We studied the safety and efficacy of combined treatment with rituximab plus CHOP in 16 patients with relapsed advanced-stage follicular lymphomas. The intent-to-treat overall response rate (ORR) was 88%, 75% complete remissions (CR) and 13% partial remissions (PR). At a median follow-up of 18 months, 63% of the patients are alive (50% CR). The combination of rituximab and CHOP in relapsed advanced-stage follicular lymphomas achieves high ORRs and CRs, with low toxicity except for in previously autografted patients

Besalduch, Joan

Domingo Domènech, Eva

Estany, Carla

Fernández de Sevilla Ribosa, Alberto

González Barca, Eva

Sureda, Anna

Haematologica

English

Diposit Digital de la Universitat de Barcelona

1229haematologica vol. 87(11):november 2002scientific correspondence8. Bastion Y, Blay JY, Divine M, Brice P, Bordessoule D, SebbanC, et al. Elderly patients with aggressive non-Hodgkin's lym-phoma: disease presentation, response to treatment, andsurvival: a Groupe d'Etude des Lymphomes de l'Adulte studyon 453 patients older than 69 years. J Clin Oncol 1997; 15:2945-53.9. Tirelli U, Errante D, Van Glabbeke M, Teodorovic I, Kluin-Nelemans JC, Thomas J, et al. CHOP is the standard regimenin patients ≥ 70 years of age with intermediate-grade andhigh-grade non-Hodgkin's lymphoma: results of a random-ized study of the European Organization for Research andTreatment of Cancer Lymphoma Cooperative Study Group.J Clin Oncol 1998; 16:27-34.Combined treatment with anti-CD20 (rituximab) andCHOP in relapsed advanced-stage follicular lymphomasWe studied the safety and efficacy of combined treatmentwith rituximab plus CHOP in 16 patients with relapsedadvanced-stage follicular lymphomas. The intent-to-treatoverall response rate (ORR) was 88%, 75% complete remis-sions (CR) and 13% partial remissions (PR). At a median fol-low-up of 18 months, 63% of the patients are alive (50% CR).The combination of rituximab and CHOP in relapsed advanced-stage follicular lymphomas achieves high ORRs and CRs, withlow toxicity except for in previously autografted patients. haematologica 2002; 87:1229-1230(http://www.haematologica.org/2002_11/1229.htm)Non-Hodgkin’s lymphomas (NHLs) are a diverse group of lym-phoid neoplasms that range from indolent malignancies to rapid-ly growing and highly aggressive tumors. Follicular lymphomas(FL) represent the second most frequent type of B-cell NHLs,which usually present as a disseminated disease with an indolentcourse. Although a high initial response rate is achieved, repeat-ed relapses occur with progressively lower response rates andshorter durations. The efficacy and safety of rituximab as single-agent therapy1-4 or in combination with interferon-α 25 has beendemonstrated in patients with either relapsed or refractory lowgrade lymphomas, as well as first-line therapy in this type oflymphomas.6,7 Only one study has been reported8 of combinedtreatment with rituximab and CHOP in low grade lymphomas,achieving higher response rates than rituximab as single agenttherapy.The current study is an open-label non-randomized multicen-ter phase II study designed to investigate the toxicity and effi-cacy of rituximab plus CHOP in the treatment of patients withrelapsed advanced follicular lymphoma. We included patientswith CD20 positive relapsed follicular lymphoma according tothe REAL classification, whatever the cell type, between 18 and70 years of age. They had disease stage III or IV according to theAnn-Arbor classification, ECOG <2 and adequate renal andhepatic functions.The treatment schedule consisted of six intravenous infusionsof rituximab (375 mg/m2) on days 1, 8, 78, 85, 155, 162 (2 ini-tial infusions to reduce tumor mass and 2 final infusions to endup with minimal residual disease), and six standard cycles ofCHOP on days 15, 36, 57, 92, 113, 134. Treatment was discon-tinued if disease progression was observed or if a severe adversetherapy-related event appeared. Patients were evaluated for dis-ease status at base line, after the third cycle of CHOP, at the endof treatment and every three