Clinical Outcome of Mantle Cell Lymphoma Patients with High Risk Biology (high Ki-67, blastic MCL, or high p53 expression)
Authors: Dreyling Martin , Hoster Eva , Unterhalt Michael , Rosenwald Andreas , Kluin-Nelemans Hanneke , Hermine Olivier , Klapper Wolfram 
Published: November 2019

INTRODUCTION: Mantle cell lymphoma (MCL) is a distinct lymphoma subtype with a wide variation of clinical course. Previously a clinically defined risk score (MIPI) was established which partly reflects the heterogeneity of clinical outcome in this disease (Hoster, JCO 2004). Based on prospective trials, cytology (classical type vs. blastoid variant; Hoster, JCO 2016), cell proliferation as determined by Ki-67expression (Hoster, JCO 2016), and p53 alterations (Eskelund, Blood 2017; Aukema, Blood 2018) all have been identified as major drivers of a rapidly progressing disease, independent of MIPI. Aim of this study was to assess the clinical outcome of patients with at least one of these 3 different biological risk factors in a large uniformly treated patient population.
METHODS: All patients were treated in the MCL Younger (Hermine, Lancet 2016) and MCL Elderly trials (Kluin-Nelemans, NEJM 2012) of the European MCL Network. Formalin fixed paraffin embedded (FFPE) diagnostic patients' material was classified as classical or blastic/pleomorphic variant and analyzed by Ki-67 or p53 immunohistochemistry on either tissue microarrays or whole tissue sections. Patients were classified as having high risk biology if they displayed blastoid cytomorphology, Ki-67 ≥30% according to the published guidelines, or high p53 staining indicating a mutated gene status expression. As control, standard risk disease patients had classical MCL with low Ki-67 <30%, and p53 IHC expression ≤50%.
RESULTS: In 365 MCL (MCL younger: n=192, MCL elderly: n=173) out of 1229 study patients, at least one of the biological parameters indicated a high risk biology, or high risk biology was excluded by determination of all 3 parameters. No major survival difference was observed for patients with and without IHC data available, excluding a major selection bias. 65 of 319 analysed cases displayed a blastoid cytomorphology (20%), 175 of 345 cases had an increased Ki-67>30% (51%), and 54 of 254 cases displayed a mutated p53 status (21%). Based on the selection procedure of the cases, a total of 224 cased displayed a high risk biology (63%) vs 130 cases with confirmed standard risk disease(37%).
Median failure-free (6.3 years vs, 2.2 years; p< 0.0001) and overall survival (median not reached vs. 4 years; p<0.0001) was significantly prolonged in the standard risk cohort compared with the high risk biology group. These significant differences were detected in both, patients treated with conventionally dosed chemotherapy (median PFS: 3.8 vs. 1.3 years, p=0.0001; OS: median not reached vs 2.5 years, p<0.0001) as well as patients receiving a cytarabine containing induction and autologous transplantation (median PFS: 7.5 vs. 3.7 years, p=0.0011; OS: median not reached vs 6.5 years, p<0.0001). Interestingly, MIPI remained a prognostic factor in the groups of patients without and with high-risk biology (FFS low risk disease: p=0.0223); PFS high risk disease: p<0.0001), and distribution of risk groups differed only slightly in these subsets of patients (biological low risk: 51% low/32%intermediate/17% high MIPI; biological high risk: 31% low/35% intermediate/34% high MIPI). Similar results were observed for overall survival.
CONCLUSIONS: Although our enrichment strategy does not allow the estimation of the frequency of high risk biology and the patient group with standard risk disease is underrepresented in this evaluation, the patients with high risk biology as defined by blastoid variant, Ki-67 >30%, or high p53 expression had a significantly shorter failure-free and overall survival even without consideration of the clinical features of the disease (MIPI). As these biological factors seems to dictate the sometimes dismal clinical course of the disease, we recommend to incorporate these factors in routine diagnostic practice. Future studies should investigate the differential impact of targeted therapies in this biologically defined subset of patients.

Disclosures
Dreyling: Sandoz: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Novartis: Other: Scientific advisory board; Mundipharma: Other: Scientific advisory board, Research Funding; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau. Hoster:Roche Pharma AG: Other: Travel support; Janssen: Research Funding. Unterhalt:F. Hoffmann-La Roche: Research Funding. Hermine:AB science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding.