Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial

Abstract

The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR4.5 underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR4.5. Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR4.5. The Kaplan–Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1IS levels at 48 weeks of TFR and stable MR4.5 response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.

Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

“…Most patients requiring nilotinib retreatment rapidly regained MMR, MR4.0, or MR4.5 (34,35). The longterm follow-up results showed a 5-year TFR rate of 42.9% (36), comparable to the results of the ENESTfreedom study (31). These results illustrate the long-term durability of TFR in patients with first or second-line nilotinib.…”

“…After stopping nilotinib, 98 (51.6%), and 93 patients (48.9%) remained in MMR at 48 and 96 weeks, respectively (29,30). At the 5-year data cut-off, 81/190 patients (42.6%) were still in sustained TFR, while 90/91 patients (98.9%) regained MMR after restarting nilotinib treatment (31).…”

“…In the ENSTnd study, with ≥10 years follow-up in newly diagnosed CML patients, the estimated cumulative rates of TFR eligibility [estimated using ENESTfreedom criteria (31)] with nilotinib 300-mg twice-daily, nilotinib 400-mg twice-daily, and imatinib, respectively, at 5 years were 20.9%, 20.6%, and 11.0% and 10 years were 48.6%, 47.3%, and 29.7% (44). The JALSG CML212 study compared the achievement of MR4.5 in newly diagnosed CML patients between nilotinib and dasatinib (45).…”

Which Tyrosine Kinase Inhibitors Should Be Selected as the First-Line Treatment for Chronic Myelogenous Leukemia in Chronic Phase?

“…In the According to Stop Imatinib (A-STIM) study with the re-initiated criterion defined as a loss of MMR [46], the TFR rate was 61% at 36 months with a median period from imatinib initiation to discontinuation of 79 months. In the ENEST freedom study with the re-initiated criterion defined as a loss of MMR [34,47], the TFR rate was 51.6% at 48 weeks and 42.6% at 5-year follow-up, with a median period from nilotinib initiation to discontinuation of 43.5 months. In the first-line dasatinib discontinue (DADI) study with the re-initiated criterion defined as a loss of DMR (BCR-ABL1 IS ≤ 0.0069%) [48], the TFR rate was 55.2% at 1-year follow-up with a median period from dasatinib initiation to discontinuation of 40.2 months.…”

Combination Therapies in Chronic Myeloid Leukemia for Potential Treatment-Free Remission: Focus on Leukemia Stem Cells and Immune Modulation

“…To date, the treatment regimens for over 3,000 CML patients reaching a deep molecular response (DMR) has been halted. Thus far, about 50% of patients qualifying for TKI discontinuation have shown sustained TFRs while relapse patients remained sensitive to TKI re-treatment and did not develop BCR-ABL mutations (36). However, it remains poorly understood why these patients relapse within six months of treatment withdrawal (28,29,37).…”