(Rituxan) has shown synergistic
antitumor activity when combined
with chemotherapy in previous studies.[
1,2] These studies suggest that
rituximab sensitizes cells to the effects
of chemotherapy through interleukin-
10, causing down-regulation of
the bcl-2 gene.
Another hypothesis suggests that
chemotherapy may instead sensitize
cells to the effect of rituximab. This
hypothesis is supported by data from
a recent study indicating that fludarabine
(Fludara) sensitizes lymphoma
cells to rituximab through the downregulation
of complement inhibitory
proteins such as CD55 and CD59.
The potential synergy between rituximab
and chemotherapy has led several
investigators to study the efficacy
of using fludarabine and cyclophosphamide
(Cytoxan, Neosar) chemotherapy
with rituximab (FCR) for the
treatment of follicular lymphoma.
At the American Society of Hematology
(ASH) 44th Annual Meeting in
Philadelphia, Stefano Sacchi, MD, of
the Universita di Modena e Reggio
Emilia in Modena, Italy, reported a
phase II, multicenter clinical trial of
the safety and efficacy of FCR in patients
with relapsed follicular lymphoma
(ASH abstract 2246). Of
the 48 patients enrolled in the study,
47% had stage IV disease. The median
number of prior chemotherapy regimens
was 1.7 (range, 1 to 4 regimens).
Patients were treated with rituximab
375 mg/m2 at weeks 2, 3, 6, and 9, and
with fludarabine 30 mg/m2/day for 3
days plus cyclophosphamide 300 mg/
m2/day for 3 days, repeated every 28
days for a total of four cycles.
Rearrangement of the bcl-2 gene
in bone marrow or peripheral blood
mononucleated cells, as evaluated by
polymerase chain reaction (PCR)
analysis, demonstrated that 22 of 38
(58%) patients had bcl-2 rearrangement.
Among 39 evaluable patients,
the overall response rate was 97% (see
Table 1). Of the 18 patients with
molecular monitoring of disease before
and after chemotherapy, 15 (83%)
achieved molecular remission. The
median duration of remission was 13
months after a median follow-up of
12 months (range, 1 to 25 months).
Complete responses have been maintained
in 28 patients. Eight patients
relapsed; two died due to disease progression,
and one patient died because
of chemotherapy-induced neutropenia.
The majority of adverse events were
mild to moderate in severity. One
patient experienced a grade 4 pulmonary
infection after the third cycle of
chemotherapy. Grade 3 or 4 leukopenia
was observed in 10 patients, and
four patients presented with grade 4
granulocytopenia. Overall, treatment
with FCR in this ongoing study was
associated with an acceptable toxicity
profile and an excellent response rate
in heavily pretreated patients with relapsed
follicular lymphoma. Comple-
tion and evaluation of response duration
and survival are eagerly anticipated.
Remarkably Similar Results
In a separate study, Amos Cohen,
MD, and colleagues of the Israel Cooperative
Lymphoma Group presented
phase II data for FCR in patients
< 60 years of age with primary advanced
follicular lymphoma (ASH
abstract 1393). Most patients (26
of 33) had stage IV disease.
Patients were treated with fludarabine
25 mg/m2 plus cyclophosphamide
250 mg/m2 for 3 days, repeated
every 4 weeks for a total of four to six
cycles. Patients subsequently received
rituximab 375 mg/m2 weekly for four
cycles after a partial or complete re
response was achieved.
Molecular responses were measured
by reverse transcription PCR
analysis of bcl-2/immunoglobulin H
in bone marrow or peripheral blood
mononuclear cells. Response rates are
summarized in Table 2. The overall
response rate was 88%, with a median
follow-up period of 17 months
(range, 9 to 34 months). Of 25 patients
with molecular monitoring of
disease before and after chemothera-
py, 19 (76%) achieved molecular remission.
These results are remarkably
similar to those reported by Sacchi et
In addition, overall survival rates
were 94% at 1 year and 89% at 2 years.
Median overall and disease-free survival
were not reached at 17
Fludarabine and cyclophosphamide
chemotherapy was safe for the
treatment of primary advanced follicular
lymphoma. Hematologic toxicity
was reported in 30% of patients.
Grade 3 or 4 neutropenia was report-
ed in 6% of patients and only one
patient experienced neutropenic fever.
No cases of autoimmune
hemolytic anemia were reported. This
study suggests that FCR is safe and
active in patients with advanced follicular
Taken together, the two studies
show that FCR is safe and exhibits
promising activity in both relapsed
and primary advanced follicular lymphoma.
Continued investigation of
this treatment regimen is warranted.
1. Alas S, Bonavida B. Rituximab
inactivates signal transducer and activation
of transcription 3 (STAT3) activity
in B-non-Hodgkin’s lymphoma
through inhibition of the interleukin
10 autocrine/paracrine loop and results
in down-regulation of Bcl-2 and
sensitization to cytotoxic drugs. Cancer
Res 61:5137-5144, 2001.
2. Alas S, Emmanouilides C,
Bonavida B. Inhibition of interleukin
10 by rituximab results in down-regulation
of Bcl-2 and sensitization of
B-cell non-Hodgkin’s lymphoma to
apoptosis. Clin Cancer Res 7:709-723,
3. Di Gaetano N, Xiao Y, Erba E, et
al: Synergism between fludarabine and
rituximab revealed in a follicular lymphoma
cell line resistant to the cytotoxic
activity of either drug alone. Br
J Haematol 114:800-809, 2001.
4. Sacchi S, Tucci A, Merli F, et al:
Phase II study with fludarabine and
cyclophosphamide plus rituximab
(FC+R) in relapsed follicular lymphoma
patients (abstract 2246). Blood
5. Cohen A, Polliack A, Ben-Bassat
I, et al: Results of a phase II study
employing a combination of fludarabine,
cyclophosphamide and rituximab
(FCR) as primary therapy for
patients with advanced follicular lymphoma
(FL): the Israel Cooperative
Lymphoma Group (abstract 1393).
Blood 100:360a, 2002.