1 University Hospital of Zurich, 2 Triemli Hospital Zurich, 3 Inselspital Bern, 4 Kantonsspital Chur, 5 Kantonsspital Winterthur, Switzerland
Received 12 August 2003; revised 9 October 2003; accepted 11 November 2003
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ABSTRACT |
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Relapsed or refractory diffuse large B-cell and mantle-cell lymphoma have a poor prognosis. The EPOCH regimen and rituximab monotherapy have demonstrated activity as salvage therapies. Because of their non-overlapping toxicity, we evaluated their combination as salvage therapy in a phase II study.
Patients and methods:
Patients with relapsed or refractory CD20-positive large B-cell and mantle-cell lymphoma were offered treatment with rituximab 375 mg/m2 intravenously (i.v.) on day 1, doxorubicin 15 mg/m2 as a continuous i.v. infusion on days 24, etoposide 65 mg/m2 as a continuous i.v. infusion on days 24, vincristine 0.5 mg as a continuous i.v. infusion on days 24, cyclophosphamide 750 mg/m2 i.v. on day 5 and prednisone 60 mg/m2 orally on days 114.
Results:
Fifty patients, with a median age of 56 years (range 2372), entered the study. Twenty-five had primary diffuse large B-cell lymphoma, 18 transformed large B-cell lymphoma and seven mantle-cell lymphoma. The median number of prior chemotherapy regimens was 1.7 (range one to four). The median number of treatment cycles was four (range one to six). Possible treatment-related death occurred in two patients. Objective responses were obtained in 68% of patients (28% complete responses, 40% partial responses). Nineteen patients received consolidating high-dose chemotherapy with autologous stem-cell transplantation. The median follow-up was 33 months. Three patients developed a secondary myelodysplastic syndrome. The median overall survival was 17.9 months; the projected overall survival at 1, 2 and 3 years was 66, 42 and 35%, respectively. The median event-free survival was 11.8 months; the projected event-free survival at 1, 2 and 3 years was 50, 30 and 26%, respectively.
Conclusion:
The rituximabEPOCH regimen is effective and well tolerated, even in extensively pretreated patients with relapsed or refractory large B-cell lymphoma and mantle-cell lymphoma.
Key words: autologous stem-cell transplantation, EPOCH, high-dose chemotherapy, refractory aggressive B-cell non-Hodgkins lymphoma, relapsed aggressive B-cell non-Hodgkins lymphoma, rituximab, salvage chemotherapy
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Introduction |
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Because of the non-overlapping toxicity of rituximab and chemotherapy, we evaluated the combination of rituximab and EPOCH chemotherapy as salvage therapy for CD20-positive large B-cell and mantle-cell lymphoma in a phase II study.
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Patients and methods |
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Treatment plan
Patients received rituximab 375 mg/m2 intravenously (i.v.) on day 1, doxorubicin 15 mg/m2 as a continuous i.v. infusion on days 24, etoposide 65 mg/m2 as a continuous i.v. infusion on days 24, vincristine 0.5 mg as a continuous i.v. infusion on days 24, cyclophosphamide 750 mg/m2 i.v. on day 5 and prednisone 60 mg/m2 orally on days 114. The infusional part of the EPOCH regimen was shortened by 1 day while maintaining the original cumulative dose of etoposide, vincristine and doxorubicin [4] in order to allow for a 5-day in-patient stay. The rituximabEPOCH regimen was given for four to six cycles every 21 days. Patients with normal echocardiography after four cycles and <300 mg/m2 of doxorubicin prior to study entry were allowed to receive up to six cycles of rituximabEPOCH if they were not candidates for high-dose chemotherapy. Patients <60 years old who had not received high-dose chemotherapy prior to study entry were offered to undergo stem-cell collection and high-dose chemotherapy with autologous stem-cell transplantation if at least a partial response was achieved after three cycles of rituximabEPOCH salvage therapy. In those patients the fourth cycle was used for stem-cell mobilization. Safety evaluation consisting of a physical examination and full blood cell counts were performed weekly; routine chemical values were measured prior to each cycle.
Criteria for response and toxicity evaluation
Computer tomography scans were required within 3 weeks of registration and assessment was repeated after cycle 2 and 4, at the end of treatment, and every 3 months until disease progression. Response was evaluated by bidimensional measurements of lesions according to WHO criteria. After progression, patients were followed to determine overall survival. ECOG criteria were used to define PS. Toxicity was evaluated according to the National Cancer Institute (NCI) criteria [12].
Statistical analysis
Event-free survival was calculated from the date of study entry to the last control, progression or relapse, or death due to any reason. Overall survival was measured from study entry to the date of the last control or death. Projected survival was calculated using the KaplanMeier method.
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Results |
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Two patients died a sudden death. A 66-year-old woman with stage IVA disease died of an unknown cause at home after the first chemotherapy cycle. A 70-year-old woman with stage IVB disease died 8 days after the fourth chemotherapy cycle after the onset of diarrhea. An autopsy was performed in the latter patient, but no obvious reason for death was discovered. A probably independent cerebral hemorrhage occurred in a 44-year-old man with stage IVB disease after the first chemotherapy cycle. The platelet count was normal at the time of hemorrhage. The main toxicities are listed in Table 2.
