1 University Hospital Cologne, First Department of Internal Medicine, Germany 2 Carl-Thiem-Hospital Cottbus, Second Medical Hospital, Germany 3 University Hospital Charitè Berlin, Section for Hematology/Oncology, Germany4 University Hospital Bonn, Department of Internal Medicine, Germany 5 Klinikum Oldenburg, Department II of Internal Medicine, Germany 6 University Hospital Lübeck, Section for Hematology/Oncology, Germany
* Correspondence to: Dr A. Josting, First Department of Internal Medicine, University Hospital Cologne, Joseph-Stelzmann-Str 9, 50924 Cologne, Germany. Email: andreas.josting{at}uni-koeln.de
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Abstract |
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Patients and methods: Inclusion criteria were age 1865 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 14), 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 5862). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 8184), etoposide 150 mg/m2 12q (day 8184), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT.
Results: Fifty-seven patients (median age 43 years, range 2465) 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 176 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.
Key words: high-dose chemotherapy, non-Hodgkin's lymphoma, relapse
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Introduction |
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The explanation of high relapse rates after HDCT might be that one cycle of HDCT is not sufficient to control non-proliferate 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 NortonSimon 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 factors allow the application of the putatively most effective drugs at the highest possible dose at intervals of 13 weeks. HDSCT thereby enables the highest possible dosing over a minimum period of time (dose intensification). In recent years, HDSCT has been investigated in the treatment of solid tumors, hematological and lymphoproliferative disorders. Initial results from phase I/II studies indicated that this treatment modality is safe and effective [18
23
]. We therefore designed a dose and time-intensified HDSCT regimen after initial cytoreduction with two cycles of DHAP in patients with relapsed and refractory NHL. Here we report that this regimen is feasible, tolerable and effective in patients with relapsed NHL.
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Patients and methods |
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Primary progressive/refractory disease was defined as disease progression during first-line chemotherapy, or only transient response [complete (CR) or partial response (PR) lasting 3 months] after induction treatment. Progressive disease required the following: (1)
25% increase from nadir in the sum of the products of the greatest diameter of any previously identified abnormal node for partial responders or non-responders; and (2) the appearance of any new lesion during
3 months after the end of therapy. Relapsed disease was defined as disease progression after CR lasting
3 months.
Study design and treatment procedures
All patients received two cycles of DHAP as initial salvage treatment in order to reduce tumor volume prior to HDSCT. DHAP consisted of dexamethasone 40 mg i.v. (day 14), cisplatin 100 mg/m2 i.v. given as 24-h continuous infusion (day 1), and cytarabine 2000 mg/m2 i.v. over 3 h 12q (day 2). Hydration (250 ml/h) was started 612 h before cisplatin infusion. Corticosteroid eye drops were given topically starting 12 h before and continued for 2 days after administration of cytarabine to prevent conjunctivitis. To minimize nausea and vomiting, patients received ondansetrone 8 mg i.v. on days 1 and 2. Twenty-four hours after the last dose of cytarabine, G-CSF was given at a dose of 5 µg/kg/day subcutaneously until leukocytes increased 2500/µl for 3 days. The second cycle of DHAP was administered after 14 days providing WBC were >3000/µl and platelets >75 000/µl.
Those patients who achieved PR or CR after DHAP proceeded to the sequential high-dose regimen including high-dose cyclophosphamide (HD-CTX) 4000 mg/m2 +G-CSF (day 37) followed by PBSC harvest, high-dose methotrexate plus vincristine (HD-MTX/VCR) 8000 mg/m2 plus vincristine 1.4 mg/m2 (day 51), high-dose etoposide (HD-VP16) 500 mg/m2 +G-CSF (day 5862). Finally, a myeloablative treatment (BEAM) with carmustine 300 mg/m2 (day 80), melphalan 140 mg/m2 (day 80), etoposide 150 mg/m2 12q (day 8184) and cytarabine 200 mg/m2 12q (day 8184) was given. PBSCs were reinfused and G-CSF administered until hematological recovery (Figure 1 and Table 1). Patients with residual tumor (2 cm) at the final evaluation received involved field radiation.
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Definition of response
CR was defined as the disappearance of all clinical and radiographic evidence of disease for at least 3 months. PR was defined as a greater than 50% reduction in the product of the largest diameter and its perpendicular of measurable disease lasting >1 month. Any response less than PR was considered as treatment failure.
Statistics
The primary end point of this study was freedom from second failure (FF2F); secondary end points were toxicity, remission rate and OS.
Demographics and disease characteristics were summarized using descriptive statistics. Treatment failure was defined as death from any cause, non-CR or non-PR at the end of therapy (3 months) and further relapse, no matter which event occurred first.
FF2F was estimated from the date of beginning the protocol to first occurrence of one of the events mentioned above or, if none of these occurred, to the date of last information on complete remission. OS was estimated from the date of beginning the protocol to the date of death or, if no death occurred, to the last documented information on the patient. OS and FF2F rates were estimated according to the method of Kaplan and Meier [24]. All statistical analyses were performed using SPSS 10.0. (SPSS Inc, Chicago, IL).
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Results |
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The overall response rate (OR) for patients who responded to two cycles DHAP was 59% (44% CR and 15% PR). For those with relapsed NHL the OR was 64% (57% CR and 7% PR) and 45% (9% CR and 36% PR) in primary progressive NHL, respectively. The OR rate in patients with diffuse large B-cell lymphoma (DLBCL) was lower than in the patients with non-DLBCL, 39% (29% CR and 10% PR) versus 53% (40% CR and 13% PR), respectively (Table 6).