months thereafter. Response wasevaluated following the criteria of Cheson et al.9 Response cat-egories consisted of complete response (CR), partial response (PR)and no response (NR) or progressive disease (PD). Toxicity wasevaluated according to the WHO criteria.Results of the descriptive analysis are expressed as medianand range for continuous data and number of cases with theirproportion for qualitative data. Survival analysis was performedat the univariate level by means of Kaplan-Meier techniques.Sixteen patients were enrolled in this study in 4 centers from July1998 to August 2000. The median age was 61 years (range: 40-70 years) and 12 (75%) were males. All of them had received atleast one prior therapy (median 2; range 1-6) and three cases(19%) had been previously submitted to an autologous bonemarrow transplant. The median time between diagnosis andinclusion in the study was 35 months (range: 8-143 months)(Table 1).Infusional toxicity of rituximab appeared in 50% of thepatients, usually mild and in all cases this only occurred with thefirst infusion. It was managed by adjustments of the infusionrate and was not a cause of treatment withdrawal. CHOP toxic-ity was observed in 8 patients (50%), mainly hematologic, withgrade IV neutropenia in 5 patients. All three patients who hadpreviously undergone a peripheral stem cell transplant did notcomplete treatment, two due to hematologic toxicity and one dueto viral hepatitis B reactivation.The intent-to-treat analysis showed 12 (75%) CR and 2 (13%)PR with an 88% ORR (Table 1). Of the 12 patients in CR, 4 (33%)patients relapsed (mean duration of CR of 14 months) (Figure 1).With a median follow-up of 18 months, 10 patients (63%) arealive, 8 (50%) in CR and 2 (13%) in PR.We report a trial evaluating the clinical efficacy and safety ofcombined treatment with rituximab and CHOP in relapsedadvanced-stage follicular lymphomas. Rituximab has been used as single-agent therapy1-4 or in com-bination with interferon-α 2a5 in relapsed or refractory follicu-lar lymphomas achieving ORRs of approximately 50% (15% CR),as well as a single agent in first line low grade lymphomas6,7 with70% ORRs (20% CR).Table 1. Patient’s characteristics at the time of inclusion inthe  trial, treatment response and status.Pat. Sex Age Num Time Response Status1 M 46 2 (ASCT) 11m Withdrawn toxicity PR Died progression +16m2 F 66 6 38m PR Died progression +10m3 M 64 2 85m CR CR +11m4 M 69 3 65m CR Relapse +3mDied progression +12m5 M 63 1 27m Progression Died progression +10m6 M 59 3 64m CR CR +2m7 M 66 2 143m CR CR +13m8 M 43 2 (ASCT) 60m Withdrawn toxicity Died progression +14mProgression9 M 62 2 31m CR CR +10m10 M 63 1 13m CR CR +6m11 M 49 1 15m CR CR +18m12 F 48 2 92m CR CR +18m13 M 39 1 5m CR Relapse +3m. PR +5m14 F 39 2 (ASCT) 41m Withdrawn VHB Relapse +16m. PR +4mreactivation. CR15 M 66 2 8m CR Relapse +7mDied progression +9m16 F 45 1 11m CR CR +17mF= female; M= male; ASCT= autologous stem cell transplant.CR: complete remission; PR: partial remission.1230haematologica vol. 87(11):november 2002scientific correspondenceThese response rates, together with the fact that rituximabenhances the in vitro efficacy of conventionally used cytotoxicdrugs,10 led to the use of combined treatment using anti-CD20with conventional chemotherapy. Czuczman et al.8 included 40patients with low grade or follicular lymphomas (31 untreatedand 9 previously treated lymphomas) with an intent-to-treatORR of 95% (55% CR) (89% ORR in the previously treatedpatients (56% CR)).In our group of previously treated follicular lymphomas theintent-to-treat ORR was 88% (75% CR), similar to that obtainedby Czuczman et al.,8 which significantly improves the responserates obtained with conventional chemotherapy.Rituximab in combination with CHOP chemotherapy inpatients with relapsed advanced-stage follicular lymphomas isassociated with high ORRs and high CRs, together with low tox-icity, except for in previously transplanted patients. These resultsencourage the use of rituximab as first-line therapy in combina-tion with other