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Lymphoma New Treatment Options in Mantle Cell Lymphoma Michelle Furtado 1 and Simon Rule 1,2 1. Specialist Registrar, Derriford Hospital, Plymouth, UK; 2. Professor in Haematology, University of Plymouth, Plymouth, UK Abstract Mantle cell lymphoma is an incurable disease that generally exhibits a poor prognosis. Recent advances in targeted therapies have increased the available treatment options, in particular for patients with relapsed disease, and offer the prospect for better long-term disease control and potentially chemotherapy-free treatment. Established therapies, such as proteasome inhibition and immunomodulatory agents, are beginning to be recognised as useful in the management of mantle cell lymphoma (MCL) alongside the many emerging classes of drugs (Bruton’s tyrosine kinase [BTK] inhibitors, phosphatidylinositol-4, 5-bisphosphate 3-kinase [PI3k] inhibitors and B cell lymphoma 2 [BCL2] inhibitors) that show promise in this disease. We review the newer agents and drug combinations available for the treatment of MCL. Keywords Mantle cell lymphoma, proteasome inhibition, immunomodulatory agents, TK inhibitors, PI3k inhibitors, BCL2 inhibitors Disclosure: Michelle Furtado has nothing to disclose in relation to this article. Simon Rule sits on advisory boards for Janssen, Roche, Napp, Kite and Celgene. He has received research funding from Janssen and Celgene. No funding was received in the publication of this article Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 1 September 2015 Accepted: 28 October 2015 Citation: European Oncology & Haematology, 2015;11(2):134–40 Correspondence: Michelle Furtado, Haematology Department, Level 7, Derriford Hospital, Plymouth, Devon, PL6 8DH, UK. E: Mantle cell lymphoma (MCL) comprises ~6  % of all Non-Hodgkin lymphoma (NHL) with a median age at presentation of mid-60s. It is characterised by the t(11;14)(q13:32) translocation, which leads to overexpression of cyclin D1 resulting in subsequent dysregulation of the cell cycle and of several intracellular survival pathways. 1 Although the survival of MCL patients has been demonstrated to have improved over the last decade it is still considered incurable, typically relapsing multiple times with increasingly chemotherapy refractory disease. For younger, fit patients there is a significant benefit to overall survival (OS) with the incorporation of high-dose cytarabine to upfront treatment for MCL 2 4 and consolidation of treatment with a high-dose autologous stem cell transplant further significantly prolongs the duration of remission. 5 The median age at diagnosis, however, means that the majority of patients are ineligible for such therapies. For these patients either anthracycline, purine analogue or, more recently, bendamustine- based therapies have been used. Randomised data have demonstrated a superior OS for R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) compared with R-FC (fludarabine, cyclophosphamide and rituximab) and this can now be considered the standard of care for elderly patients unable to receive high-dose regimens. 6 There is also a role for maintenance therapy with rituximab In general, the disease becomes more refractory to chemotherapy with each relapse and it is in this setting that the treatment options have recently expanded with many newer agents showing significant activity against MCL. Here we review the available data on some of these treatments, including the four approved drugs for use in this setting (temsirolimus, bortezomib, lenalidomide and ibrutinib) (see Table 1). Temsirolimus Temsirolimus is a selective inhibitor of the mammalian target of rapamycin (mTOR), interfering with the ability of the cells to translate essential proteins. 8 This disruption extends to cell cycle regulating proteins, including cyclin D1, which is overexpressed in MCL due to the t(11:14)(q13:32) translocation, which is the hallmark cytogenetic abnormality associated with this disease. This drug received its European licence for the treatment of relapsed/refractory MCL on the basis of a phase III randomised trial comparing temsirolimus with investigators choice of single-agent chemotherapy (from a permitted list). 9 The in patients who are not eligible for autograft consolidation, to further prolong the duration of remission. 6 A small subset of MCL patients will have disease that behaves indolently and these can safely be managed with a watchful-waiting approach initially. 7 most commonly chosen agents were gemcitabine or fludarabine. The temsirolimus therapy (at the currently recommended dose of 175  mg for 3 weeks followed by 75 mg weekly) led to a higher overall response rate (ORR) (21  %) compared with investigators choice (2  %). However, the ORR is very similar to that seen in phase II studies of the two most commonly chosen agents in the comparator arm (25–33  %). 10,11 The trial also demonstrated a small (but statistically significant) increase in median progression-free survival (PFS) of 4.8 months with temsirolimus from 1.9 months with investigators choice. The treatment of first and subsequent relapses however is less well defined, with many regimens being commonly utilised, depending on the performance status of the patient and prior chemotherapy exposures. Despite being licensed for this disease, the small benefits achievable with it, combined with the significant side effects noted (marked hyperglycaemia and lipidaemia, severe thrombocytopenia and asthenia) 9 134 Tou c h ME d ica l ME d ia