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Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88(L265P) mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To i...

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Autores principales: Wang, Yingjun, Gali, Vasantha Lakshmi, Xu-Monette, Zijun Y., Sano, Dahlia, Thomas, Sheeba K., Weber, Donna M., Zhu, Feng, Fang, Xiaosheng, Deng, Manman, Zhang, Mingzhi, Hagemeister, Fredrick B., Li, Yong, Orlowski, Robert Z., Lee, Hans Chulhee, Young, Ken H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985670/
https://www.ncbi.nlm.nih.gov/pubmed/33735664
http://dx.doi.org/10.1016/j.neo.2021.02.002
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author Wang, Yingjun
Gali, Vasantha Lakshmi
Xu-Monette, Zijun Y.
Sano, Dahlia
Thomas, Sheeba K.
Weber, Donna M.
Zhu, Feng
Fang, Xiaosheng
Deng, Manman
Zhang, Mingzhi
Hagemeister, Fredrick B.
Li, Yong
Orlowski, Robert Z.
Lee, Hans Chulhee
Young, Ken H.
author_facet Wang, Yingjun
Gali, Vasantha Lakshmi
Xu-Monette, Zijun Y.
Sano, Dahlia
Thomas, Sheeba K.
Weber, Donna M.
Zhu, Feng
Fang, Xiaosheng
Deng, Manman
Zhang, Mingzhi
Hagemeister, Fredrick B.
Li, Yong
Orlowski, Robert Z.
Lee, Hans Chulhee
Young, Ken H.
author_sort Wang, Yingjun
collection PubMed
description Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88(L265P) mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To investigate the clinical impact of genetic alterations in WM, we assembled a large cohort of 219 WMs and 12 LPLs dividing into two subcohorts: a training cohort, patients sequenced by a same targeted 29-gene next-generation sequencing (NGS) panel, and a validation cohort, patients sequenced by allele specific-PCR or other targeted NGS panels. In both training and validation subcohorts, MYD88(L265P) and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4(NS/MS)), cytogenetic complex karyotypes, and a family history of lymphoma/leukemia in first-degree relatives were associated with significantly worse clinical outcomes only or more in the validation subcohort. We further investigated the efficacy of various treatments and interaction with genetic factors in the entire cohort. Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival. Ibrutinib/BTKi showed potential benefit in relapsed/refractory patients and patients without CXCR4(NS/MS) including those with TP53 mutations. In conclusion, genetic testing for MYD88(L265P), TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic.
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spelling pubmed-79856702021-04-01 Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia Wang, Yingjun Gali, Vasantha Lakshmi Xu-Monette, Zijun Y. Sano, Dahlia Thomas, Sheeba K. Weber, Donna M. Zhu, Feng Fang, Xiaosheng Deng, Manman Zhang, Mingzhi Hagemeister, Fredrick B. Li, Yong Orlowski, Robert Z. Lee, Hans Chulhee Young, Ken H. Neoplasia Original Research Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88(L265P) mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To investigate the clinical impact of genetic alterations in WM, we assembled a large cohort of 219 WMs and 12 LPLs dividing into two subcohorts: a training cohort, patients sequenced by a same targeted 29-gene next-generation sequencing (NGS) panel, and a validation cohort, patients sequenced by allele specific-PCR or other targeted NGS panels. In both training and validation subcohorts, MYD88(L265P) and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4(NS/MS)), cytogenetic complex karyotypes, and a family history of lymphoma/leukemia in first-degree relatives were associated with significantly worse clinical outcomes only or more in the validation subcohort. We further investigated the efficacy of various treatments and interaction with genetic factors in the entire cohort. Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival. Ibrutinib/BTKi showed potential benefit in relapsed/refractory patients and patients without CXCR4(NS/MS) including those with TP53 mutations. In conclusion, genetic testing for MYD88(L265P), TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic. Neoplasia Press 2021-03-15 /pmc/articles/PMC7985670/ /pubmed/33735664 http://dx.doi.org/10.1016/j.neo.2021.02.002 Text en © 2021 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Wang, Yingjun
Gali, Vasantha Lakshmi
Xu-Monette, Zijun Y.
Sano, Dahlia
Thomas, Sheeba K.
Weber, Donna M.
Zhu, Feng
Fang, Xiaosheng
Deng, Manman
Zhang, Mingzhi
Hagemeister, Fredrick B.
Li, Yong
Orlowski, Robert Z.
Lee, Hans Chulhee
Young, Ken H.
Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia
title Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia
title_full Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia
title_fullStr Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia
title_full_unstemmed Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia
title_short Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia
title_sort molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for waldenström macroglobulinemia
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985670/
https://www.ncbi.nlm.nih.gov/pubmed/33735664
http://dx.doi.org/10.1016/j.neo.2021.02.002
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