APhase I-IIStudy to Determine the Maximum Tolerated Infusion Rate of Rituximabwith Special Emphasis on Monitoring theEffectofRituximabonCardiacFunction MarcoSiano,ErikaLerch,LauraNegretti,EmanueleZucca,DelvysRodriguez-Abreu,MichelOberson, LedaLeoncini,OresteMora,CristianaSessa,AugustoGallino,andMicheleGhielmini Abstract Purpose: This phase I infusion rate escalation trial was undertaken to evaluate the maximum applicable infusion rate for rituximab without steroid premedicationinpatientshaving received onepreviousrituximabinfusion. Experimental Design: Cohortsofatleastthreepatientswereassignedtorituximabwithor without concomitant chemotherapy.The initial infusion rate was 200 mg/h in the first cohort,andwasincreasedby100mg/hineachsubsequentcohorttoamaximumof700mg/h. Ineachpatienttheinfusionratewasincreasedby100mg/hevery30minutestothetotaldose (375 mg/m 2 ). In the first sixcohorts (21patients), two well-tolerated rituximab administrations were required; in the 7th cohort (11patients) one previously well-tolerated rituximab infusion was required. Patients didnot receive steroid premedication and were monitored with electro- cardiograms(ECG),echocardiograms,HolterECGs,troponin,andbrainnatriureticpeptide(BNP). Results: Thirty-twopatientswereincludedand128cyclesweredone,85atarateof700mg/h. Patientstoleratedinfusionrateswithoutmajorsideeffects.Therewerenonewclinicallyrelevant ECGalterations.Troponin(< 0.1ng/L)andmeancardiacejectionfraction(65%)remainedinthe referencerange;BNPbaselinelevelincreasedsignificantly24hoursafterrituximabadministration (from30.4to64.1ng/L; P < 0.0001). Conclusions: Rituximabcanbeadministeredsafelyat700mg/hwithoutsteroidpremedication inpatientshavingreceivedatleastonerituximabdoseintheprevious3months. Rituximab is a monoclonal antibody against the lymphocyte surface antigen CD20. First introduced in 1995 for the treatment of non–Hodgkin’s B-lymphoma, rituximab has today a broad spectrum of indications, including treatment of rheumatoid arthritis, thrombotic thrombocytopenic purpura, and systemic lupus erythematosis, among many others (1–6). Treatment with rituximab is generally well tolerated and can be combined with chemotherapy, improving response rate, response duration, and in some cases overall survival of patients with B-cell lymphomas (1). Infusion-related reactions can occur in approximately one fourth of patients during the first administration, probably due to a release of cytokines into the blood as a consequence of the rapid destruction of circulatingBcells(7).Thisiswhyitisrecommendedtochoose a low initial infusion rate. The incidence and the severity of infusion-related side effects consistently decrease in the successive administrations; indeed after the second rituximab infusionalmostnoBcellsareleftinthebloodforatleast2to 3 months. The reconstitution begins usually after 6 months and is completed after a median of 12 months (8, 9). We hypothesized that no infusion-related reaction should occur from the second infusion, and that a faster application of rituximab could be considered safe. Although the duration of theinfusionisusually4to5hoursforthefirstadministration, thepresentstudywasundertakentoevaluateiffromthesecond infusion rituximab could be administered over 1 hour. PatientsandMethods Patient eligibility. Patients with any type of B-cell lymphoma were eligible. In the first part of the study (21 patients) two previous well- tolerated rituximab administrations (the last one given no longer then 3 mo before) were required, whereas in the second part (11 patients) one previous rituximab infusion in the previous 3 mo was accepted. The first rituximab administration(s) should be given according to the manufacturer’s guidelines (10). Rituximab could be given with chemotherapy, provided the latter (including steroids) was adminis- tered after rituximab infusion. A left ventricular ejection fraction of z50% (assessed by echocardiography in the month before inclusion) was required. No severe reaction to prior rituximab infusions could have occurred. Cancer Therapy: Clinical Authors’Affiliation: DepartmentsofMedicalOncologyandCardiology,Ospedale SanGiovanni,Bellinzona,Switzerland Received5/19/08;revised7/8/08;accepted7/27/08. Grantsupport: RocheLtd.,Basel,andtheSwissInsuranceCompanyAssociation (SVK),whichreimbursedthecostsofrituximab. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.Thisarticlemustthereforebeherebymarked advertisement inaccordance with18U.S.C.Section1734solelytoindicatethisfact. Requests for reprints: Michele Ghielmini, Medical Oncology Department, Oncology Institute of Southern Switzerland,Ospedale San Giovanni, CH-6500 Bellinzona,Switzerland.Phone: 419-181-18111;Fax: 419-181-18731;E-mail: michele.ghielmini@eoc.ch. F 2008AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-08-1124 www.aacrjournals.org ClinCancerRes2008;14(23)December1,2008 7935 Research. on May 30, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from