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Discussion |
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Rituximab has single-agent activity in refractory and relapsed B-cell lymphoma. The first report from Coiffier et al. [4] on 55 patients demonstrated an overall response rate of 31%, including 37 and 33%, respectively, for large B-cell and mantle-cell lymphoma. Duration of response exceeded 3 months. These results have recently been confirmed in patients with large B-cell and mantle-cell lymphoma relapsing after high-dose chemotherapy and autologous stem-cell transplantation [17]. The median time to relapse was 10 months in that study.
Our phase II trial evaluated the safety and efficacy of rituximab in combination with EPOCH chemotherapy in patients with relapsed or refractory diffuse large-cell or mantle-cell lymphoma. The rituximabEPOCH regimen was found to be effective and well tolerated, even in extensively pretreated patients. A response rate of 68% was achieved. With a median follow-up of 33 months, median overall survival was 17.9 months and median event-free survival was 11.8 months. The projected 3-year event-free survival was 26%, and the projected 3-year overall survival was 35%. The regimen was well tolerated, the major toxicity being hematological, leading to hospitalization for fever and neutropenia in 7% of the treatment cycles. Two patients died a sudden death and three patients developed a secondary myelodysplastic syndrome.
The feasibility of combining rituximab with EPOCH has also been reported by another group [18]. In their study, 24 patients with untreated and 15 patients with relapsed or refractory lymphomas of different histologies were treated. In contrast to our study, hospitalization for febrile neutropenia occurred in 20% of treatment cycles.
How do our results compare with EPOCH alone? In the absence of randomized studies we had to compare our results with those from the two large published studies mentioned above [5, 13]. There does not appear to be a difference in the overall response rates or complete response rates. The overall response rate in our study is within the range of 57 to 74%, as published in studies with EPOCH alone. The median event-free survival in our study was 12 months, compared with 7 and 4 months in the studies with EPOCH alone [5, 13]. The median 3-year event-free survival in our study was 26%, compared with 15 and 7% in the studies with EPOCH alone [5, 13]. Thus rituximabEPOCH chemotherapy appears to offer a benefit over EPOCH alone in relapsed or refractory large B-cell and mantle-cell lymphoma. It is unlikely that the benefit could be entirely explained by the fact that 38% of patients in our study underwent subsequent high-dose chemotherapy and autologous stem-cell transplantation. High-dose chemotherapy with autologous hematopoietic stem-cell transplantation does improve the outcome in patients with relapsed or refractory aggressive non-Hodgkins lymphoma [2], but only to a small degree, and a considerable number of patients in the two studies using EPOCH chemotherapy alone also received treatment intensification. One fact that has to be considered, however, is the eligibility bias in our study for patients with CD20 expression.
A major difficulty in comparing overall survival data regards the inclusion of 25% of patients with low-grade lymphoma in the two reports of EPOCH chemotherapy alone [5, 6]. However, neither of these could identify histology as a prognostic factor for survival. Poor prognostic factors identified in our study were lack of response to first-line chemotherapy and high-intermediate/high IPI. Achieving a response to first-line chemotherapy appears to be a good prognostic factor [1, 19].
While it is obvious that patients <60 years of age eligible for subsequent high-dose chemotherapy with autologous stem-cell transplantation have a better outcome than the remainder of the patients, it remains of note that a long-term benefit with rituximabEPOCH was also seen in the absence of high-dose consolidation. The 2-year event-free survival in this subgroup of patients was 16%.
Our study was restricted to patients who had received a cumulative dose of doxorubicin of 300 mg/m2. This might have been an overly cautious selection of patients, since infusional doxorubicin is associated with a low cardiac toxicity [5]. Given the potential benefit of the treatment strategy used in our study, patients who have received larger cumulative doses of doxorubicin might also be considered for rituximab and EPOCH under appropriate cardiac monitoring
Based on Coiffier et al.s [20] initial report of the combination of rituximab and CHOP and the prospectively randomized study of CHOP with or without rituximab as first-line therapy for large B-cell lymphoma in patients aged 6080 years, there is currently an increasing trend towards using rituximab in first-line chemotherapy for aggressive non-Hodgkins lymphoma [21, 22]. However, this is unlikely to influence the use of rituximab in combination for patients with relapsed or refractory disease. In follicular lymphoma, retreatment with rituximab has proven to be save and effective [23].
Our study demonstrated the combination of rituximabEPOCH chemotherapy to be well tolerated and effective for patients with relapsed and refractory large B-cell and mantle-cell lymphoma. It suggests this regimen to be superior in event-free survival compared with EPOCH chemotherapy alone, with the potential bias that the regimen is only applicable to CD20-positive tumors. The high activity of this regimen suggests that drug resistance in aggressive lymphoma might not be drug specific per se, but could be due to an increase of the apoptotic threshold of tumor cells, which could, at least in part, be overcome by pretreatment with rituximab.
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Acknowledgements |
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FOOTNOTES |
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