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

Abstract

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).

Keywords: CML; NK; TKI; dasatinib; stop.

Conflict of interest statement

TK received honoraria from Bristol‐Myers Squibb, Novartis, Pfizer, and Otsuka pharmacology. CN received honoraria from Bristol‐Myers Squibb, Pfizer, and Novartis, and grants from Bristol‐Myers Squibb and Pfizer. KN received the research funding from Novartis. CY received honoraria and Speakers Bureau from Bristol‐Myers Squibb, Pfizer, and honoraria, Speakers Bureau, and grants from Otsuka. KM received honoraria from Celgene. SM received honoraria from Bristol‐Myers Squibb. JS received remuneration from Yakult Honsha Co. Ltd. IK received research grants from Bristol‐Myers Squibb, and honoraria from Bristol‐Myers Squibb, Novartis, Celgene, and Pfizer.

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1

Estimated treatment‐free survival (TFS) in the D‐STOP trial. Estimated TFS of patients who discontinued dasatinib (Y‐axis) and the duration (mo) of discontinuation (X‐axis). Dotted line, 95% confidence interval (CI)

Figure 2

Changes in the numbers of total lymphocytes, natural killer (NK) cell subsets, and T cell subsets during consolidation therapy with dasatinib after attaining a deep molecular response (DMR). In all figures, the solid line indicates successful (S) patients who attained successful discontinuation without molecular relapse for >12 mo; the dotted line denotes failed (F) patients who relapsed molecularly within 12 mo after discontinuation. Data are presented as averages ± standard errors (SE) as the graphs and data numbers described under the graphs. The X‐axis indicates the duration of consolidation (mo). The following data are presented on the Y‐axis during consolidation (P‐values were presented to compare the data to the baseline before consolidation). A, Numbers of the total lymphocytes in S and F patients. B, Increased numbers of CD3–CD56+ NK cells compared with the baseline before consolidation. C, Increased numbers of CD16+CD56+ NK cells compared with the baseline before consolidation. D, Increased numbers of CD57+CD56+ NK‐LGL (large granular lymphocyte) cells compared with the baseline before consolidation. E, Increased numbers of CD8+CD4– cytotoxic T cells compared with the baseline before consolidation. F, Increased numbers of CD57+CD3+ T‐LGL cells compared with the baseline before consolidation. G, Increased numbers of CD4+CD8– helper T cells compared with the baseline before consolidation. H, Increased numbers of CD4+CD25+CD127low Tregs compared with the baseline before consolidation

Figure 3

Estimated treatment‐free survival (TFS) according to the increase in the cell number of each NK cell subset during consolidation. TFS curves in patients with the higher or lower counts of each NK cell subsets. For the following comparative Kaplan‐Meier curves, the cutoff level was determined using a receiver‐operating characteristic (ROC) curve analysis as described in the Materials and methods section. A, TFS rates of patients with CD3–CD56+ NK cell counts > +376 cells or ≤ +376 cells at the end of consolidation, compared with the baseline before consolidation. B, TFS rates of patients with CD16+CD56+ NK cell counts > +241 cells or ≤ +241 cells at the end of consolidation, compared with the baseline before consolidation. C, TFS rates of patients with CD57+CD56+ NK‐LGL cell counts > +242 cells or ≤ +242 cells at the end of consolidation, compared with the baseline before consolidation. D, TFS rates of patients with CD8+CD4– cytotoxic T cell counts > +212 cells or ≤ +212 cells at the end of consolidation, compared with the baseline before consolidation

Figure 4

The estimated treatment‐free survival (TFS) according to the increase in the cell number of each NK cell subset during consolidation. TFS curves were described as shown in Figure 3. TFS rates with CD3–CD56+ NK cell counts > +376 cells or ≤ +376 cells at the end of consolidation compared with the baseline before consolidation in patients who had taken imatinib (imatinib → dasatinib) (A) or dasatinib (dasatinib → dasatinib) before consolidation (B). TFS rates with CD57+CD56+ NK‐LGL cell counts > +242 cells or ≤ +242 cells at the end of consolidation compared with the baseline before consolidation in patients who had taken imatinib (imatinib → dasatinib) (C) or dasatinib (dasatinib → dasatinib) before consolidation (D). Data of patients who achieved DMR by dasatinib after imatinib intolerance or resistance before consolidation were shown (E, F). As described in Figure 2, the solid line and dotted line indicate successful (S) without molecular relapse ≤ 12 mo and failed (F) patients with molecular relapse ≤ 12 mo, respectively. Data are presented as averages (± standard errors). The X‐axis indicates the duration of consolidation (mo). The following data are presented on the Y‐axis during consolidation (P‐values were presented to compare the data to the baseline before consolidation): E, number of CD3‐CD56+NK cells. F, relative increase (%) in number of CD3–CD56+ NK cells compared with the baseline before consolidation