¹Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano Milano, Italy

High-dose chemotherapy (HDCT) and autologous bone marrow (ABMT) or peripheral blood stem cell transplantation (PBSCT) is the treatment of choice for relapsed or refractory lymphoma patients.^1,2 Although the optimal HDCT regimen is unknown, combinations with non-cross-resistant agents are commonly used.^3,4

Data about the efficacy of single-agent high-dose melphalan (HD-PAM) in lymphoma patients are few.^5,6,7 From July 2000, in our Institution, we investigated the efficacy of HD-PAM in poor-prognosis lymphoma patients.

Between July 2000 and April 2003, 60 patients underwent HD-PAM (200 mg/mq) and PBSCT. Out of 60 patients, 42 were evaluable for response because of evidence of disease before HD-PAM. The main patient characteristics are as follows: non-Hodgkin's lymphoma (NHL) 24 (aggressive histology 22); Hodgkin's disease (HD) 18; males 29; stage III–IV 35; IPI 2 17; median previous chemotherapy regimens 2; median age 44 years (range 21–64 years). At the time of transplantation 30 patients (71%) were in partial remission, and 12 had stable or progressive disease after induction chemotherapy. Following PBSC harvest according to standard techniques, patients were treated with HD -PAM (200 mg/mq intravenously), and 24 h later PBSCs were reinfused. The median number of reinfused CD34⁺ cells was 4.6 10⁶/kg (range 2.6–18). Patients were discharged from the bone marrow transplantation (BMT) unit the day after reinfusion and readmitted on day +5 for aplasia management. All patients engrafted after PBSC and the median time to neutrophil (N>500/l) and platelet (PLT>20.000/l) recovery was 7 (range 4–18) days and 5 (range 0–35) days, respectively. Gastrointestinal mucositis was the most relevant extra-hematological toxicity. Severe oral mucositis (grade 3–4), occurred in 25 patients (60%). No moderate/severe cardiac, renal, or hepatic toxicities were documented (Table 1). Late extra-hematological toxicities were not recorded. In all, 35 patients developed fever during the aplasia period. Fever of unknown origin (FUO) was diagnosed in 22 patients, and infection was documented in nine patients including seven cases of bacteremia and two cases of pneumonia. No patient died from transplant-related toxicity (TRM). The median duration of hospitalization was 12 days (range 8–32 days). Among the whole series of 42 patients, 27 (64%) achieved complete remission (CR) and seven partial remission (PR), with an overall response rate of 81% (Table 2). Of the 24 patients with NHL, 18 obtained CR, and one PR. Of the 18 patients with HD, nine obtained CR, and six PR. At present, nine patients (20%) have died of disease progression, and one is in complete remission. A total of 32 patients (73%) are still alive with a median follow-up of 12 months (range 2–36 months) from transplantation, and 23 (54%) remain in complete remission.

Table 1 - Acute nonhematological toxicity.

Full table

Table 2 - Response to HD-PAM.

Full table

For all 60 patients, 10 patients (16%) died from disease progression, and two died in CR. In all, 48 patients (80%) are still alive with a median follow-up of 12 months (range 2–37 months) from transplantation, and 38 (63%) are in complete remission.

HD-PAM is feasible, and well tolerated, with an efficacy similar to that reported with multiagent HDCT regimens. As HD-PAM is given on day -1, neutropenia does not generally develop before day +6. Multi-agent HDCT regimens usually start on day –6 or -4 and produce neutropenia by day +1, +2. Thus, compared to other regimens, HD-PAM is associated with a reduction in the absolute duration of severe pancytopenia and days of hospitalization. Ideally, a randomized trial of HDM vs BEAM (BCNU, etoposide, aracytin, melphalan) or CBV (cyclophosphamide, BCNU, etoposide) should be undertaken to assess the relative survival rates, toxicity rates, and costs. We consider that the next logical step is to explore the use of HDM as a part of high-dose sequential therapy. We are currently evaluating tandem high-dose treatment with HDM followed by BEAM for relapsed/refractory lymphoma patients.