Fludarabine Combinations Showing Efficacy in Low-Grade Lymphomas

December 1, 2002

LUGANO, Switzerland-Forlow-grade lymphomas, fludarabine(Fludara)-based combination therapymay have greater efficacy thansingle-agent fludarabine, especiallywhen a monoclonal antibody is partof the combination, a series of recentEuropean investigations suggest.The investigations, presentedat the Eighth International Conferenceon Malignant Lymphoma(ICML), show that various combinationtherapies hold promise, althougha lack of coordinationamong non-US study groups hashampered progress somewhat.

LUGANO, Switzerland-Forlow-grade lymphomas, fludarabine(Fludara)-based combination therapymay have greater efficacy thansingle-agent fludarabine, especiallywhen a monoclonal antibody is partof the combination, a series of recentEuropean investigations suggest.The investigations, presentedat the Eighth International Conferenceon Malignant Lymphoma(ICML), show that various combinationtherapies hold promise, althougha lack of coordinationamong non-US study groups hashampered progress somewhat."It is a little bit disappointing . . .that there are still so many patientsbeing entered into so many differenttrials," said Emili Montserrat,MD, of the University of Barcelona."We could work much more quicklyand have results faster by establishingsome kind of internationalcooperation."Dr. Montserrat, who moderated astanding-room-only session onfludarabine combination therapy,stressed that none of the combinationsunder investigation are yet partof standard clinical practice andshould not be used except in clinicaltrials. Nonetheless, the rationale fortrying such combinations is backedby preclinical data showing synergisticcytotoxicity against malignant cells.Furthermore, fludarabine combinationsdo seem superior to fludarabinealone, at least when compared withhistorical data, experts said."The phase II combination studiesappear to be superior, particularlywhen you add in monoclonalantibodies," said John Seymour,MB, BS, BSc, FRACP, of the PeterMacCallum Cancer Institute,Melbourne, Australia. "They havethe highest overall response rate and,particularly, an extremely high molecularresponse rate, which appearsto be best surrogate predictive factorfor long-term disease control."Adding Rituximab
The field is changing rapidly. Dr.Seymour said that his institution'scurrent standard treatment is a combinationof fludarabine, cyclophosphamide,and rituximab (Rituxan).That combination, he said, is basedmainly on interim analyses andsometimes phase II data, rather thanrandomized phase III studies.INDUSTRY WATCH
Phase I Clinical
Trial of CpG 7909
Plus Rituximab
in NHL

WELLESLEY, Mass-ColeyPharmaceutical Group, Inc. hasinitiated a multicenter phase Istudy of its lead product candidateCpG 7909 in combinationwith rituximab (Rituxan) inrelapsed or refractory non-Hodgkin's lymphoma (NHL)patients. CpG 7909 is a syntheticoligonucleotide sequencethat activates a comprehensivehumoral and cellular attack oncancer cells, the company saidin a news release.For example, Dr. Seymour andhis colleagues have participated in aGermany-based study showing thatcombined immunochemotherapy-rituximab plus fludarabine, cyclophosphamide,and mitoxantrone(Novantrone) (FCM)-is superiorto FCM alone in recurrent follicularand mantle cell lymphoma (ICMLabstract 186).At the ICML meeting, researchersfrom University HospitalGrosshadern, Munich, reported interimresults on 80 of 147 cases. Theyobserved an overall response rate of89% (36% complete responses) forfour courses of rituximab/FCM vsan overall response rate of 53% forFCM alone (P < .0001)."We have been very impressedby the dramatic improvement of theresponse rate, as well as the absenceof any worsening toxicity with theaddition of rituximab used concurrently,"Dr. Seymour said.Italian Study
Some researchers are evaluatingfludarabine-based immunochemotherapyas first-line treatment. Alsoat ICML, the Italian CooperativeStudy Group on Lymphoma reporteda randomized trial in which patientsreceived six cycles of eitherfludarabine/mitoxantrone or CHOPchemotherapy; then, responders ineither group received rituximab(ICML abstract 185).Of 150 enrolled patients, 93 wereevaluable for response. Postchemotherapy,complete response rateswere significantly higher (P = .003)in the fludarabine/mitoxantrone/rituximab arm (68% complete responses)vs the CHOP-rituximabarm (37% complete responses).Molecular response was numericallyhigher for the group randomizedto the fludarabine-containingcombination (34% vs 20%,P = .115). Post-rituximab, molecularlyconfirmed complete clearancewas seen in approximately 60% ofpatients in the fludarabine arm and40% in the CHOP arm.These results confirm the efficacyof fludarabine/mitoxantrone in previouslyuntreated patients and suggesta role for rituximab in improvingresponse rates followingchemotherapy, said Pier LuigiZinzani, MD, University of Bologna,Italy. Final results of the trialwill be available by the end of 2002.BNLI Study
Not all the current investigationsof fludarabine-based combinationsincluded an immunotherapy component.Researchers with the BritishNational Lymphoma Investigation(BNLI) group are looking atfludarabine, doxorubicin, and dexamethasonein 31 patients with newlydiagnosed stage III/IV follicularlymphoma (ICML abstract 182).Previously, the combination offludarabine, mitoxantrone, and dexamethasonewas shown, in a phaseII study, to have a high completeresponse rate (47%) in relapsed follicularnon-Hodgkin's lymphoma(McLaughlin P et al: Ann Oncol7[suppl 3]:109, 1996).At the ICML meeting, the BNLIgroup reported a 100% overall responserate in 31 newly diagnosedpatients (14 complete responses),with "acceptable" rates of hematologictoxicity. They projected, withmedian follow-up of 28 months, a3-year progression-free survival of49% and a median progression-freesurvival of 29 months."It is not clear whether an overallsurvival benefit (compared with conventionalfirst-line therapy) is evidentfrom this study, but a sound basis forfurther studies has been established,"said Dr. A. McMillan of NottinghamCity Hospital, Nottingham, UK.