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TFR after 2-year nilotinib consolidation
tained DMR without loss of MR4.5 was confirmed by reg- ular BCR-ABL1IS RQ-PCR testing for 2 years.
Among 78 patients who entered the TFR phase, 53 remained in TFR in the first 12 months; the 12-month TFR primary endpoint was, therefore, 67.9% (95% CI: 56.4– 78.1%). Although the TFR rate is higher than that in the STIM1 trial (41%; 95% CI: 29–52%), it is difficult to com- pare this result with those in other TFR studies with vary- ing designs. Among 29 patients with a molecular recur- rence, MR4.5 was rapidly regained in 25 patients who were readministered nilotinib, and no patients progressed to accelerated phase or blast crisis CML in this study. Thus, our findings suggest that nilotinib therapy may allow the majority of patients to achieve successful TFR after discon- tinuation of nilotinib; this result is comparable to those of previous TFR studies with imatinib.8-10
In this study, the identified predictive factor for success- ful 12-month TFR was UMRD with MR5 before discontin- uation of nilotinib. In the EURO-SKI trial, there were no differences in MMR status at 6 months after treatment stop between depths of molecular response (MR4.5 versus no MR4.5).15 However, our finding suggests that a deeper MR favors successful achievement of TFR in CML patients, which is consistent with data from previous studies.16,17 Among four patients without TFR in the late TFR phase, in whom MR4.5 loss occurred at 16, 16, 17, and 20 months, three patients had MRD before entering the TFR phase. It is difficult to determine the quantity of BCR-ABL1 mRNA below MR4.5/MR5 because of the sensitivity of IS-RQ- PCR.18 However, UMRD with MR5 before TFR is one of the minimum requirements for TFR and the sustained duration of DMR might be a surrogate marker for the mag- nitude of the MR or the eradication of MRD during TKI treatment.19,20 Meanwhile, 1-year consolidation with either dasatinib or nilotinib, which are both second-generation TKI, was proposed in the DADI trial11 and the ENEStop study,21 respectively. Although the 1-year consolidation enabled identification of enrolled patients who had sus- tained MR4.5 and were eligible to stop treatment,21 it is still unknown whether 1 year of consolidation with a second- generation TKI is sufficient to achieve DMR/UMRD below MR4.5/MR5 for TFR.
Of the 96 patients in the safety analysis set, 78 achieved a sustained MR4.5 on nilotinib consolidation and entered the TFR phase, including 33 patients (42.3%) who were treated with nilotinib following imatinib prior to enroll- ment in STAT2. Most patients (n=29, 72.5%) were switched from imatinib to nilotinib at the patients’ request prior to the trial, primarily to obtain a deeper and more sus- tained MR, despite not having imatinib resistance or intol- erance. Similarly, the ENESTcmr study showed that a sig- nificant minority of patients who continued with imatinib therapy did later achieve DMR.4 In the subanalysis evalu- ating prior TKI exposure, the 12-month TFR was almost identical between patients treated with only imatinib (62.5%) and those treated with nilotinib following ima- tinib (69.7%). This suggests that, regardless of the specific TKI, DMR is the first step for achieving successful TFR in patients with CML.
The proportion of natural killer cells in peripheral blood has been reported as a predictive marker, which might be related to a previously reported immuno-oncological effect.22,23 However, it was beyond the remit of this trial to
identify the significance of either the activity or the propor- tion or natural killer cells in peripheral blood.
TKI withdrawal syndrome is the most common muscu- loskeletal pain-related adverse event in imatinib TFR stud- ies, being first reported in the EURO-SKI trial.24 TKI with- drawal syndrome was detected in 11 patients in the TFR phase in this study. Rousselot et al. suggested that pro- longed inhibition of c-Kit signaling by imatinib may mod- ulate nociceptive sensitivity, and that the sudden discontin- uation of imatinib may reverse this phenomenon.25 As nilo- tinib targets the same tyrosine kinases as imatinib, includ- ing BCR-ABL kinase and c-Kit, albeit with differing poten- cies, nilotinib may also result in TKI withdrawal syndrome via the same mechanisms. Although TKI withdrawal syn- drome was reported as an independent predictive factor for successful TFR by a Korean group,26 there was no sig- nificant relationship between TKI withdrawal syndrome and TFR identified in this nilotinib TFR study. However, because of the limited number of events during the TFR phase, univariate analysis is definitely limited in identify- ing a significant relationship between TKI withdrawal syn- drome and TFR. Further examination with larger numbers of patients will be necessary to identify biomarkers for suc- cessful TFR.
Although the safety of nilotinib is generally regarded as being acceptable, vascular adverse events are an important concern in nilotinib therapy. The frequency of such events in this study was similar to the frequency in the nilotinib 300 mg twice daily arm in the ENESTnd trial.3 The inci- dence of vascular adverse events in patients treated with nilotinib 300 mg twice daily was estimated to be 2.8 per 100 patient-years in a meta-analysis.27 In the STAT2 trial, all patients with vascular adverse events, except one, either recovered or improved with intervention or supportive care after nilotinib discontinuation. Moreover, three patients achieved TFR after the occurrence of vascular adverse events during the TFR phase of STAT2. Since four of the six patients had at least one traditional risk factor for vascular adverse events, patients should be carefully screened for risk factors prior to nilotinib administration, with appropriate treatment or supportive care of comor- bidities to avoid the development of vascular adverse events. After considering the risk of vascular adverse events in patients given consolidation with nilotinib, we conclude that this therapeutic agent can be safely adminis- tered to achieve a successful TFR in CML patients.
In conclusion, although previous evidence regarding TFR after discontinuation of second-line nilotinib therapy is limited, our study suggests that a 2-year consolidation peri- od of nilotinib therapy can safely induce higher TFR rates in patients with MR4.5. Thus, 2-year consolidation therapy with this agent may be an effective strategy for achieving TFR in large numbers of CML patients.
Acknowledgments
This study was supported by research funding from Novartis Pharmaceuticals to NT. The authors would like to thank all study participants and their families, and the study investigators at partic- ipating study sites. We also thank Professor Takuhiro Yamaguchi for some advice as a biostatician, the STAT data center (EPS, Co.) for monitoring the clinical trial, and Dr. Toshihiro Miyamoto, Dr. Yosuke Minami, and Dr. Hidetaka Niitsu for their cooperation as members of the data and safety monitoring committee.
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