This week we met Mr Jones, a 77 year old man who had an abnormal result when he attended his GP for annual well man bloods. His FBC revealed a moderate thrombocytopenia, a slight lymphocytosis and a normochromic anaemia. When his GP recalled him to discuss the results he admitted to a several month history of drenching night sweats although he had not lost any weight. His GP was unable to palpate any lymph nodes.
In the mean time the lab staff examined his blood film. The lymphocytes were quite pleomorphic, with clefted nuclei and occasional nucleoli. There were no smear cells. The lab staff therefore sent the sample for flow cytometry in order to identify the cell markers expressed by the cells. The result was not diagnostic, but did help to narrow down the possible diagnoses, as they confirmed a B cell disorder (CD19 and CD20+), were CD10-, making follicular lymphoma unlikely, were CD5 +, making CLL and mantle cell lymphoma a possibility, but the CD23- status of the cells made CLL less likely. Of course there is a great deal more subtlety to cell marker interpretation than this, but following this kind of schema is a good starting point.
We discussed the options for making a formal diagnosis. Many of you asked for a Cyclin D1, as this the hallmark of Mantle Cell Lymphoma (which were backing at this point) but it is important to remember that this cannot be done by flow cytometry, but requires a solid tissue sample for immunohistochemistry. This can be done on bone marrow or a lymph node or other biopsy specimen. We had none of these at this point.
We also discussed the genetic markers of Mantle Cell Lymphoma. Classically Mantle Cell Lymphoma is associated with t(11;14) which is the mutation responsible for upregulating Cyclin D1, by bringing CCND1 adjacent to the heavy chain locus. Overexpression of Cyclin D1 causes increased cycling of cells and thus proliferation. Modern FISH techniques are able to detect t(11;14) in nearly all cases of Mantle Cell Lymphoma. It is very occasionally identified in CLL/PLL (and is associated with a poorer prognosis and more aggressive disease) and in 5% of Myeloma patients.
In this case the flow laboratory, working as part of a haemato-oncology diagnostiscs service sent the sample straight to the cytogenetics laboratory, who were able to confirm the presence of t(11;14) in the lymphocytes contained within the specimen. The patient went on to have a staging CT scan which did not reveal any bulky disease.
Treatment options were then briefly discussed. It is reasonable to state that this is a rapidly evolving field, and significantly influenced by the healthcare structure of any given country. We can speak only to the UK position, which may not reflect practice worldwide.
Until recently the treatment for OLDER ADULTS (those not considered fit for autologous stem cell transplantation) was a broad field: the BCSH guidelines published in 2012 list a number of ‘Rituximab plus chemo’ combinations, including RCHOP, R-Chlorambucil, R-Bendamustine, FCR and R-CVP, none of which was felt to be superior.
Recent data has lead to NICE approval for VRCAP, a regimen containing bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisolone. This approval was based on data from the LYM-3002 trial, a large study in MCL which randomised 486 patients to receive the combination VRCAP or RCHOP. All patients had a new diagnosis of MCL, were of good performance status and were ineligible or not considered for autologous stem cell transplantation. The primary endpoint was progression free survival (PFS). The median duration of follow-up was 40 months. PFS was significantly superior with VRCAP at 24.7 months versus 14.4 months for RCHOP (HR0.63, 95% confidence interval 0.50-0.79, p<0.001). Overall survival has not yet been established as the patients in the VRCAP group have yet to reach median survival.
It should be noted that diarrhoea, fever and thrombocytopenia were all more common in those receiving VRCAP, although there were no major differences in treatment related fatalities between the two groups.
Younger patients (fit for autologous transplant) continue to be treated with a regimen containing cytarabine. In the USA (and many other countries I am sure) this is achieved with HYPER-CVAD, but the UK opinion is that this is too toxic (leading to incomplete therapy due to infection or toxicity, early death or later risk of MDS/AML) and the ‘Nordic’ protocol is used, alternating MAXI-CHOP with HDAC (and rituximab with every cycle). Patients then receive an autologous transplant.
Relapsed and Refractory Disease
Ibrutinib is currently the therapy of choice for relapsed Mantle Cell Lymphoma in the UK, although the high cost may prove prohibitory in time. Ibrutinib is most effective in the more indolent form of Mantle Cell Lymphoma, with nearly 100% efficacy, but this falls to 50% in high risk (as defined by the MIPI-c score) when used as a monotherapy.
Lenalidomide, Temsirolimus and Bortezomib all show promise in relapsed disease and are licensed for monotherapy by the FDA (except Temsirolimus); the challenge for the future is likely to be finding ways to combine these agents to improve survival in the mantle cell population.
LYM3002 Trial: Robak et al (2015) Bortezomib based therapy for newly diagnosed Mantle Cell Lymphoma. . N Engl J Med; 372:944-953.
BCSH Guideline: McKay, P., Leach, M., Jackson, R., Cook, G. and Rule, S. (2012), Guidelines for the investigation and management of mantle cell lymphoma. Br J Haematol, 159: 405–426. doi:10.1111/bjh.12046
Review Article: Elias Campo and Simon Rule (2015) Mantle cell lymphoma: evolving management strategies. Blood; 125(1):48-55