“Hiper CVAD Followed by Rituximab Purging Previous to Autologous Stem-Cell Transplantation as Therapy of Mantle Cell Lymphoma. Results of Manto 2000 study”.

Multicentre phase II study in newly diagnosed Mantle cell lymphoma patients to determine the feasibility, overall response (OR) and failure free survival (FFS) of intensive chemotherapy type Hyper-CVAD followed by in vivo purging with Rituximab previous peripheral stem-cell transplantation.

Treatment scheme consisted in four cycles of Hyper-CVAD chemotherapy as is described by Romaguera et al. After chemotherapy four weekly Rituximab courses (375mg/m2) were administrated previously to peripheral stem-cell collection. Rituximab was not added at the same time as chemotherapy cycles; its role consisted in working as a purging agent previous stem-cell mobilization. After Rituximab administration peripheral blood progenitors were collected. Mobilization was performed using Cyclophosphamide plus G-CSF at dose of 10 μg/Kg/day. If the first mobilization was unsuccessful, a second scheme was used, using Ifosfamide (10 g/m2 in 72 hours infusion on day 1), Mesna (10 g/m2 days 1 and 2), VP16 (150 mg/m2 days 1 to 3) plus G-CSF at dose of 5 μg/Kg each 12 hours. The aim was obtain 2×106 CD34 cells/Kg. After mobilization peripheral autologous stem-cell transplantation (PASCT) was performed using BEAM (BCNU, Ethoposide, Ara-C and Melphalan) as conditioning regimen. .A week after platelet recovery (>50×109/L) another four weekly Rituximab courses (375mg/m2) were added. Patients were followed after treatment in each centre.

Forty-four patients diagnosed of mantle cell lymphoma and previously not treated were enrrolled from fifteen Spanish Institutions from 2000 to 2006. The median age of the patients were 55.77 year old. Male/female rate was 3:1. Forty patients had an Ann-Arbor stage IV, and gastrointestinal involvement was present in twenty-nine. Marrow was infiltrated in 83.3% of the cases. Age IPI adjusted were ≥2 in 45% of the cases respectively (table 2). Blastic mantle cell lymphoma was diagnosed in 5 patients (11.9%). The median follow-up of the patients was 75,07 months. In the intention to treat, of the forty-four patients only 26 patients receive all the treatment (59%). Autologous peripheral stem-cell transplantation was not performed in 16 patients. The causes of not complete the treatment schedule was: three patients refuse to be transplanted; mobilization failure in four; death before ABMT in four patients and progression of the lymphoma during HyperCVAD treatment in five patients (table 2). Two patients have a compatible sibling and an allogenic bone marrow was performed; these patients are not included in the series, as protocol violation.

Median overall survival (OS) was 77.37 months. The OS of the patients who performed all the planned treatment was 73.6% and 61.96% at three and five years. At the end of the study 21 of the patients were alive. Univariate analysis showed that prolonged overall-free survival was associated to initial ECOG, response achieve (CR or uCR vs PR, non Remission or progression), non-blastic morphology, bone marrow infiltration and performing ASCT. The median FFS was 52.53 months. A plateau was observed in the FFS plot at 72 months. FFS was of 63% at three years of surveillance and 32% at six years for all the patients. For the patients who complete autologous stem-cell transplantation FFS at three and five years were 75.91% and 42.70%. The latest relapse occurred at 73 months after treatment. Nowadays four patients are in remission more than 82 months after diagnosis. Univariate analysis showed that factors that influence were: blastic subtype of MCL, achievements of CR or uCR., and if the patient complete ASCT.

Recently two groups have published his results conducting protocols similar with our scheme of protocol. Disappointingly, our results contrast with the rather more optimistic of the Nordic Lymphoma Group with a shorter median follow up (median 3.9 years, 46,8 months) and with the recent up-date of the M.D. Anderson (Blood 2009). In both phase II essays, the 4 year FFS was of 63% and the 6 year PFS of 46% respectably. We noted that even though this prolonged relapse free survival we have relapses up to 6 years of surveillance. Differences with Nordic Lymphoma Group might be caused by not using Rituximab concomitantly with Hyper-CVAD regiment and perhaps increased toxicity of Hyper-CVAD regimen.

Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria.