Analyses of Predictors of Durable Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase Following Frontline or Second-Line Nilotinib

Introduction: Some patients with chronic myeloid leukemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) with tyrosine kinase inhibitors (TKIs) can discontinue therapy and achieve treatment-free remission (TFR). Thus far, no consistent variables that predict TFR have been identified. In long-term follow-up of patients who attempted TFR following front- or second-line nilotinib in the ENESTfreedom and ENESTop TFR studies, respectively, 192-week TFR rates were 44.2% (ENESTfreedom) and 46.0% (ENESTop), and adverse event rates tended to decrease over time during TFR. Previous analyses in ENESTfreedom suggested that lower Sokal risk score and consistent MR^4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [IS]) in the consolidation phase were associated with maintaining TFR, whereas in ENESTop, a longer time in MR^4.5 was associated with maintaining TFR. We sought to identify clinical predictors of a durable TFR by analyzing pooled data from ENESTfreedom and ENESTop.

Methods: In ENESTfreedom, patients with MR^4.5 and ≥ 2 years of frontline nilotinib were enrolled and entered a 1-year nilotinib consolidation phase. Those who maintained a DMR in 4 quarterly assessments (MR^4.5 in the last assessment, ≤ 2 assessments between MR⁴ [BCR-ABL1^IS ≤ 0.01%] and MR^4.5, and no assessments worse than MR⁴) could enter the TFR phase to attempt TFR. Patients were required to restart nilotinib upon loss of major MR (MMR [BCR-ABL1^IS ≤ 0.1%]).

In ENESTop, patients with > 4 weeks of imatinib followed by ≥ 2 years of nilotinib (≥ 3 years of TKI therapy overall) who achieved MR^4.5 on nilotinib were enrolled and entered a 1-year nilotinib consolidation phase. Those without a confirmed loss of MR^4.5 during the consolidation phase could enter the TFR phase. Patients were required to restart nilotinib upon loss of MMR or confirmed loss of MR⁴.

For the current analysis, data from all patients who entered the TFR phases of ENESTfreedom (n = 190) and ENESTop (n = 126) were pooled, and univariate and multivariate analyses were conducted to identify predictors of a durable TFR (defined for these analyses as remaining in the TFR phase with MR^4.5 at 24 weeks after treatment stop [as the majority of molecular relapses occur by week 24]). Age, sex, time since MR^4.5 achievement until TFR phase entry, and duration of nilotinib prior to TFR phase entry were assessed as potential predictive factors. All variables other than sex were considered to be continuous. Additionally, receiver operating characteristic (ROC) curve analyses (Youden indices) were conducted separately for each trial to further investigate age, time since MR^4.5 achievement until TFR phase entry, and duration of nilotinib prior to TFR phase entry as potential predictors of durable TFR.

Results: In ENESTfreedom and ENESTop, 104/190 (54.7%) and 76/126 (60.3%) patients, respectively, remained in the TFR phase with MR^4.5 at 24 weeks after TFR phase entry. Thus, in the pooled analysis of both studies, a total of 180/316 patients (57.0%) remained in the TFR phase with MR^4.5 at 24 weeks. In the univariate analysis of pooled data, time since MR^4.5 achievement until TFR phase entry and duration of nilotinib prior to TFR phase entry were significantly associated with durable TFR at 24 weeks (Table). However, in the multivariate analysis of the pooled data, duration of nilotinib prior to TFR phase entry was the only significant predictor. An increase of 1 month in the duration of nilotinib treatment was associated with an increase of 3.6% (95% CI, 1.5%-5.8%) in the odds of durable TFR at week 24.

In the ROC curve analysis of patients who attempted TFR in ENESTfreedom, statistically significant results were not found for any of the assessed factors, including duration of nilotinib prior to TFR phase. In ENESTop, statistical significance was found for time since MR^4.5 achievement until TFR phase entry (P = .0165) and duration of nilotinib prior to TFR phase entry (P = .0007) but not for age.

Conclusions: Pooled analyses from ENESTfreedom and ENESTop suggest that durable TFR at 24 weeks following nilotinib stop was associated with duration of nilotinib prior to TFR, although this effect seems to be driven by the results of the ENESTop trial, in which both time since achievement of MR^4.5 and duration of nilotinib were identified as key factors in an increased likelihood of durable TFR at 24 weeks. These results will help guide physicians with patients who are considering attempting TFR.

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