High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study

Annals of Oncology, Aug 2005

Background: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. Patients and methods: Inclusion criteria were age 18–65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1–4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58–62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81–84), etoposide 150 mg/m2 12q (day 81–84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. Results: Fifty-seven patients (median age 43 years, range 24–65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1–76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively. Conclusions: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

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High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study

A. Josting 2 3 M. Sieniawski 2 3 J.-P. Glossmann 2 3 O. Staak 2 3 L. Nogova 2 3 N. Peters 1 2 M. Mapara 0 2 B. D orken 0 2 Y. Ko 2 6 B. Metzner 2 5 J. Kisro 2 4 V. Diehl 2 3 A. Engert 2 3 0 University Hospital Charite` Berlin, Section for Hematology/Oncology , Germany 1 Carl-Thiem-Hospital Cottbus, Second Medical Hospital , Germany 2 Medicine, University Hospital Cologne , Joseph-Stelzmann-Str 9, 50924 Cologne , Germany 3 University Hospital Cologne, First Department of Internal Medicine , Germany 4 University Hospital Lu beck, Section for Hematology/Oncology , Germany 5 Klinikum Oldenburg, Department II of Internal Medicine , Germany 6 University Hospital Bonn, Department of Internal Medicine , Germany Background: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. Patients and methods: Inclusion criteria were age 18 - 65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1 - 4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58 - 62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81 - 84), etoposide 150 mg/m2 12q (day 81 - 84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. Results: Fifty-seven patients (median age 43 years, range 24 - 65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1 - 76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P = 0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P = 0.0044), respectively. Conclusions: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL. Introduction Patients with aggressive non-Hodgkins lymphoma (NHL) treated at first diagnosis with polychemotherapy alone or combined chemoradiotherapy can achieve high response rates [1 7]. However, patients with relapsed or progressive disease still have a poor prognosis. High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is the treatment of choice for these patients [8 16]. The most compelling evidence for the superiority of HDCT compared with conventional-dose salvage therapy in relapsed and progressive NHL is based on the randomized Parma trial [15]. In this study, all patients received two cycles of conventional chemotherapy. The responders were randomized to receive either four cycles of conventional chemotherapy or HDCT (BEAM) followed by autologous stem cell transplantation (ASCT). The response rate was 44% in the group with conventional chemotherapy and 84% in the HDCT group. The analysis at 5 years revealed that patients treated with HDCT had superior outcome as measured by freedom from second failure (FF2F) (12% versus 46%) and by overall survival (OS, 32% and 53%). Therefore, two cycles of conventional salvage chemotherapy followed by HDCT and PBSCT is considered standard treatment for these patients. However, in the Parma trial more than 50% of patients treated in the HDCT-arm relapsed and most of them died. The explanation of high relapse rates after HDCT might be that one cycle of HDCT is not sufficient to control nonproliferate lymphoma cells. Since NHL is a chemosensitive disease, we hypothesized that a more stringent chemotherapy program might improve the treatment results of patients with relapsed/refractory NHL. Sequential high-dose chemotherapy (HDSCT) in accordance with the Norton Simon hypothesis [17] is one possibility of treatment intensification. Following initial cytoreduction, non-cross-resistant agents are given in high doses at short intervals. In general, the transplantation of peripheral blood stem cells and the use of growth facto (...truncated)


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A. Josting, M. Sieniawski, J.-P. Glossmann, O. Staak, L. Nogova, N. Peters, M. Mapara, B. Dörken, Y. Ko, B. Metzner, J. Kisro, V. Diehl, A. Engert. High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study, Annals of Oncology, 2005, pp. 1359-1365, 16/8, DOI: 10.1093/annonc/mdi248