Page 96 - 2018_11-Haematologica-web

N. Takahaski et al.
results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).
Introduction
Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) that has been shown to be highly efficacious as a first- or second-line treatment for patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase. In patients newly diag- nosed with CML in chronic phase superior rates of deep molecular response (DMR) were achieved with nilotinib in comparison with imatinib, which is a first-generation TKI currently used as the standard treatment for this disease.1-3 In addition, switching to nilotinib after a minimum of 2 years on imatinib led to increased DMR rates compared to remaining on imatinib.4
Recently, treatment-free remission (TFR) has been pro- posed as a goal for CML treatment.5-7 Indeed, prospective trials have indicated that imatinib therapy can be success- fully discontinued in CML patients who have maintained a DMR for at least 2 years.8-10 In these prospective trials, the TFR rate was 43% [95% confidence interval (CI): 33–52%] at 6 months9 and 41% (95% CI: 29–52%) at 12 months in the STIM1 trial,8 while the TWISTER study revealed a TFR rate of 47.1% (95% CI: 31.5–62.7%) at 24 months.10 Moreover, the first TFR study of second-generation TKI, the DADI trial reported by Imagawa et al., showed that second-generation TKI therapy can be successfully discon- tinued.11 In this trial, all patients received dasatinib consol- idation therapy for at least 1 year. The estimated TFR rate was 49% (95% CI: 36–61%) at 6 months.11 On the other hand, the ENESTfreedom study, which is a TFR study fol- lowing frontline nilotinib treatment, required that all patients sustained DMR during the consolidation phase with nilotinib for 1 year. The TFR rate at 48 weeks was 51.6% (95% CI: 44.2–58.9%).12 Although the DMR in the consolidation phase with a second-generation TKI was sustained in both the DADI trial and the ENESTfreedom study, the TFR rate was not superior to those in the previ- ously reported imatinib TFR studies.8-10 Most relapses occurred within 6 months of discontinuing second-genera- tion TKI or imatinib therapy, and there was no disease pro- gression in patients with molecular relapse after discontin- uation.8-12 All patients who relapsed remained sensitive to TKI re-treatment in these TFR studies.8-12
Compared to imatinib, nilotinib may enable a greater proportion of patients with CML in chronic phase to achieve successful TFR if they receive nilotinib consolida- tion therapy for 2 years to sustain DMR; this is the same length of time required to achieve TFR in imatinib stud- ies.8,9 The aim of this STAT2 trial (Stop Tasigna® Trial) was to evaluate the efficacy of 2-year consolidation treatment with nilotinib for achieving successful TFR in patients with chronic phase CML.
Methods
Patients and study design
The eligibility criteria for this multicenter, phase II, single-treat- ment arm, open-label clinical trial included: patients with CML in
chronic phase, age ≥16 years, an Eastern Cooperative Oncology Group performance status of 0–2, and no severe primary organ dysfunction. Patients who had accelerated phase or blast crisis CML, a T315I mutation, or who had received allogeneic hematopoietic stem-cell transplantation were excluded from this study. Patients with a DMR (BCR-ABL1IS ≤0.0032% or a molecu- lar response, MR4.5, defined as a 4.5-log reduction in BCR-ABL1 transcripts according to the international scale], assessed by real- time quantitative polymerase chain reaction (RQ-PCR), under treatment with imatinib or a second-generation TKI following imatinib were eligible for the STAT2 trial. Nilotinib (300 mg) was administered twice daily (600 mg/day) for 2 years in the consoli- dation phase. Patients who maintained a MR4.5 during the 2-year consolidation phase were eligible to enter the TFR phase and cease nilotinib treatment. Molecular recurrence was defined as the loss of a major molecular response (MMR: BCR-ABL1IS ≤0.1%) or confirmed loss of MR4.5 (at two consecutive assessments within 4 weeks) after discontinuing nilotinib, based on criteria used both in the STIM1 trial8 and the TWISTER study.9 Patients with molec- ular recurrence during the TFR phase restarted nilotinib 300 mg twice daily, thus entering the re-treatment phase.
Endpoints and assessments
The primary endpoint of the STAT2 trial was the 12-month TFR rate after discontinuing nilotinib treatment; secondary end- points were the 24-month TFR rate after discontinuing nilotinib treatment, the 3-year treatment-free survival, and the MR4.5 rate and time to MR4.5 achieved by nilotinib in the re-treatment phase. Safety profiles, especially vascular adverse events in the consoli- dation phase or symptoms related to TKI withdrawal syndrome in the TFR phase, were evaluated. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
MR was evaluated by BCR-ABL1IS RQ-PCR analysis upon study entry and every 3 months thereafter in the consolidation phase. After discontinuing nilotinib in the TFR phase, molecular recur- rence was monitored by monthly BCR-ABL1IS RQ-PCR testing in the first year, bi-monthly testing in the second year, then every 3 months thereafter. In the re-treatment phase, BCR-ABL1IS was monitored by monthly RQ-PCR testing. The study protocol was terminated when MR4.5 was re-achieved, or when BCR-ABL1IS increased twice consecutively in the re-treatment phase.
BCR-ABL1IS RQ-PCR was performed using a Molecular MD One-Step qRT-PCR BCR-ABL kit (BML Inc., Kawagoe, Japan). To validate BCR-ABL1 amplification, ABL1 was used as an internal control. A MMR was defined as a 3-log reduction in the BCR- ABL1 transcript according to the international scale (BCR-ABL1IS ≤0.1%), MR4.5 was defined as a 4.5-log reduction in the BCR-ABL1 transcript (BCR-ABL1IS ≤0.0032%), and MR5 was defined as a 5- log reduction in the BCR-ABL1 transcript (BCR-ABL1IS ≤0.001%), as described above. Undetectable molecular residual disease was defined as undetectable BCR-ABL1 transcript with MR5 (UMRD with MR5). At least 100,000 control genes (ABL1) were required for a sample to be considered as adequate.
Ethics
Forty-six institutions participated in this study. The study was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from each par-
1836
haematologica | 2018; 103(11)