BUFFALOCombining rituximab (Rituxan) with fludarabine
(Fludara) for low-grade or follicular B-cell lymphomas may be as effective as
but less toxic than rituximab plus CHOP (cyclophosphamide, doxorubicin, Oncovin
[vincristine], prednisone). Phase II trial data supporting this assertion were
Although initial problems with hematologic toxicity required
changes in the planned regimen, including a 40% dose reduction in fludarabine
for some patients, lead investigator Myron Czuczman, MD, said that the
rituximab/fludarabine combination produced an overall response rate of 93%
while preserving immunoglobulin levels and natural killer (NK) cells. Dr.
Czuczman is assistant professor of clinical medicine and head of the Lymphoma
Section at Roswell Park Cancer Institute, Buffalo.
The rationale for combining these two drugs was that
fludarabine has demonstrated single-agent efficacy in chronic lymphocytic
leukemia and in refractory or recurrent low-grade B-cell non-Hodgkin’s
lymphoma (NHL). Fludarabine inhibits DNA synthesis in sensitive cells.
Rituximab has demonstrated single-agent efficacy against B cells. The two drugs
have mechanisms of action that are not cross resistant and have no apparent or
significant overlapping toxicities. Dr. Czuczman also said that in vitro
studies have demonstrated synergistic antitumor activity when fludarabine and
rituximab are combined.
Goal and Objectives
The goal of this study was "to maintain excellent
antitumor activity with less nonhematologic toxicity than observed in the
recent CHOP plus rituximab trial.’’ The main study objectives were to
evaluate the safety and efficacy of the combination regimen in treatment-naive,
recurrent, or refractory patients with low-grade or follicular NHL and to
evaluate changes in lymphocyte subsets (especially NK cells) during treatment
The pilot study has completed enrollment of 40 patients as
originally planned, and data on 30 evaluable patients were presented at the
Inclusion criteria were:
low-grade or follicular NHL;
Karnofsky performance status
no prior treatment or up to
four prior standard chemotherapies; and
adequate hematologic, renal,
and hepatic function
Exclusion criteria included:
positive for HIV;
primary or secondary CNS
prior treatment with fludarabine or any other purine
antimetabolite, or with prior anti-CD20 immunotherapy.
The first 10 patients in this open- label, single-arm,
single-center phase-II study were treated with the planned regimen of seven
doses of rituximab (375 mg/m2/dose) in combination with six cycles of
fludarabine (25 mg/m2/d ´ 5 days q 28 days). Two infusions of rituximab were
given at the beginning and end of therapy and single infusions of rituximab
were given prior to the second, fourth, and sixth cycles of fludarabine.
Trimethoprim-sulfamethoxazole (Bactrim) was given as prophylaxis. Growth factor
support was not routinely given.
Hematologic toxicity in the first 10 patients treated caused
the investigators to revise the treatment regimen. Two of the first 10 patients
discontinued treatment due to cytopenia. Adverse events included grade IV
neutropenia in four patients, neutropenic fever with negative cultures in two
patients, and need for G-CSF/GM-CSF support in seven patients. Limited herpes
zoster infections also developed in 2 of 10 patients.
"Unique to the rituximab plus fludarabine combination was
the observation of significant neutropenia in the first 10 patients treated,
which led to discontinuation of prophylactic Bactrim, limited use of growth
factors, and if needed, a 40% reduction of fludarabine in patients with
prolonged cytopenia," Dr. Czuczman said.
Six of the seven patients who completed therapy with the
original regimen had complete responses, and one had a partial response. Of the
20 patients treated with the revised regimen, only four required transient
growth factor support. Seven patients developed grade IV neutropenia, and one
discontinued treatment as a consequence. Only one patient had neutropenic fever
with negative culture. One patient discontinued treatment due to cytopenia.
Three patients developed herpes zoster. Fludarabine dose reductions were
required for three patients.
Excellent Antitumor Activity
Sixteen of the 17 patients who completed treatment with the
revised regimen had complete responses, and one patient had a partial response.
Considering all 30 treated patients, the overall response rate was 93%. This
included 80% complete responses and 13% partial responses. The median duration
of response is 14+ months, ranging from 4 to over 26 months, according to Dr.
He said that 89% of patients showed nodal responses in the
midtreatment restaging studies and 24 of 28 patients maintain ongoing
responses. Polymerase chain reaction studies showed elimination of cells with
the bcl-2 (t[14;18]) rearrangement from peripheral blood in 9 of 9 patients
studied and from bone marrow in 6 of 7 patients studied, Dr. Czuczman reported.
A striking characteristic of this regimen was its ability to
preserve immunoglobulin levels and NK cell numbers. No significant change in
quantitative serum immunoglobulins occurred in 17 of 26 patients studied, and
immunoglobulin levels actually improved in two of 26 patients. Decreases in
levels of IgM, IgG, or IgA were seen in seven patients.
Multiparameter flow cytometry was used to evaluate the effect
of rituximab/fludarabine on peripheral blood lymphocyte subsets. According to
Dr. Czuczman, "CD3+ T cells were significantly decreased in the majority
of patients (Figure 1a). B cells (CD19+ and CD20+) were essentially depleted
from peripheral blood in all cases (Figure 1b). NK cells and activated NK cells
were essentially spared in the majority of patients (Figures 1c and 1d)."
The most common adverse events attributed to rituximab were
fever and chills, observed primarily with the first infusion.
"In summary, interim results of rituximab plus fludarabine
combination therapy demonstrate excellent antitumor activity with acceptable
toxicity. This is a novel approach for the treatment of indolent NHL," Dr.