Mantle cell lymphoma represents 3-10% of non-Hodgkin's lymphomas. It has been considered incurable with standard chemotherapy. However, in recent years the overall survival for mantle cell lymphoma has improved. The optimal treatment approach is contentious. The respective roles of watchful waiting, chemo-immunotherapy alone or followed by consolidation with autologous stem cell transplantation is beyond the scope of this document.
The Nordic MCL 2 study is a prospective multi centre study. It enrolled 160 untreated patients, aged under 66 years, with mantle cell lymphoma. The study follows on from the MCL 1 study. The MCL 1 study used maxi-CHOP followed by BEAM or BEAC autograft for newly diagnosed mantle cell lymphoma. The results of MCL 1 were disappointing with an 18% EFS at 4 years. The MCL 2 study added rituximab and high dose cytarabine to the MCL 1 protocol. The results are compared to the historical controls from the MCL1 study. The MCL2 study had an EFS of 63% and OS of 81% at 4 years.r
The 10 year follow up of the MCL 2 study continued to show impressive results. On an intention to treat basis the 10 year overall survival is 58% and event free survival is 43%. Unfortunately, there have been 6 relapses that occurred more than 5 years post transplant.r
The majority of patient received only 4 doses of rituximab. This appeared to be adequate in terms of providing in vivo purging of the stem cell product. There was no difference in EFS between 4 and 6 doses of rituximab.r
Treatment with the MCL2 study protocol should be undertaken with the view to autologous transplantation in CR1 or PR1 after 6 cycles of chemo-immunotherapy. Further chemo-immunotherapy beyond cycle 6 was undertaken in some patients pending transplant. This was associated with increased cardiotoxicity and as such should be avoided if possible.rr
Alternative induction chemotherapy prior to autograft with BEAM or TBI based conditioning have also been described. Dreyling et al conducted the only randomised control trial of autologous transplant in mantle cell lymphoma. This compared CHOP followed by interferon or autologous transplant. This showed improved PFS but not OS at 3 years with TBI/Cyclophosphamide autograft following CHOP chemotherapy and Dexa-BEAM to mobilise stem cells.r
Since the publication of the MCL2 data, a variety of alternative induction therapies incorporating cytarabine have been published. These have used either sequential or alternating R CHOP and RDHAP followed by TBI based conditioning. This approach resulted in EFS of 84 and 88 months.rr The 5 year OS was 75% with the sequential approach.5 These studies have highlighted the activity of cytarabine in the treatment of mantle cell lymphoma. It should be noted the Nordic MCL 5 study using single agent cytarabine as induction was prematurely terminated due to lack of response.r
Khouri et al conducted TBI/Cyclophosphamide autograft following hyperCVAD + Methotrexate/cytarabine induction. Obtaining 5yr OS and DFS of 77% and 43% respectively.r
Romaguera reported impressive results with Rituximab-HyperCVAD+ Methotrexate/Cytarabine with 87% achieving CR/Cru, without autologous transplant. The 10 year survival was 64% and failure free survival 52%. These results are very similar to the 10 year follow up of the MCL 2 study. However, the multi centre SWOG 0213 using Rituximab hyper CVAD+ Methotrexate Cytarabine was less impressive with a median survival of 6.8 years after 4.8 years of follow up.rr
Event-free survival (A) and overall survival (B) of patients of NLG protocols MCL-1 and MCL-2, respectively, based on intention-to-treat of all included patients. (C) Progression-free survival of protocols MCL-1 and MCL-2, respectively, of responders who completed treatment.
At the time of publication 27 patients were observed in remission at 5 years. 78 in sloping part of curve.
© Blood 2008
Overall survival and time to failure in 97 patients treated with R-hyperCVAD alternating with R- methotrexate-cytarabiner
© British Journal of Haematology 2010
Reports of trials for untreated MCL including more than 20 patients.r
© British Journal of Haematology 2010
The hospitalisation rate for grade 3 or 4 toxicities was 17% with maxi-CHOP and 12% with cytarabine. The majority of these, 80%, were due to febrile neutropenia. 15 patients failed to proceed to high dose therapy; 5 due to toxicity, 4 due to failed mobilisation and 6 for unresponsive disease. There were 8 deaths due to non relapse mortality. 4 occurred during high dose therapy (1 graft failure, 3 infectious). 4 later deaths; 3 from cardiac failure and one PE.r
This compares favourably with the toxicity of R hyper CVAD + Methotrexate/Cytarabine in which up to 29% patients had sufficient toxicity to stop therapy. This compares with 3% in the MCL2 study.r