High dose cytarabine with rituximab is not enough in first-line treatment of mantle cell lymphoma with high proliferation: early closure of the Nordic Lymphoma Group Mantle Cell Lymphoma 5 trial

New Paradigms in Mantle Cell Lymphoma: Is It Time to Risk-Stratify Treatment Based on the Proliferative Signature?

“…Unfortunately, MCL5 was closed very early due to the limited efficacy of the treatment in the initially enrolled patients. Thus, higher doses of cytarabine alone are most likely not sufficient to overcome the dismal role of proliferation, supporting the hypothesis that anthracycline combinations are still worthwhile (74).…”

“…For patients requiring treatment, MIPI is the most important prognostic tool, as well as Ki-67 proliferative index and MIPI-b (13,(65)(66)(67)(68). Nevertheless, to the best of our knowledge, only one clinical trial ("MCL5," from the Nordic Lymphoma Group, EudraCT 2011-001557-85) offering tailored therapies has been performed to date (74). MCL5 was launched in 2011, aimed at improving the outcome of younger patients with MCL with high-risk MIPI or MIPI-b.…”

Single-agent cytarabine is insufficient for the treatment of human mantle cell lymphoma in mouse xenograft model

“…Here, we focused on the simple question, which of the two agents in the DHAP regimen, Pt or araC (or both) are key contributors of improved efficacy of this regimen. Recently, the Nordic Lymphoma Group MCL trial 5 was prematurely terminated because of insufficient antilymphoma efficacy of front-line therapy based solely on high-dose araC in combination with rituximab [8]. To simulate the situation in patients with aggressive MCL disease, we used mouse xenograft models of aggressive metastatic human MCL, and subjected the MCLbearing mice to equally toxic therapies consisting of Pt, araC and three different combinations of Pt+araC.…”

“…The enthusiasm for HDAC in front-line therapy of MCL led even to attempts to avoid other chemotherapy agent in the front-line setting. However, the latest Nordic Lymphoma Group Mantle Cell Lymphoma 5 trial that evaluated "single"-agent HDAC (in combination with rituximab, but not other genotoxic agent standardly used in front-line therapy of MCL) was prematurely terminated because of insufficient efficacy [8]. Results from these clinical trials raised a crucial question, which of the two agents, Pt or araC (or both), actually contributed to the improved outcome of MCL patients.…”

The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive?

“…39 Moreover, the attempt to improve the prognosis of "high-risk" MCL (according to MIPI and MIPI-b) by offering increased doses of cytarabine did not yield satisfying results ("MCL5"). 88 Therefore, although broadly validated, neither MIPI nor Ki-67 nor MRD are currently routinely applied to guide treatment decisions in MCL. 36 Thus, a practical application of these predictors in the next clinical trials is eagerly awaited, to finally investigate tailored therapies in MCL.…”