SAN FRANCISCOInterim results of a trial of the
combination of rituximab (Rituxan) and fludarabine (Fludara), a novel approach
for the treatment of low-grade or follicular B-cell lymphoma, suggest excellent
antitumor activity. Rituximab, an anti-CD20 monoclonal antibody, is the only
approved monoclonal antibody therapy for refractory or relapsed low-grade or
follicular non-Hodgkin’s lymphoma (NHL).
Both rituximab and fludarabine monotherapy have demonstrated
good antitumor activity in patients with indolent lymphoma, said Myron
Czuczman, MD, assistant professor of medicine and head of the Lymphoma Service,
Roswell Park Cancer Institute.
Furthermore, prior experience with rituximab and CHOP
(cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy has
demonstrated very durable remissions in this patient population, Dr. Czuczman
said at the 42nd Annual Meeting of the American Society of Hematology (ASH).
In a recently updated analysis, median duration of response has
not been reached after 50.4+ months of observation, and time to progression has
not been reached after 52.1 months.
"We were looking at other combinations that potentially
are as beneficial, and we realized that fludarabine as a single agent has
excellent activity in CLL [chronic lymphocytic leukemia] and in previously
treated or untreated lymphomas," Dr. Czuczman said.
Fludarabine is a fluorinated nucleotide analogue of ara-A
(cytarabine) that inhibits DNA synthesis in sensitive cells. He noted that
French investigators have reported a 65% response rate in 49 assessable
previously untreated patients with 37% complete responses and 28% partial
responses after a median of seven cycles of fludarabine.
In addition, in vitro data demonstrate synergistic activity
against resistant cell lines when rituximab and fludarabine are combined.
Importantly, rituximab and fludarabine have non-cross-resistant mechanisms of
action and no apparent overlapping toxicities.
Dr. Czuczman and his colleagues, therefore, conducted a phase
II single-institution trial of rituximab plus flu-darabine for both
treatment-naïve and previously treated patients with advanced-stage indolent
Thirty-nine of 40 planned patients have been enrolled and are
receiving seven doses of rituximab (375 mg/m2/dose) in combination with six
cycles of fludarabine (25 mg/m2/d × 5 days every 28 days). Two infusions of
rituximab are given at the beginning and end of therapy, and single infusions
of rituximab are given prior to the second, fourth, and sixth cycles of
Evaluable patients (n=30, median age 55.5 years, 47% male)
include 60% who are treatment-naïve and 40% relapsed. Twenty-seven percent had
small B-cell lymphocytic lymphomas.
The protocol was modified after the first 10 patients, Dr.
Czuczman explained, when three patients were withdrawn from therapy, two for
cytopenia and one for pulmonary hypersensitivity reaction. The investigators
discontinued the use of prophylactic Bactrim (trimethoprim-sulfamethoxazole),
limited the use of growth factors, and, when needed because of prolonged
cytopenia, reduced fludarabine doses by 40%.
In the initial 10 patients, complete response was reported in 6
of 7 patients who completed therapy and partial response in 1. Seven of the
initial 10 patients had growth factor support. Limited herpes zoster infections
occurred in 2 patients.
With the next 20 patients, complete response was reported in 16
of 17 patients completing therapy. Partial response was reported in 1. Of the 3
discontinuations, 1 was for cytopenia and 2 were secondary to transformed NHL.
Three patients developed limited herpes zoster infections, and no serious or
opportunistic infections occurred.
In an interview with ONI, Dr. Czuczman said that about halfway
through planned therapy, about 90% of patients have demonstrated significant
responses. "We saw an elimination of bcl-2 cells from blood and marrow in
the majority of patients," he said.
Dr. Czuczman noted that nonhema-tologic toxicities have been
minimal. While flow cytometry has shown significant decreases in T cells (CD3)
and depletion of B cells (CD19, CD20), mean quantitative immunoglobulin levels
and natural killer cells were preserved in the majority of patients.
"That explains why we are not seeing opportunistic
infections," Dr. Czuczman said. Avoiding steroids, he added, which
increase opportunistic infection risk with fludarabine, also helps.
He commented that the 17% (5 of 30) incidence of herpes zoster
has led to initiation of prophylactic oral acyclovir therapy. The most common
adverse events attributed to rituximab were fever and chills, seen primarily
with the first infusion, he added.
Dr. Czuczman concluded: "Rituxi-mab and fludarabine
chemoimmuno-therapy is associated with excellent antitumor activity in patients
with low-grade or follicular B-cell lymphoma. Long-term follow-up will
determine the durability of this promising combination for this
Subsequent investigations might evaluate even fewer days (3
rather than 5) of fludarabine to determine whether similar responses with
reduced hematologic toxicity can be achieved. Also, larger
trials in a cooperative group setting might compare rituximab/fludarabine with
rituximab/CHOP, Dr. Czuczman commented.