Blood, 1 January 2003, Vol. 101, No. 1, pp. 1-1
Is a complete response in CLL now a realistic goal?
When therapy is indicated for patients with chronic lymphocytic
leukemia who have symptomatic or advanced-stage disease, the standard
therapies often provide improvement of blood counts and symptoms, but
only a minority of patients achieve a complete response. Until
recently, chlorambucil or other alkylator agents were the standard
treatment. Fludarabine has replaced chlorambucil as the initial therapy
of choice for patients with CLL due to a higher complete response rate,
overall response rate, and longer progression-free survival. Despite
the improved results seen with fludarabine, fewer than 20% of patients
achieve CR.
Rituximab is a chimeric antibody that binds to the B-cell surface
antigen CD20. This agent has activity in follicular non-Hodgkin lymphoma, where there are high levels of CD20 expression. Rituximab also appears to have a synergistic effect in B-cell non-Hodgkin lymphoma when used in combination with chemotherapy. In CLL, the level
of CD20 expression is lower than other low-grade B-cell neoplasms, and as a consequence, response rates using rituximab at
standard doses are inferior to those obtained in follicular lymphoma.
Whereas this agent has activity in CLL, rituximab as a single
agent has limited utility in initial management of this disease.
The report by Byrd and colleagues from CALGB (page 6) suggests that
adding rituximab to fludarabine in the initial therapy for CLL may
produce an increase in CR rate. In this randomized phase 2 study,
patients either received rituximab concurrently with
fludarabine followed by 4 additional doses of rituximab, or received
fludarabine followed by rituximab therapy. Both regimens had high
overall response rates; the complete response rate was 47% in patients
who received concurrent therapy and 28% in the sequential therapy
group. The only unanticipated toxicity was more granulocytopenia in
patients who received concurrent fludarabine and rituximab; this was
not associated with increased risk of infection when compared with
historic use of fludarabine alone. Infusional toxicity was acceptable
even in the concurrent arm, particularly when rituximab was given over
several days with the initial administration.
This trial is an important step on the road to improving the complete
response rate and, ultimately, the outcome in CLL. A phase 3 intergroup
trial is now underway to determine whether the addition of
cyclophosphamide to fludarabine is superior to fludarabine alone.
Exploring the concept of combination therapy further, investigators at
the M. D. Anderson Cancer Center have reported a CR rate of 66%
with a fludarabine-rituximab-cyclophosphamide combination.
Despite enthusiasm for combination therapy for CLL, carefully performed
phase 3 clinical trials are needed in order to evaluate the efficacy
and complications of these new therapies. As therapy becomes more
intensive, unforeseen toxicity such as the granulocytopenia seen in
Byrd et al's study or other complications such as opportunistic
infections and myelodysplasia may be seen. These clinical trials are
also needed for the appropriate correlative studies to understand this
disease, as well as to improve therapy, so that achievement of a
complete response in CLL is routine rather than a rarity.
Stephen H. Petersdorf
University of
Washington
