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N. Takahaski et al.
chronic kidney disease). Percutaneous intervention was performed in three patients with ischemic heart disease. All patients, except one, with vascular adverse events recovered or improved. Although three patients with vas- cular adverse events stopped nilotinib treatment and switched to another TKI, three patients continued the study treatment and entered the TFR phase, eventually achieving successful TFR. No patients developed new vas- cular adverse events during the TFR phase.
Arthralgia was reported only in the TFR phase (Online Supplementary Table S2). Eleven patients reported muscu- loskeletal pain events during the early phase of the TFR; these events were categorized as TKI withdrawal syn- drome. The characteristics of the patients with TKI with- drawal syndrome are described in Table 5. The median time of onset of the TKI withdrawal syndrome in the TFR phase was 1 month (range, 0–6). All patients recovered completely with or without treatment. Of the 11 patients with the syndrome, eight (73%) maintained TFR at 12 months and remained in remission throughout the 36- month follow-up period. There were no significant differ- ences in the TFR survival curves between subgroups based on TKI withdrawal syndrome.
Discussion
The design of the STAT2 trial resembled that of the STIM18,9 and TWISTER trials,10 with the aim of adminis- tering a TKI during a 2-year consolidation phase to obtain a sustained DMR before TKI discontinuation. In this trial, in contrast to the aforementioned studies, imatinib was replaced with nilotinib as the consolidation TKI therapy. However, the assessment of BCR-ABL1 and the definition of molecular recurrence in this trial are identical to those in the aforementioned studies.8-10 Nilotinib was adminis- tered instead of imatinib because previous studies had indicated that nilotinib could induce DMR in a greater number of patients than imatinib,1-3 thereby potentially increasing the number of patients who achieve successful TFR. The 2-year period of consolidation therapy in this study was selected as the STIM18,9 and TWISTER10 trials required 2 years of sustained DMR before stopping ima- tinib therapy. Additionally, our retrospective study revealed that a DMR duration of at least 2 years was a significant predictive factor for successful TFR in Japanese CML patients.14 Therefore, the treatment duration for this trial involved a consolidation phase of 2 years, and sus-
Table 4. Treatment-related vascular adverse events in the consolidation phase.
Age Sex Duration (decade) (M/F) of imatinib
(months)
40s M 99.4
70s F 41.5 70s F 87.2 40s F 70.3
80s M 45.7
70s M 124.6
Duration of nilotinib (months)
22.6
22.4 52.6 10.5
24.0
17.9
Traditional risk factors
Hypertension
None Hypertension None
Hypertension
DM, CKD
Vascular CTCAE adverse grade
events
CI 2
ACS 3 AP 3 CI 2
CI 2
ACS 3
Outcome
Improvement
Improvement by PCI Improvement by PCI Recovery
No change
Recovery by PCI
Treatment outcome
Nilotinib discontinuation, switched TKI
Entered TFR phase
Entered TFR phase
Nilotinib discontinuation,
switched TKI
Entered TFR phase
Nilotinib discontinuation,
switched TKI
M: male; F: female; CTCAE: Common Terminology Criteria for Adverse Events; DM: diabetes mellitus; CKD: chronic kidney disease; CI: cerebral infarction; AP: angina pectoris; ACS: acute coronary syndrome; PCI: percutaneous intervention; TFR: treatment-free remission; TRI: tyrosine kinase inhibitor.
Table 5. Tyrosine kinase inhibitor withdrawal syndrome in the treatment-free remission phase.
Age (decade)
50s
50s 50s 30s 60s 30s 50s 50s 40s 50s
60s
Duration of TKI (months)
103
94 120 140 139 99 135
Muscle Time CTCAE pain of WS grade
before DC (months)
WS therapy
None
NSAID
NSAID
NSAID 7 No
Prednisolone 19 No None 13 Yes Prednisolone 26 Yes
None 17 No None 14 Yes
Sex (M/F)
F
F
F
F
F
M
F
F
M
M
Yes
No
No 51 No
0 1
1 2 1 2 1 1
Localization of symptoms
Myalgia, whole body
Arms
Hands, wrists, arms, shoulders, legs
Hands,elbows
Hands, feet
Hands, wrists, shoulders, lower back, legs
Shoulders, legs, knees
Hands, wrists, elbows, arms
Hands, wrists, elbows, arms
Duration of WS
5
TFR at 12 months (months)
Yes
107 124
10 5
Yes Yes
F 88
No 1 3 Yes 1 1 No 2 2 No 3 1 No 3 1 No 5 2 No 6 2
Hands Prednisolone 15 Yes
Hands, wrists, elbows, lower back NSAID 11 Yes
M: male; F: female; TKI: tyrosine kinase inhibitor; DC: discontinuation of nilotinib; WS: withdrawal syndrome; CTCAE: Common Terminology Criteria for Adverse Events (for the highest grade in the TFR phase); TFR: treatment-free remission; NSAID: non-steroidal anti-inflammatory drugs.
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