Upfront treatment of mantle cell lymphoma by sequential high dose immunochemotherapy supported by in vivo-purged stem cell double autologous transplantation : a single institution experience

Background.Mantle Cell Lymphoma (MCL) is characterized by a good response rate to conventional anthracycline-based regimens but long-lasting remissions are sporadic. Aims. we retrospectively analyzed the outcome of 15 MCL patients upfront treated with sequential high dose immunochemotherapy followed by double autologous stem cell transplant (ASCT). Patients and Methods. from 2000 to 2009, 15 MCL patients, eligible for ASCT, have been consecutively treated as follow: a) standard dose phase: APO: doxorubicin, 75 mg/sqm i.v., day 1; prednisone, 60 mg/sqm orally, day 1 to 5 and day 9 to 12; vincristine, 1.4 mg/sqm i.v., day 1 and 8; DHAP: cisplatin 70 mg/sqm, day 1; cytarabin 1500 mg/sqm i.v., days 2-3; dexametasone 40 mg i.v., days 1 to 3; b) rituximab high dose sequence: high dose cyclophosphamide (CTX 5 g/sqm) and high dose cytarabine (Ara-C 2 g/sqm every 12 for 6 consecutive days) followed by leukapheresis; c) high dose melphalan (180 mg/sqm) and high dose mitoxantrone plus melphalan (60 mg/sqm and 180 mg/sqm, respectively) followed by PSC infusion. Rituximab (375 mg/sqm) was infused twice after CTX, cytarabine and double autologous transplantation (modified from Gianni et al., Blood, 102, 749, 2003). All patients (8 female and 7 male) had a histological diagnosis of MCL according to WHO classification criteria; molecular rearrangement of bcl-1 locus was detected by PCR in the bone marrow of 7 patients. The median age at diagnosis was 57 years (range 37-68); 13 patients were in stage IV and 2 in stage III; 2 patients had bulky disease at presentation. Four patients were in overt leukemic phase and 2 had extranodal localization. According to MIPI score, 10 patients were classified as low risk (67%), 3 as intermediate risk (2%) and 2 as high risk (1%). Double transplant was performed in all but 2 patients (one for refusal and one because second procedure is currently ongoing).Results. The standard dose phase, which included a median number of 4 cycles (range 3-5), was generally well tolerated, with only one patient experiencing tumor lysis syndrome. After induction, clinical CR was achieved in four patients. PBSC were successfully collected after both CTX/rituximab (1.8-9.7¥106/Kg) and Ara-C/rituximab (7.1- 40.0¥106/Kg) cycles. At the end of these phases, 5 patients were in CR while 10 were in PR. Following transplants, median times to ANC >500/mL were 11 days (range 10- 14) in both the procedures, whereas median times to platelet recovery (>50000/mL) were 18 days (range 10-172) after the first transplant and 23 days (range 11-298) after the second one. Most frequent complications were FUO and grade III-IV mucositis, especially following the second transplant. After a median follow-up of 28 months (range 13-105), 11 patients (73%) were alive, whereas 4 died from disease progression. With regard to disease status, 11 patients were in CR and 4 patients were in PR. Both overall and disease free survival at 7-years were 70%, respectively. Conclusions.Our results confirmed that in MCL the use of sequential high dose immunochemotherapy followed by double autologous transplantation associates to high remission rates with long-term survival.