Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: a phase II multicenter study

Abstract

BackgroundWe investigated the addition of rituximab to dose-dense and high-dose chemotherapy with autologous stem cell transplantation in patients with untreated poor-prognosis diffuse large B-cell lymphoma. Design and MethodsNinety-four young patients (age, 18-60) with stage III-IV diffuse large B-cell lymphoma at intermediate/high or high risk according to the age-adjusted International Prognostic Index were enrolled into a phase II trial. The treatment was as follows: four courses of bi-weekly rituximab-cyclophosphamide-epirubicin-vincristine-prednisone (R-MegaCEOP14), two courses of rituximab-mitoxantrone-cytarabine-dexamethasone (R-MAD) and carmustineetoposide-cytarabine-melphalan (BEAM) with autologous stem cell transplantation. ResultsThe complete response and toxic death rates were 82% and 5%, respectively. Failure-free survival and overall survival rates at 4 years were 73% and 80%, respectively. The outcomes of these patients were retrospectively compared to those of 41 patients with similar characteristics enrolled into a previous phase II trial of high-dose chemotherapy without rituximab. This historical group was treated with eight weekly infusions of methotrexatedoxorubicin-cyclophosphamide-vincristine-prednisone-bleomycin (MACOP-B), two courses of MAD and BEAM with autologous stem cell transplantation. The 4-year failurefree survival rates for the rituximab and historical groups were 73% versus 44%, respectively (p=0.001); the 4-year overall survival rates were 80% and 54%, respectively (p=0.002). A Cox's multivariable model was applied to adjust the effect of treatment for unbalanced or important prognostic factors: failure and death risks were significantly reduced in the rituximab group compared to the historical group, with an adjusted hazard ratio of 0.44 (p=0.01) for failure-free survival and 0.46 (p=0.02) for overall survival. ConclusionsThese results suggest that the addition of rituximab to high-dose chemotherapy is effective and safe in diffuse large B-cell lymphoma with a poor-prognosis and such regimens need to be compared to dose-dense chemoimmunotherapy without autologous stem cell transplantation in randomized trials. (ClinicalTrials.gov Identifier: NCT00556127).Key words: diffuse large B-cell lymphoma, autologous stem cell transplantation, dose-dense chemotherapy, rituximab, poor prognosis, high-dose chemotherapy. II multicenter study. Haematologica 2009;94:1250-1258. doi:10.3324/haematol.2009 Citation: Vitolo U, Chiappella A, Angelucci E, Rossi G, Liberati AM, Cabras MG, Botto B, Ciccone G, Gaidano G, Falchi L, Freilone R, Novero D, Orsucci L, Pavone V, Pogliani E, Rota-Scalabrini D, Salvi F, Tonso A, Tucci A, and Levis A on behalf of Gruppo Italiano Multiregionale Linfomi e Leucemie (GIMURELL). Dose-dense and high-dose chemotherapy plus rituximab with autologous stem cell transplantation for primary treatment of diffuse large B-cell lymphoma with a poor prognosis: a phase

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial

“…190 patients (97%) in the R-ACVBP group received the fi rst four cycles of the planned treatment and 177 (97%) in the R-CHOP group. The median interval between these cycles was 14 days (range 12-57, IQR [14][15][16][17] in the R-ACVBP group and 21 days in the R-CHOP group. Based on data collected from the population who received the fi rst four cycles of each treatment, the received dose intensities for doxorubicin were 92·1%, for cyclophosphamide were 93·0%, and for rituximab were 92·3% of the planned dose for R-ACVBP, and 98·4%, 98·6%, and 98·6% for R-CHOP, respectively.…”

“…In recent years, several phase 2 trials have shown promising results regarding the association of intensive chemotherapy and rituximab. [16][17][18][19] Most of these regimens were proposed for patients with high-risk disease and contained an intensive chemotherapy schedule with stem-cell support. [16][17][18] By contrast, dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is an intensifi ed regimen where pharma codynamic dosing is on the basis of neutrophil nadir.…”

“…[16][17][18][19] Most of these regimens were proposed for patients with high-risk disease and contained an intensive chemotherapy schedule with stem-cell support. [16][17][18] By contrast, dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is an intensifi ed regimen where pharma codynamic dosing is on the basis of neutrophil nadir. 19 A phase 2 study of dose-adjusted EPOCH plus rituximab showed promising outcomes in low and intermediate International Prognostic Index groups with progression-free survival similar to that of R-ACVBP.…”

Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA

“…[10][11][12][13] Data for patients with 3 or more IPI factors treated with R-CHOP from the British Columbia registry suggest a 4-year progressionfree survival (PFS) at 53%, 1 in agreement with the 58% 3-year PFS seen in several German randomized studies. 14 However, very few prospective studies have been reported on large series focusing on DLBCL with 2 or 3 aa-IPI factors with a long follow up 15,16 in a population under 60 years of age.…”

Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi

“…2,[9][10][11] Indeed, as the median age of patients diagnosed with DLBCL is in the mid-60s, 1,12,13 many older individuals and others with comorbidities are in particular need of better initial therapy because they cannot tolerate intensive salvage chemotherapy with stem cell transplantation. 14 Novel therapeutic approaches beyond rituximab are, therefore, still required.…”