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TFR after 2-year nilotinib consolidation
ticipant before enrollment. The study was approved by the Ethics Committee of Akita University (N. 786) and by all institutional ethic committees that participated in this study. The study was registered with UMIN-CTR (UMIN000005904).
Results
Patients and treatment
Between July 2011 and December 2012, 96 patients who achieved MR4.5 were enrolled in the STAT2 trial. These patients started treatment in the consolidation phase and were defined as the safety analysis set. Seventy-eight patients entered the TFR phase and were analyzed as the full analysis set for TFR. The baseline demographics of the safety and full analysis sets are shown in Table 1.
The median age in the safety analysis set was 55.5 years (range, 20–83). Thirty-six (37.5%) patients were female and 16 (16.7%) patients had been administered interferon- a before TKI treatment. Based on TKI therapy prior to entry into the current study, patients were classified into three groups: 50 patients (52.1%) who had received only imatinib (‘imatinib only’), 40 patients (41.7%) who had received nilotinib following imatinib (‘nilotinib following imatinib’, including patients from the STAT1 study), and six patients (6.3%) who had received other therapy
Table 1. Baseline demographics of all patients included in the study.
(‘other’). The STAT1 study (Switch to Tasigna® Trial) is a clinical trial to evaluate the efficacy of 2-year consolidation treatment with nilotinib for achieving DMR in chronic phase CML patients with MMR, recently reported by our study group.13 Among 40 patients in STAT2 treated by nilo- tinib following imatinib, 21 patients joined this study from STAT1 since they achieved MR4.5 in the STAT1 study. The reasons for switching from imatinib to nilotinib in the 40 patients included imatinib resistance in 7.5%, imatinib intolerance in 20.0%, and upon patients’ request in 72.5% (Online Supplementary Table S1). The median duration of imatinib or nilotinib treatment was 73.6 months (range, 11–126) or 7.7 months (range, 0–35), respectively. All patients showed MR4.5 at the time of entry into the study, and the median time to MR4.5 on TKI therapy was 48.1 months (range, 6–128). Among 96 patients in the safety analysis set, 70 (73.7%) achieved the MR4.5 by prior ima- tinib treatment and 25 (26.3%) by prior nilotinib treat- ment. Comparing patients in different subgroups based on prior TKI therapy (‘imatinib only’ versus ‘nilotinib follow- ing imatinib’), there were no significant differences except in the duration of imatinib therapy and time to MR4.5 (Online Supplementary Table S1). Of these, 40 patients in the ‘imatinib only’ group, 33 patients in the ‘nilotinib follow- ing imatinib’ group, and five patients in the ‘other’ group entered the TFR phase.
Nilotinib was taken twice daily (600 mg/day) for 2 years in the consolidation phase (median dose intensity, 600 mg/day). Patients’ outcomes at the end of the consolida- tion phase at 24 months are summarized in Table 2. Among the 96 patients in the safety analysis set, 18 (18.8%) discontinued the study treatment. The most fre- quent reason for discontinuation was adverse events; dis- ease progression was not observed in any of the patients.
Treatment-free remission after nilotinib discontinuation
Among the 96 patients in the safety analysis set, 78 with sustained MR4.5 during the consolidation phase were eligi- ble for nilotinib discontinuation in the TFR phase. The median follow-up of patients in the TFR phase was 35.4 months (range, 1.8–44.2). Among the 78 patients, 53 remained in the TFR phase without a confirmed loss of MR4.5 in the first 12 months; the 12-month TFR primary endpoint was 67.9% (95% CI: 56.4–78.1%), exceeding the targeted 40% success rate. The 24-month TFR rate was 62.8% (95% CI: 51.1–73.5%). The Kaplan-Meier curve for
Table 2. Patients’ outcomes and dose intensity at the end of the 2-year nilotinib consolidation phase.
Age (years)
Sex Male Female
Sokal risk Low
SAS (n=96) before entering
the consolidation phase
55.5 (20–83)
60 (62.5)
36 (37.5)
56 (59.6) 20 (21.3) 18 (19.1)
16 (16.7)
50 (52.1) 40 (41.7) 6 (6.3)
75.6 (8–131)
73.6 (11–126) 7.7 (0–35) 5.6 (1–63) 14.5 (3–103) 48.1 (6–128)
70 (73.7)
25 (26.3) 96 (100)
29 (30.2)
FAS (n=78) before entering the TFR phase
57.0 (22–85)
45 (57.7)
33 (42.3)
44 (57.1) 17 (22.1) 16 (20.8)
12 (15.4)
40 (51.3) 33 (42.3) 5 (6.4)
99.0 (25–156)
74.9 (11–125) 25.3 (23–60) 5.5 (1–63) 14.2 (3–103) 47.9 (6–128)
58 (75.3)
19 (25.7) 78 (100)
41 (52.6)
Intermediate High
Prior interferon-a
Prior TKI before the trial Only imatinib
Nilotinib following imatinib Other
Total duration of TKI
treatment (months)
Duration of imatinib (months)
Duration of nilotinib (months)
Time to CCyR (months)
Time to MMR (months)
Time to MR4.5 (months)
Treatment at achieving MR4.5 Imatinib
Nilotinib
Molecular status MR4.5
UMRD with MR5
Dose reduction
Interruption
Treatment discontinuation Adverse events Confirmed loss of MR4.5 Withdrawal of consent Lost to follow-up
Other
Duration of nilotinib (days)
Dose intensity of nilotinib (mg/day)
SAS (n=96)
14 (14.6)
13 (13.5)
18 (18.8) 6 (6.3) 3 (3.1) 4 (4.2) 1 (1.5) 6 (6.3)
737.5 (14–859)
600 (204.6–674.5)
Data are given as median (range) or n (%). SAS: safety analysis set; FAS: full analysis set; TFR: treatment free remission; TKI: tyrosine kinase inhibitor; CCyR: complete cyto- genetic response; MMR: major molecular response; MR4.5: 4.5-log reduction of BCR- ABL1 transcripts by IS-PCR; UMRD: undetectable BCR-ABL1 transcript; MR5: 5-log reduction of BCR-ABL1 transcripts by IS-PCR.
Data are given as n (%) or median (range). SAS, safety analysis set; MR4.5, 4.5-log reduc- tion of BCR-ABL1 transcripts by IS-PCR.
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