The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial.

Abstract

The sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) has been demonstrated to predict the response to high-dose cytarabine consolidation treatment in acute myeloid leukemia patients. Here, we evaluated SAMHD1 as potential biomarker for the response to high-dose cytarabine in mantle cell lymphoma (MCL) patients. We quantified SAMHD1 protein expression and determined the mutation status in patients of the MCL Younger and Elderly trials (n = 189), who had received high-dose cytarabine- or fludarabine-based polychemotherapy. Additionally, we quantified SAMHD1 expression in B cell lymphoma cell lines and exposed them to cytarabine, fludarabine, and clinically relevant combinations. Across both trials investigated, SAMHD1 mutations had a frequency of 7.1% (n = 13) and did not significantly affect the failure-free survival (FFS, P = .47). In patients treated with high-dose cytarabine- or fludarabine-containing regimes, SAMHD1 expression was not significantly associated with FFS or complete remission rate. SAMHD1 expression in B cell lymphoma cell lines, however, inversely correlated with their in vitro response to cytarabine as single agent (R = .65, P = .0065). This correlation could be reversed by combining cytarabine with other chemotherapeutics, such as oxaliplatin and vincristine, similar to the treatment regime of the MCL Younger trial. We conclude that this might explain why we did not observe a significant association between SAMHD1 protein expression and the outcome of MCL patients upon cytarabine-based treatment.

• Authors: Tobias Roider, Xi Wang, Katrin Hüttl, Carsten Müller-Tidow, Wolfram Klapper, Andreas Rosenwald, James Peter Stewart, David Gonzalez de Castro, Peter Dreger, Olivier Hermine, Hanneke C Kluin-Nelemans, Niels Grabe, Martin Dreyling, Christiane Pott, German Ott, Eva Hoster, Sascha Dietrich
• Journal: International journal of cancer (Int J Cancer) Vol. 148 Issue 1 Pg. 150-160 (01 01 2021) ISSN: 1097-0215 [Electronic] United States
• PMID: 32638373 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 UICC.

Chemical References

• Biomarkers, Tumor
• R-CHOP protocol
• Cytarabine
• Oxaliplatin
• Rituximab
• Vincristine
• Doxorubicin
• Cyclophosphamide
• SAM Domain and HD Domain-Containing Protein 1
• SAMHD1 protein, human
• Vidarabine
• fludarabine
• Prednisone

Topics

• Adult
• Age Factors
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Biomarkers, Tumor (genetics)
• Cell Line, Tumor
• Cyclophosphamide (pharmacology, therapeutic use)
• Cytarabine (pharmacology, therapeutic use)
• DNA Mutational Analysis
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• Lymphoma, B-Cell (drug therapy, genetics, pathology)
• Lymphoma, Mantle-Cell (drug therapy, genetics, mortality)
• Male
• Middle Aged
• Mutation
• Oxaliplatin (pharmacology, therapeutic use)
• Prednisone (pharmacology, therapeutic use)
• Primary Cell Culture
• Rituximab (pharmacology, therapeutic use)
• SAM Domain and HD Domain-Containing Protein 1 (genetics)
• Tissue Array Analysis
• Vidarabine (analogs & derivatives, pharmacology, therapeutic use)
• Vincristine (pharmacology, therapeutic use)