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Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission

This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D‐STOP, after a 3‐year follow‐up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Est...

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Autores principales: Kumagai, Takashi, Nakaseko, Chiaki, Nishiwaki, Kaichi, Yoshida, Chikashi, Ohashi, Kazuteru, Takezako, Naoki, Takano, Hina, Kouzai, Yasuji, Murase, Tadashi, Matsue, Kosei, Morita, Satoshi, Sakamoto, Junichi, Wakita, Hisashi, Sakamaki, Hisashi, Inokuchi, Koiti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419041/
https://www.ncbi.nlm.nih.gov/pubmed/32614159
http://dx.doi.org/10.1111/cas.14518
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author Kumagai, Takashi
Nakaseko, Chiaki
Nishiwaki, Kaichi
Yoshida, Chikashi
Ohashi, Kazuteru
Takezako, Naoki
Takano, Hina
Kouzai, Yasuji
Murase, Tadashi
Matsue, Kosei
Morita, Satoshi
Sakamoto, Junichi
Wakita, Hisashi
Sakamaki, Hisashi
Inokuchi, Koiti
author_facet Kumagai, Takashi
Nakaseko, Chiaki
Nishiwaki, Kaichi
Yoshida, Chikashi
Ohashi, Kazuteru
Takezako, Naoki
Takano, Hina
Kouzai, Yasuji
Murase, Tadashi
Matsue, Kosei
Morita, Satoshi
Sakamoto, Junichi
Wakita, Hisashi
Sakamaki, Hisashi
Inokuchi, Koiti
author_sort Kumagai, Takashi
collection PubMed
description This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D‐STOP, after a 3‐year follow‐up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Estimated treatment‐free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7‐74.3] and 59.3% (95% CI: 45.0‐71.0), respectively. CD3(−)CD56(+ )NK, CD16(+)CD56(+ )NK, and CD57(+)CD56(+ )NK large granular lymphocyte (NK‐LGL), CD8(+)CD4(–) cytotoxic T cell, and CD57(+)CD3(+ )T‐LGL cell numbers were relatively elevated throughout the 24‐month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients, these subsets elevated transiently after 12 months, but returned to basal levels after 24‐month consolidation. Therefore, smaller changes in NK/T, particularly the NK subset throughout consolidation, reflected higher TFR rates. TFR rates of those patients exhibiting elevation in CD3(−)CD56(+ )NK >376 cells/μL, CD16(+)CD56(+ )NK > 241 cells/μL, or CD57(+)CD56(+ )NK‐LGL >242 cells/μL during consolidation compared with others were 26.7% (8.3%‐49.6%) vs 78.3% (55.4%‐90.3%), HR 0.032 (0.0027‐0.38; P = .0064), 31.2% (11.4%‐53.6%) vs 85.0% (60.4%‐94.9%), HR 0.039 (0.0031‐0.48; P = .011), or 36.8% (16.5%‐57.5%) vs 77.3% (53.7%‐89.8%), HR 0.21 (0.065‐0.69; P = .010), respectively. Therefore, silent responses of T/NK subsets to dasatinib throughout consolidation were significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, may be immunologically insufficient to maintain TFR. Their decline, subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR, might be immunologically significant. (D‐STOP, NCT01627132).
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spelling pubmed-74190412020-08-12 Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission Kumagai, Takashi Nakaseko, Chiaki Nishiwaki, Kaichi Yoshida, Chikashi Ohashi, Kazuteru Takezako, Naoki Takano, Hina Kouzai, Yasuji Murase, Tadashi Matsue, Kosei Morita, Satoshi Sakamoto, Junichi Wakita, Hisashi Sakamaki, Hisashi Inokuchi, Koiti Cancer Sci Original Articles This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D‐STOP, after a 3‐year follow‐up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Estimated treatment‐free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7‐74.3] and 59.3% (95% CI: 45.0‐71.0), respectively. CD3(−)CD56(+ )NK, CD16(+)CD56(+ )NK, and CD57(+)CD56(+ )NK large granular lymphocyte (NK‐LGL), CD8(+)CD4(–) cytotoxic T cell, and CD57(+)CD3(+ )T‐LGL cell numbers were relatively elevated throughout the 24‐month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients, these subsets elevated transiently after 12 months, but returned to basal levels after 24‐month consolidation. Therefore, smaller changes in NK/T, particularly the NK subset throughout consolidation, reflected higher TFR rates. TFR rates of those patients exhibiting elevation in CD3(−)CD56(+ )NK >376 cells/μL, CD16(+)CD56(+ )NK > 241 cells/μL, or CD57(+)CD56(+ )NK‐LGL >242 cells/μL during consolidation compared with others were 26.7% (8.3%‐49.6%) vs 78.3% (55.4%‐90.3%), HR 0.032 (0.0027‐0.38; P = .0064), 31.2% (11.4%‐53.6%) vs 85.0% (60.4%‐94.9%), HR 0.039 (0.0031‐0.48; P = .011), or 36.8% (16.5%‐57.5%) vs 77.3% (53.7%‐89.8%), HR 0.21 (0.065‐0.69; P = .010), respectively. Therefore, silent responses of T/NK subsets to dasatinib throughout consolidation were significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, may be immunologically insufficient to maintain TFR. Their decline, subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR, might be immunologically significant. (D‐STOP, NCT01627132). John Wiley and Sons Inc. 2020-06-26 2020-08 /pmc/articles/PMC7419041/ /pubmed/32614159 http://dx.doi.org/10.1111/cas.14518 Text en © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Kumagai, Takashi
Nakaseko, Chiaki
Nishiwaki, Kaichi
Yoshida, Chikashi
Ohashi, Kazuteru
Takezako, Naoki
Takano, Hina
Kouzai, Yasuji
Murase, Tadashi
Matsue, Kosei
Morita, Satoshi
Sakamoto, Junichi
Wakita, Hisashi
Sakamaki, Hisashi
Inokuchi, Koiti
Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission
title Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission
title_full Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission
title_fullStr Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission
title_full_unstemmed Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission
title_short Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission
title_sort silent nk/t cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419041/
https://www.ncbi.nlm.nih.gov/pubmed/32614159
http://dx.doi.org/10.1111/cas.14518
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