effective agents.Eva Domingo-Domènech,* Eva González-Barca,*Cristina Estany,° Ana Sureda,#Joan Besalduch,@Alberto Fernández de Sevilla**Departments of Clinical Haematology of Institut Catalàd’Oncología; °Hospital Mutua de Terrassa; #Hospital de laSanta Creu i Sant Pau, Barcelona; @Hospital Son Dureta,Palma de Mallorca, SpainAcknowledgments: we would like to thank Maite Encuentra forperforming the statistical calculations.Fundings: this study was supported in part by grants from theFundació “August Pi i Sunyer” and by FIJC-01/P-AG from theFundació “Josep Carreras”.Correspondence: Eva Domingo Domènech, MD, Avda. Gran Vias/n, km 2.7. 08907 L’Hospitalet de Llobregat, Barcelona, Spain.Phone: international +34.9.32607812. Fax: international+34.9.34141630. E-mail: 31577edd@comb.esKey words: rituximab, CHOP, relapsed, advanced-stagefollicular lymphoma.Manuscript processingThis manuscript was peer-reviewed by two external refereesand by Professor Gilles Salles, who acted as an Associate Edi-tor. The final decision to accept this paper for publication wastaken jointly by Professor Salles and the Editors. Manuscriptreceived May 15, 2002; accepted August 20, 2002.References1. JM Foran, RK Gupta, D. Cunningham, Popescu RA, Gold-stone AH, Sweetenham JW, et al. A UK multicentre phase IIstudy of rituximab (chimaeric anti-CD20 monoclonal anti-body) in patients with follicular lymphoma, with PCR mon-itoring of molecular response. Br J Haematol 2000; 109:81-8.2. M. Feuring-Buske, M. Kneba, M. Unterhalt, Engert A, Gra-matzki M, Hiller E, et al. IDEC-C2B8 (rituximab) anti-CD20antibody treatment in relapsed advanced-stage follicularlymphomas: results of a phase-II study of the German low-grade lymphoma study group. Ann Hematol 2000; 79:493-500.3. Piro LD, CA White, AJ Grillo-Lopez, Janakiraman N, Saven A,Beck TM, et al. Extended rituximab (anti-CD20 monoclon-al antibody) therapy in relapsed or refractory low-grade orfollicular non-Hodgkin’s lymphoma. Ann Oncol 1999;10:655-61.4. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, CzuczmanMS, Williams ME, et al. Rituximab chimeric anti-CD20 mon-oclonal antibody therapy in relapsed indolent lymphoma:half of patients respond to a four treatment program. J ClinOncol 1998; 16:2825-33.5. Sacchi S, Federico M, Vitolo U, Boccomini C, Vallisa D, Bal-dini L et al. Clinical activity and safety of combinationimmunotherapy with IFN-α 2a and Rituximab in patientswith relapsed low grade non-Hodgkin’s lymphoma. Haema-tologica 2001; 86: 951-8.6. Colombat P, Salles G, Brousse N, Eftekhari P, Soubeyran P,Delwail V, et al. Rituximab (anti-CD20 monoclonal anti-body) as single first-line therapy for patients with follicu-lar lymphoma with a low tumor burden: clinical and mole-cular evaluation. Blood 2001; 97:101-6.7. Hainsworth JD, Burris HA III, Morrissey LH, Litchy S, ScullinDC Jr, Bearden JD III, et al . Rituximab monoclonal antibodyas initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood 2000; 95:3052-6.8. Czuczman MS, Grillo-Lopez AJ, White CA, Saleh M, GordonL, LoBuglio AF, et al. Treatment of patients with low-gradeB-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J ClinOncol 1999; 17:268-76.9.  Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Con-nors JM, et al. Report of an international workshop to stan-dardize response criteria for non-Hodgkin’s lymphomas. JClin Oncol 1999; 17:1244-53.10. Chow KU, Sommerlad WD, Boehrer S, Schneider B, SeipeltG, Rummel MJ, et al. Anti-CD20 antibody (IDEC-C2B8, rit-uximab) enhances efficacy of cytotoxic drugs on neoplas-tic lymphocytes in vitro: role of cytokines, complement, andcaspases. Haematologica 2002; 87:33-43.Figure 1. Disease free survival curve of patients who achieveda CR. The mean duration of CR is of 14 months.

Combined treatment with anti-CD20 (rituximab) and CHOP in relapsed advanced-stage follicular lymphomas

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Combined treatment with anti-CD20 (rituximab) and CHOP in relapsed advanced-stage follicular lymphomas

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