Immunohistochemical expression of cereblon and MUM1 as potential predictive markers of response to lenalidomide in extranodal marginal zone B‐cell lymphoma of the mucosa‐associated lymphoid tissue (MALT lymphoma)

Abstract

Lenalidomide is an active agent for the treatment of MALT lymphoma. Recently, high expression levels of cereblon (CRBN) and MUM1 have been associated with better response rates in multiple myeloma treated with lenalidomide. However, there are no data on CRBN and MUM1 expression in MALT lymphoma. In the current study, we have systematically investigated a potential correlation of CRBN/MUM1 immunohistochemical expression and response to lenalidomide-based therapy in a series of 46 patients with MALT lymphoma treated at the Medical University Vienna 2009 to 2014. In total, 28% (13/46) of biopsy specimens derived from gastric tissues, while 72% (33/46) originated from extragastric MALT lymphoma. In terms of CRBN, 54% showed high expression (CRBN+, ≥50% positive cells); the remaining 46% were classified as low expression (CRBN-). In contrast to other reports, there was a non-significant trend towards worse response rates in CRBN+ (68% versus 86%, P = 0.161). Relapse rates (P = 0.592) and PFS (P = 0.306) did not differ between CRBN+/CRBN-, but all 3 patients progressing on lenalidomide were CRBN+ and both patients completely lacking CRBN expression responded to treatment. Concerning MUM1, 62% were MUM1-negative (MUM1-) and 38% positive (MUM1+). There was no difference in response to lenalidomide by MUM1-status (MUM1+ 71% versus MUM1- 79%, P = 0.546) and also relapse rates (P = 0.828) and PFS (P = 0.681) did not differ. Interestingly, a subgroup analysis of gastric lymphoma revealed a significantly better PFS for CRBN- and MUM1- patients, respectively (both P < 0.05). To conclude, there was no significant difference in response to lenalidomide between patients with low or high expression of CRBN/MUM1 in a general population of MALT lymphoma, and immunohistochemical CRBN/MUM1 assessment cannot be recommended in the clinical routine.

Immunomodulatory treatment for mucosa‐associated lymphoid tissue lymphoma (MALT lymphoma)

“…However, given the high efficacy of chemotherapy‐based treatment approaches used for symptomatic patients, such as R‐bendamustine and (R‐) chlorambucil with CR rates up to 90%, predictive biomarkers for response to immunomodulatory treatment would be of interest to precisely select optimal candidates. Markers evaluated so far include only cereblon and MUM1 expression for lenalidomide‐based therapy, which did not correlate with efficacy and thus cannot be recommended for clinical routine 55 …”

Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort

“…Strong expression of lenalidomide's target cereblon in the leukemic blasts was rather associated with an unfavorable OS, which has also been documented for gastric marginal zone lymphomas [36], but has until now not been addressed in myeloid neoplasms and may deserve attention in larger studies. Interestingly, all of the described effects were independent from the genotype of the cereblon gene (CRBN), which is in line with data from other IMiDs [23].…”

Prolonged follow‐up on lenalidomide‐based treatment for mucosa‐associated lymphoid tissue lymphoma (MALT lymphoma)—Real‐world data from the Medical University of Vienna

“…For the time being, however, there are no pathological or strict clinical criteria, and also immunohistochemical assessment of cereblon or MUM-1 expression has not been useful with regards to this question. 36 Finally, activity of LEN was not influenced by stage, prior immuno-/chemotherapy and MALT-IPI, but patients with primary gastric MALT lymphoma had a significantly shorter PFS than patients with extragastric lymphoma, which might be explained by the fact that almost all patients with gastric lymphoma had already been pretreated at least with HP-eradication before being included into therapy with a LEN-based regimen. Furthermore, it is not feasible to draw any strong conclusions following this observation due to the limited number of cases included in this series, precluding also direct comparison of the two different treatment regimens used.…”

“…In view of these findings, definition of prognostic parameters for response to LEN would be highly welcome. For the time being, however, there are no pathological or strict clinical criteria, and also immunohistochemical assessment of cereblon or MUM‐1 expression has not been useful with regards to this question …”