Mantle cell lymphoma (MCL) represents 3-10% of non-Hodgkin's lymphomas. It has been considered incurable with standard chemotherapy. However, in recent years the overall survival (OS) for MCL 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 was a prospective multi-centre study performed by the Nordic Lymphoma group. It enrolled 160 untreated patients with MCL under the age of 66 between 2000 and 2006. MCL-2 followed on from the MCL-1 study, which originally used four cycles of maxi-CHOP followed by BEAM (carmustine, etoposide, cytarabine, and melphalan) or BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide) autograft for newly diagnosed MCL. The results of MCL-1 were disappointing with an 18% event-free survival (EFS) at 4 years. The MCL-2 study incorporated rituximab and alternated three cycles of maxi-CHOP with 3 cycles of high dose cytarabine prior to transplant, with results compared to the historical controls from the MCL-1 study. Importantly, MCL-2 also allowed for pre-emptive treatment at molecular relapse post transplant with up to 4 doses of single agent rituximab, which was received by 26 patients. Nevertheless the MCL-2 study resulted in a significant improvement in EFS of 63% and OS of 81% at 4 years.r
The 15-year follow up of the MCL-2 trial continued to show impressive results, with mean OS and progression-free survival (PFS) being 12.7 and 8.5 years across all patient groups overall on an intent to treat basis. High risk patients on the basis of mantle cell lymphoma international prognostic index (MIPI) score did significantly worse, with OS and PFS of 4 and 2.5 years respectively. Disappointingly, even in low and medium risk patients with long durations of response, survival curves never appear to have plateaued, emphasising the ongoing risk of late relapse despite intensive therapy.r
The majority of patients 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 MCL-2 trial protocol should be undertaken with the view to proceed with autologous transplantation in complete remission (CR) 1 or partial response (PR) 1 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
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Phase II trial |
Nordic MCL-2 2008r |
Y |
Y |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
NCCN |
15/06/2022 |
Y |
Y |
BCCA |
N/A |
N/A |
N/A |
CCO |
N/A |
N/A |
N/A |
Alternative induction chemotherapy prior to autologous transplant with BEAM or total body irradiation (TBI) based conditioning have also been described. Dreyling et al conducted the only randomised control trial of autologous transplant in MCL. This compared CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) followed by interferon or autologous transplant. This showed improved PFS but not OS at 3 years with TBI/cyclophosphamide autologous transplant following CHOP chemotherapy and Dexa-BEAM to mobilise stem cells.r
Since the publication of the MCL-2 data, a variety of alternative induction therapies incorporating cytarabine have been published. The LyMA studyr used an induction method of R-DHAP (rituximab dexamethasone cytarabine and P referring to a platinum derivative e.g. cisplatin/carboplatin/oxaliplatin at the investigator’s choice), resulting in an overall response rate (ORR) of 89% and complete response rate (CRR) of 77%. Following autologous transplantation with rituximab-BEAM conditioning, patients were then randomised to maintenance rituximab every 2 months or observation. Those that received rituximab maintenance had 4-year OS and PFS rates of 89% and 83% respectively, compared to those who did not (80% and 64% respectively). The 4 year EFS rates with this method of 4 cycles of R-DHAP pre-autologous transplant were 79% in the rituximab group and 61% in the observation group. Interestingly, the median OS nor EFS from either group has not been reached.
Another two studies used either sequential or alternating R-CHOP and R-DHAP followed by TBI-based conditioning. This approach resulted in EFS of 84 and 88 months.rr The 5 year OS rate was 75% with the sequential approach.r The MCL-Younger trialr investigated alternating R-CHOP and R-DHAP and recently published their 15-year follow-up results. The EFS was 64% at 5 years and 46% at 10 years, with a PFS of 64% at 5 years and 44% at 10 years. OS was 76% at 5 years and 60% at 10 years in the alternating group. The median PFS was 8 years, with a median OS that has not yet been reached. These studies highlight the crucial role of high-dose cytarabine in the treatment of MCL. However, it should be noted the Nordic MCL-5 study using single agent high-dose cytarabine as induction was prematurely terminated due to lack of response.r
Khouri et al conducted TBI/cyclophosphamide autologous transplant following hyper CVAD + methotrexate/cytarabine induction and reported a 5-year OS and disease-free survival (DFS) of 77% and 43% respectively.r
Romaguera reported impressive results with rituximab-hyper CVAD + methotrexate/cytarabine with 87% achieving CR/unconfirmed complete response (CRu), without autologous transplant. The 10-year survival was 64% and failure free survival 52%r. 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
Efficacy
Updated follow-up for the Nordic MCL-2 trial (A) Overall survival (OS), (B) progression-free survival (PFS) and (C) cumulative incidence of relapse (CIR) after an intent-to-treat principle.r
© British Journal of Haematology 2016
OS and PFS according to prognostic scores. (A, B) Mantle Cell Lymphoma International Prognostic Index (MIPI), (C, D) biological MIPI including Ki-67 expression (MIPI-B) and (E, F) MIPI algorithm including miR-18b expression (MIPI-B-miR).r
© British Journal of Haematology 2016
Overall survival and time to failure in 97 patients treated with R-hyper CVAD 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
Toxicity
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 MCL-2 study.r
At 15 year follow-up there had been 15 cases identified of solid organ malignancies (excluding non-melanoma skin cancers) and 5 cases of haematological malignancies (3 myelodysplastic syndromes and 2 cases of AML).r