Safety, Feasibility and Efficacy of High Dose Ranimustine (MCNU), Carboplatin, Etoposide, and Cyclophosphamide (MCVC) Therapy Followed by Autologous Stem Cell Transplantation for Malignant Lymphoma.

High-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) has been shown to be appropriate approach compared with standard salvage therapy in patients with chemo-sensitive relapsed/refractory malignant lymphoma. Although a regimen consisting of high dose ranimustine (MCNU), carboplatin, etoposide and cyclophosphamide (MCVC) is widely used in clinical practice in Japan as HDCT followed by auto-HSCT for refractory malignant lymphoma, there have been few studies that tried to clarify the details of this therapy. We have conducted a multicenter prospective study involving 7 centers in Japan in order to investigate safety, feasibility and efficacy of MCVC regimen followed by auto-HSCT.

This study was carried out according to the principles set out in the Declaration of Helsinki, 1975, and the protocol and informed-consent forms were approved by the institutional review board before the initiation of the study. All patients provided written informed consent. Between July 2007 and June 2009, 30 patients with relapsed/refractory/poor-risk non-Hodgkin lymphoma (NHL n=27) or Hodgkin lymphoma (HD n=3) were uniformly treated with MCVC regimens and underwent auto-HSCT as follows: ranimustine (MCNU) 200mg/m² i.v. on day-8 and -3 (total dose 400 mg/m²), carboplatin 300mg/m² i.v. on day-7 to -4 (total dose 1200mg/m²), etoposide (VP-16) 500mg/m² i.v. on day -6 to -4 (total dose 1500 mg/m²), and cyclophosphamide 50mg/kg i.v. on day-3 and -2 (total dose 100mg/kg). Hematopoietic stem cells were reinfused on day 0 and G-CSF administrated until hematological recovery.

Median age at transplantation was 51 (range, 18–62). Four (13%) of these patients were older than 60 years. Diffuse large B-cell lymphoma was the most main histologic subtype in these patients (43%). At transplantation, 16 (53%) were in CR and the others showed PR (n=12, 40%) or PD (n=2, 7%). Median number of CD34+ cells reinfused was 4.8 × 10⁶/kg (range, 2.0–11.2 × 10⁶/kg). All patients achieved prompt engraftment after auto-SCT; that is, the median numbers of days to achieve engraftment of neutrophils (>500/μ l) and platelets (>20000/μ l) were 10 and 13, respectively. The median amounts of red blood cell and platelet transfusions after auto-HSCT were 4 units and 50 units, respectively. The major toxicities (>50% in patients) were appetite loss (all grade 97%, grade 3/4 70%), febrile neutropenia (grade 3/4 70%), nausea/vomiting (all grade 80%, grade 3/4 56%), diarrhea (all grade 77%, grade 3/4 17%), alopecia (all grade 63%) and mucositis (50%). Treatment-related mortality (TRM) was 3.3% with one death caused by sinusoidal obstructive syndrome. With median post-transplantation follow up times of 15 months, median over all survival was not reached and median event-free survival was 18.9 months (95% CI, 14.3–23.7 months). These data suggested that the time of bone marrow recovery from transplantation and the incidence of febrile neutropenia of the MCVC were similar to that of the BEAM and BEAC. The incidence of nausea/vomiting, diarrhea and mucositis seemed to be more frequent with the MCVC than the BEAC and BEAM, and the incidence of TRM of MCVC seems to be lower than that of the BEAC and BEAM regimens.

These outcomes suggest that the MCVC regimen followed by auto-SCT is a feasible, tolerable and effective therapy for relapsed/refractory malignant lymphoma.

No relevant conflicts of interest to declare.