low-grade lymphomas, fludarabine
(Fludara)-based combination therapy
may have greater efficacy than
single-agent fludarabine, especially
when a monoclonal antibody is part
of the combination, a series of recent
European investigations suggest.
The investigations, presented
at the Eighth International Conference
on Malignant Lymphoma
(ICML), show that various combination
therapies hold promise, although
a lack of coordination
among non-US study groups has
hampered progress somewhat.
"It is a little bit disappointing .....
that there are still so many patients
being entered into so many different
trials," said Emili Montserrat,
MD, of the University of Barcelona.
"We could work much more quickly
and have results faster by establishing
some kind of international
Dr. Montserrat, who moderated a
standing-room-only session on
fludarabine combination therapy,
stressed that none of the combinations
under investigation are yet part
of standard clinical practice and
should not be used except in clinical
trials. Nonetheless, the rationale for
trying such combinations is backed
by preclinical data showing synergistic
cytotoxicity against malignant cells.
Furthermore, fludarabine combinations
do seem superior to fludarabine
alone, at least when compared with
historical data, experts said.
"The phase II combination studies
appear to be superior, particularly
when you add in monoclonal
antibodies," said John Seymour,
MB, BS, BSc, FRACP, of the Peter
MacCallum Cancer Institute,
Melbourne, Australia. "They have
the highest overall response rate and,
particularly, an extremely high molecular
response rate, which appears
to be best surrogate predictive factor
for long-term disease control."
The field is changing rapidly. Dr.
Seymour said that his institution's
current standard treatment is a combination
of fludarabine, cyclophosphamide,
and rituximab (Rituxan).
That combination, he said, is based
mainly on interim analyses and
sometimes phase II data, rather than
randomized phase III studies.
For example, Dr. Seymour and
his colleagues have participated in a
Germany-based study showing that
rituximab plus fludarabine, cyclophosphamide,
(Novantrone) (FCM)-is superior
to FCM alone in recurrent follicular
and mantle cell lymphoma (ICML
At the ICML meeting, researchers
from University Hospital
Grosshadern, Munich, reported interim
results on 80 of 147 cases. They
observed an overall response rate of
89% (36% complete responses) for
four courses of rituximab/FCM vs
an overall response rate of 53% for
FCM alone (P < .0001).
"We have been very impressed
by the dramatic improvement of the
response rate, as well as the absence
of any worsening toxicity with the
addition of rituximab used concurrently,"
Dr. Seymour said.
Some researchers are evaluating
as first-line treatment. Also
at ICML, the Italian Cooperative
Study Group on Lymphoma reported
a randomized trial in which patients
received six cycles of either
fludarabine/mitoxantrone or CHOP
chemotherapy; then, responders in
either group received rituximab
(ICML abstract 185).
Of 150 enrolled patients, 93 were
evaluable for response. Postchemotherapy,
complete response rates
were significantly higher (P = .003)
in the fludarabine/mitoxantrone/
rituximab arm (68% complete responses)
vs the CHOP-rituximab
arm (37% complete responses).
Molecular response was numerically
higher for the group randomized
to the fludarabine-containing
combination (34% vs 20%,
P = .115). Post-rituximab, molecularly
confirmed complete clearance
was seen in approximately 60% of
patients in the fludarabine arm and
40% in the CHOP arm.
These results confirm the efficacy
of fludarabine/mitoxantrone in previously
untreated patients and suggest
a role for rituximab in improving
response rates following
chemotherapy, said Pier Luigi
Zinzani, MD, University of Bologna,
Italy. Final results of the trial
will be available by the end of 2002.
Not all the current investigations
of fludarabine-based combinations
included an immunotherapy component.
Researchers with the British
National Lymphoma Investigation
(BNLI) group are looking at
fludarabine, doxorubicin, and dexamethasone
in 31 patients with newly
diagnosed stage III/IV follicular
lymphoma (ICML abstract 182).
Previously, the combination of
fludarabine, mitoxantrone, and dexamethasone
was shown, in a phase
II study, to have a high complete
response rate (47%) in relapsed follicular
(McLaughlin P et al: Ann Oncol
7[suppl 3]:109, 1996).
At the ICML meeting, the BNLI
group reported a 100% overall response
rate in 31 newly diagnosed
patients (14 complete responses),
with "acceptable" rates of hematologic
toxicity. They projected, with
median follow-up of 28 months, a
3-year progression-free survival of
49% and a median progression-free
survival of 29 months.
"It is not clear whether an overall
survival benefit (compared with conventional
first-line therapy) is evident
from this study, but a sound basis for
further studies has been established,"
said Dr. A. McMillan of Nottingham
City Hospital, Nottingham, UK.