44
ASH Clinical News
progression-free survival
(PFS; the study’s primary
endpoint) was 56.8 months
for patients in the FCR
cohort, compared with
32.9 months for the FC
cohort (hazard ratio [HR]
= 0.59; 95% CI 0.50-0.69;
p<0.001). The median overall survival (OS) was not
reached for the FCR cohort
and was 86 months for the
FC group (HR=0.68; 95% CI
0.54-0.89; p=0.001).
There were fewer
deaths in the patients receiving rituximab: 125/408
(30.6%) in the FCR group
and 154/409 (37.7%) in
the FC group. The most
common causes of death
were infections, followed
by progressive disease and
secondary malignancies
(including solid tumors
and lymphoma). Patients
receiving FCR had higher
rates of prolonged neutropenia during the first year
after treatment compared
with those taking FC: 16.6
percent versus 8.8 percent,
respectively (p=0.007),
though at 12 months posttreatment the rates of
neutropenia did not differ
between the two treatment cohorts.
Dr. Fischer and colleagues found several
factors that were independently associated with
shorter PFS and OS, including: FC therapy, del17p CLL,
umutated IGHV status,
del11q, mutated TP53, and
age >65 years. The presence of TP53 mutation,
del17p, and unmutated
IGHV showed the strongest
prognostic impact on both
PFS and OS (TABLE 1).
“The IGHV-mutated
group treated with FCR had
a significantly longer PFS
the authors noted that the
study was not designed to
differentiate between CLLrelated and CLL-unrelated
deaths and the competing
risk was not analyzed.
The second study, led
by Philip A. Thompson,
MBBS, from the Department of Leukemia at MD
Anderson Cancer Center in
Houston, Texas, examined
the results of an earlier
phase II trial to identify CLL
patients who are likely to
achieve long-term, diseasefree survival with FCR.
The original phase II study,
conducted between 1999
and 2003, demonstrated
the superiority of FCR over
FC therapy (in terms of
rates of complete remission
and failure-free survival)
and established FCR as the
current standard of care for
CLL. The current analysis
presents long-term data on
disease-free survival.
Patients received the
following treatment regi-
than those treated with FC
(median PFS: not reached
for FCR vs. 41.9 months
for FC; HR = 0.47 [9 Ԕ