Ifosfamide salvage treatment before autologous stem cell transplantation in patients with refractory and relapsed Hodgkin's lymphoma: a GELA experience.

Most patients with Hodgkin’s lymphoma (HL) can be cured with chemotherapy (CT), either associated with radiotherapy (RT) or not. However, patients who fail to achieve an initial complete remission (CR), i.e. who relapse within the first year after CR, have a poor outcome. Salvage CT regimens with high-dose therapy and autologous stem cell transplantation (ASCT) have been widely investigated in such patients, and are associated with a higher response rate and improved progression-free survival [1–3]. The aim of using a salvage regimen prior to transplantation is to achieve maximum tumor reduction and to mobilize peripheral blood progenitor cells (PBPC) for ASCT. Patients in complete response before transplantation have a reduced probability of relapse. The choice of salvage regimen is based on several considerations, such as cumulative toxicity with prior exposure to doxorubicin, non-cross-resistant drugs. In the past 15 years, the members of the Groupe d’Etude des Lymphomes de l’Adulte (GELA) have tried to explore new salvage regimens [3, 4] in order to analyze prognostic factors and the place of ASCT in the treatment of such patients [5]. We first developed a prospective trial to test an intensive regimen followed, in chemosensitive patients, by high-dose therapy and ASCT. The mitoguazone, ifosfamide, mesna, vinorelbine and etoposide (MINE) regimen was derived from the initial mitoguanzone, ifosfamide, methotrexate and etoposide (MIME) regimen [6], and comprised mitoguazone 500 mg/m 2 on days 1 and 5, ifosfamide 1500 mg/m 2 on days 1–5 with concomitant administration of mesna 1500 mg/m 2 and vinorelbine 15 mg/m 2 on days 1 and 5 and etoposide 150 mg/m 2 on days 1–3 [5]. Among the 100 patients included in the study, 54 had untreated relapses, 41 had induction failure and five patients had resistant relapses. Response was evaluable in 97 patients (Table 1). Thirtyfour patients (35%) achieved CR, 24 (25%) a very good partial response (PR) and 15 (15%) a PR >50%, yielding a 75% overall response rate. Only 24 patients (25%) did not respond, including 18 induction failures. The response rate was 92.5% in patients with untreated relapse and 53% in patients with resistant relapse or induction failure. MINE was myelotoxic but was given at the calculated dosage without delays in 80% of patients; moreover, it allowed apheresis to harvest peripheral blood stem cells. Seventy-two patients responding to MINE received high-dose therapy and ASCT with a 2-year survival of 61%. Patients who had achieved CR or a very good PR after MINE had an 81% estimated 2-year survival after ASCT, while patients who had PR or who did not respond had a 2-year survival of 36%. In multivariate analysis, only disease status at time of transplantation had a significant prognostic value. The high response rate observed with this regimen led to its incorporation as a planned salvage treatment in the H89 trial, comparing the role of RT or two additional cycles of CT in disseminated stage IIIB–IV disease after six cycles of CT in responding patients [7]. Evaluation of response was made after four and six cycles of CT and at the end of treatment. The 5-year event-free survival and overall survival of 533 patients was 62% and 79%, respectively. There was no difference in overall survival and event-free survival between the two arms. The secondary objective was to treat patients <60 years of age and with a response <75%, progressive disease or relapse with salvage CT and ASCT. Patients were assigned to receive intensified cytoreductive CT with preferentially the MINE regimen. The conditioning regimen consisted of BCNU (bis-chloro-ethylnitrosourea), etoposide, cytarabine and melphalan (BEAM) followed by ASCT. RT was indicated for residual masses after ASCT. Among the 533 patients randomized in the study, 157 patients with induction failure (n = 67), PR (n = 22) or relapse (n = 68) were included in the study. ASCT was performed in 101 patients and 80 were in CR after transplantation. Forty-eight were salvaged without transplantation and 14 were in CR. The overall response rate after salvage CT was 62%, 83% and 89% for patients with induction failure, PR and relapse, respectively. With a median follow-up of 50 months, the 5-year survival estimates were 30%, 72% and 76% for the induction failure, PR and relapse groups, respectively (P = 0.0001), 71% for the 101 patients given ASCT and 32% for the 48 patients treated without ASCT (P = 0.0001). Multivariate analysis using a time-dependent Cox model indicated that B symptoms at progression, salvage without ASCT and chemoresistant disease before ASCT were significantly associated with shorter overall survival. Despite the encouraging results of salvage CT with ASCT, it remains difficult to predict whether all patients with relapsing HL will benefit significantly from such intensive approaches, and most reports in this context have included heterogeneous groups of patients, including those with refractory disease and multiple relapses. On the other hand, the high cure rate observed might be associated with an increase in the mortality rate not related to