Fludarabine Combos Showing Efficacy in Lymphomas

LUGANO, Switzerland—For low-grade lymphomas, fludarabine (Fludara)-based combination therapy may have greater efficacy than single-agent flu-darabine, 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 cooperation."

Not Yet Standard Practice

Dr. Montserrat, who moderated a standing-room-only session on fludara-bine 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, 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 the best surrogate predictive factor for long-term disease control."

Adding Rituximab

The field is changing rapidly. Dr. Sey-mour 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 combined immunochemotherapy—rituximab plus fludarabine, cyclophosphamide, and mitoxantrone (Novantrone) (FCM)—is superior to FCM alone in recurrent follicular and mantle cell lymphoma (ICML abstract 186).

At the ICML meeting, researchers from University Hospital Grosshadern, Mu-nich, 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 concurrent rituximab," Dr. Seymour said.

Italian Study

Some researchers are evaluating fludarabine-based immunochemother-apy 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. Postchemother-apy, complete response rates were sig-nificantly 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.

BNLI Study

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 flu-darabine, mitoxantrone, and dexamethasone was shown, in a phase II study, to have a high complete response rate (47%) in relapsed follicular non-Hodgkin’s lymphoma (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.