All patients evaluated for NHL had refractory or relapsed disease after previous chemotherapy. The eligibility criteria for patients in this study included: (1) men or women aged between 16-75 yr; (2) a histologically proven diagnosis of NHL (previous diagnoses were reformulated according to the WHO classification of lymphoid neoplasms)[10]; (3) documentation of refractory or relapsing disease after one or more chemotherapy treatment regimens; (4) an Eastern Cooperative Oncology Group Scale performance status less than 2; (5) at least one site of disease measurable in two dimensions using clinical examination, CT scan, or MRI scans; (6) no previous therapy with gemcitabine, high-dose chemotherapy, or stem cell transplantation; (7) a glomerular filtration rate of >60 mL/min, normal hepatic function, and normal bone marrow function. The patients were graded according to the Ann Arbor classification and international prognostic index (IPI). We excluded patients with acquired immunodeficiency syndrome (AIDS)-related lymphoma and those testing positive for human immunodeficiency virus. The study was conducted in accordance with the Declaration of Helsinki and was consistent with the International Conference in Harmonization Good Clinical Practice (ICH GCP) and applicable regulatory requirements. A recognized ethics committee reviewed and approved the study protocol.

The initial evaluation before commencement of chemotherapy included: medical history and physical examination; laboratory analyses including a complete blood count; renal and liver function and serum lactate dehydrogenase (LDH); glomerular filtration rate assessment by EDTA51Cr clearance; CT scans of the chest, abdomen and pelvis; and bone marrow biopsies for all NHL patients. All assessments were performed within 7 days of the first treatment, except the CT scans and bone marrow biopsies, which were performed within 28 days.

The GEPD regimen consisted of gemcitabine (700 mg/m²) and was delivered as a continuous intravenous infusion over 70 min on days 1 and 8. Etoposide (40 mg/m²) was delivered as an intravenous infusion over 30 min on days 1-4. Cisplatin (60 mg/m²) was given over 1 hour on day 1. Pre- and post-chemotherapy hydration was given on the day of cisplatin administration. Patients also received dexamethasone (40 mg) intravenously on days 1-4. The cycle was repeated every 21 days. Patients were given allopurinol 300 mg once a day for the first cycle. Throughout their treatment, cotrimoxazole (480 mg) was given twice a day three times a week to all patients for prophylaxis against pneumocystis carinii pneumonia. The institutional standard antiemetic regimen including metoclopromide, any anti-serotonin anti-emetic agent, and dexamethasone was provided prior to chemotherapy. Chemotherapy was delayed on day 8 until recovery for a maximum of 3 weeks if the neutrophil count was <0.5×10⁹/L and/or the platelet count was <50×10⁹/L or if the patient demonstrated grade 3/4 non-hematological toxicity (except for nausea, vomiting, and alopecia). If, on day 21, the neutrophil count was <1.0×10⁹/L and/or the platelet count was <75×10⁹/L chemotherapy treatment was delayed. The dose of cisplatin was reduced by 50% in the event of grade 2 neurological toxicity or grade 1 renal toxicity. In the event of febrile neutropenia, grade 4 thrombocytopenia, or ≥ grade 3 non-hematological toxicity (except alopecia), treatment with 75% of the dose for the three drugs (except for dexamethasone) was given and was returned to the full dose if the reduced dose was well-tolerated (absence of toxicity).

The response to salvage therapy was assessed after a minimum of two courses of chemotherapy. International Workshop NHL response criteria were used to assess the response to treatment [11]. In addition, the toxicity was evaluated and graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 3.0 grading system.

This study was designed as a prospective, non-randomized, open-labeled, multicenter, phase II study. The primary end points of the study were overall response (CR+CRu+PR) and toxicity. The secondary end points were efficacy of stem cell mobilization, progression-free survival, and overall survival. The patient characteristics, responses, toxicities, and efficacy of stem cell mobilization were evaluated by descriptive methods. The progression-free survival and overall survival were calculated using the Kaplan-Meier method. Statistical analysis was performed using SPSS 13.0 for Windows. All p values<0.05 were considered to be significant. In addition, the current trial used a two-stage optimal design, as proposed by Simon, with an 80% power to accept the hypothesis and 5% significance to reject the hypothesis. The duration of a complete remission was measured from the date of achieving the complete remission to the date of relapse for patients who relapsed, or the date of the last contact for patients who had not relapsed. The disease-free survival was estimated from the start date of chemotherapy to the date of relapse for patients who relapsed, or the date of last contact for patients who had not relapsed. Patients who died in remission were included as treatment failures and were not excluded from the analysis. Overall survival was estimated from the start date of chemotherapy to the date of death for patients who died.

Twenty patients were enrolled between January 2005 and January 2006 from three medical centers in Korea. The patients' characteristics are summarized in Table 1. Among these patients, WHO performance status I and II were noted in 14 and 6 patients, respectively. The histological type was diffuse large B cell in 10 patients, PTCL (peripheral T cell lymphoma) in 6 patients, and mediastinal large B cell, extranodal NK/T cell, anaplastic large B cell, and T-cell rich B cell in the remaining patients. Before the first GEPD cycle, the disease status was primary refractory in 11 patients, and relapses had occurred in 9 patients. Patients with stage I, II, III, and IV disease included 2, 3, 6, and 9 patients, respectively. Previous treatment regimens were R-CHOP in 7 patients, CHOP in 6 patients, CHEP in 2 patients, DHAP in 2 patients, A-CHOP in 1 patient, COBLAM in 1 patient, and ESHAP in 1 patient. The median disease-free interval was 5.2 months.

The objective response rate (RR) for all evaluated patients was 50.0% (95% CI:28.1-71.9%). Two CRs (10.0%) and 8 PRs (40.0%) were noted. The response was not evaluated for 2 patients who died early due to progression of disease. However, they are included in the analysis of response rate for intent-to-treat analysis. The responses are summarized in Table 2. Each of the response rates were divided into pretreatment status and histological type. The response rate of B-cell type lymphoma was better than that of T-cell type lymphoma. The response rates of B-cell type and T-cell type lymphomas were 61.5% (95% CI:23.5-76.5%) and 28.6% (95% CI:11.0-68.2%), respectively. The response rates of the relapsed patients and the primary refractory patients were 66.7% (95% CI:34.0-99.4%) and 36.4% (95% CI:6.6-68.2%), respectively. One of the relapsed patients and one of the primary refractory patients were not evaluated for response, due to early death. Autologous SCT as a consolidation therapy was performed in 7 patients. The mobilization regimen was GEPD or ESHAP. The CD34 positive cell yields were adequate (median: 6.03×10⁶/kg, Table 3). No transplant-related mortality occurred. The median follow-up duration was 5.2 months (range, 1.0-16.0 months). The median survival time and the median time to progression were not reached due to short follow-up duration (data not shown).

Toxicity was recorded in all 20 patients. The most important toxicity was myelosuppression. NCI-CTC grade IV neutropenia was observed in 13 patients (65%, Table 4).