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Toxicity of the sequential high-dose chemotherapy
The sequential high-dose chemotherapy was well tolerated by most of the patients. Most frequently observed hematological toxicities were myelosuppression and thrombocytopenia. Leukocytopenia with leukocytes 1000/µl were observed for a median duration of 5 days (range 013) after cyclophosphamide, for a median duration of 0 day (07) after methotrexate, for 7 days (013) after etoposide and for 9 days (619) after BEAM. The median duration of thrombocytopenia of less than 25 000/µl was 3.5 days (range 020) after cyclophosphamide, 0 day (07) after methotrexate and 7 days (015) after etoposide.
The mean number of RBC-transfusions was 3.3 after cyclophosphamide (range 08), 0.8 after methotrexate (04), 3.6 after etoposide (010) and 3.6 after BEAM (014). The mean number of platelet transfusions was 2.1 after cyclophosphamide (range 09), 0.3 after methotrexate (05), 2.3 after etoposide (07) and 5.8 after BEAM (022). Results are summarized in Table 7.
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Discussion |
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Several phase II studies evaluated HDCT and ASCT in patients with relapsed or refractory NHL [816
]. Based on the results of a randomized trial, HDCT followed by ASCT is being considered standard treatment for patients with aggressive non-Hodgkin lymphoma failing first-line chemotherapy [15
]. This strategy produces long-term disease-free survival rate in selected patients, mainly those with chemosensitive relapse [14
].
The high relapse rates observed in most trials using a single HDCT, however, suggest that this strategy might not be sufficiently effective against non-proliferative cells. Therefore, according to the NortonSimon hypothesis [17], sequential high-dose chemotherapy regimens have been introduced in the treatment of solid tumors and lymphoproliferative disorders [18
23
]. After initial cytoreduction, single-agent non-cross-resistant drugs are given at short intervals. In general, the transplantation of PBSC and the use of growth factors allow the application of the putatively most effective drugs at the highest possible doses with intervals of 13 weeks. Sequential high-dose chemotherapy thereby enables the highest possible dosing over a minimum period of time (dose intensification). In a retrospective study, Cortelazzo et al. [25
] reported the use of a HDSCT regimen in 103 patients with relapsed or refractory NHL. Seventy-nine patients achieved a complete response after autotransplantation. Three-year estimates of overall survival, event-free survival and disease-free survival after a median follow up of 24 months were 67%, 44% and 47%, respectively. The toxicity was low with treatment-related mortality of 4% and the regimen was associated with remarkable response rates allowing further therapy with ASCT.
In our study the patients were treated with two cycles of salvage chemotherapy to reduce tumor burden and to evaluate the chemosensitivity of disease as a predictive factor for HDCT [2527
]. In addition, all patients were treated with DHAP plus G-CSF to shorten the intervals between cycles. The median time between the first and second cycle of DHAP was 18 days. This represents a dose-escalation by a factor of 1.6 compared with DHAP given at 28-day intervals. The OR after two cycles of DHAP was 72% (9% CR, 64% PR) and thus at least comparable to results observed with other salvage regimens [28
32
]. The toxicity profile was excellent with WHO grade III and IV leucocytopenia and thrombocytopenia occurring in 40% and 51% of all cycles with a mean duration of 0 days, respectively. One patient developed acute pancreatitis and was excluded from further treatment. Neither severe infections nor treatment-related deaths occurred.
The second part of the sequential treatment program consisted of high-dose cyclophosphamide at a dose of 4000 mg/m2. This drug does not have a strong proliferation-dependent cytotoxicity and, therefore, will also kill tumor cells that are out of the cell cycle [33]. Methotrexate 8000 mg/m2 and vincristine 1.4 µg/m2 are class II specific anticancer agents with an expected optimal activity when given after cyclophosphamide. Importantly, methotrexate and vincristine are marrow non-toxic drugs and obviate the risk of a second myelosuppressive treatment during early recovery of the marrow after cyclophosphamide [33
]. Etoposide at 2000 mg/m2 as the final course prior to myelosuppressive therapy with BEAM is a highly active cytotoxic drug in lymphoma patients with moderate toxicity when given as a single agent at high doses. The conditioning regimen used was BEAM (BCNU, etoposide, cytarabine and melphalan) at standard doses.
Despite possible concerns of additive toxicity, the four-step high-dose sequential program as reported in this study proved to be well tolerated. The observed CR rate was 32% and the OR rate was 43% for all patients. In patients with relapsed NHL, the CR rate was 50% and the OR rate was 56%; in contrast, in patients with progressive disease the CR rate was only 4% and the OR rate 22%. These results demonstrate that this regimen is highly effective in patients with relapsed NHL but ineffective in patients with progression during first-line therapy. By the analysis of patients who responded to the first two cycles of DHAP, CR was observed in 44% and OR in 59% patients. The OR in patients with relapsed NHL versus progressive NHL was 64% versus 45%, but the CR was 57% versus 9%, respectively. In addition, patients with relapse had a better outcome than patients with primary progressive disease. 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.
In conclusion, this new three-phase treatment regimen is well tolerated, feasible 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 the addition of rituximab for patients with relapsed aggressive NHL.
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