Full Treatment-Free Remission Outcome in Patients with Chronic Myeloid Leukemia in Chronic Phase Following One Year of Nilotinib De-Escalation: 96-Week Update of Dante Study

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is achievable and recommended for patients (pts) in sustained deep molecular response (DMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment while maintaining responses. Studies investigating TKI de-escalation before TFR are mainly in imatinib-treated CML chronic phase (CP) pts and suggest that this stepwise approach is feasible. Although nilotinib (NIL) is the first and only TKI approved for stopping therapy, nilotinib-based TFR optimization strategy has not been formally studied. Our phase II, single-arm, prospective, multicenter DANTE study (NCT03874858) aims to shed light on frontline NIL de-escalation in terms of full treatment-free remission (FTFR) (primary endpoint) and TFR rate (secondary endpoint) 96 weeks after the start of consolidation in CML-CP Italian patients. Our previously analysis on 40 pts with sustained DMR who entered in the TFR phase showed that approximately 68% of pts remained disease-free 1 year after stopping NIL ¹. Here we present the data of 89 patients who successfully completed NIL de-escalation and at least 1 year of TFR.

Methods: Adults patients with CML-CP treated with NIL 300 mg twice daily (bid) in first line for ≥3 years who achieved sustained DMR for ≥1 year (≥MR 4.0; BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sustained DMR entered TFR phase and NIL was discontinued. Patients with major molecular response (MMR [BCR-ABL ≤0.1% IS]) but without sustained DMR continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96 and then every 3 months. Here we report updated results collected until the cut-off date of 8th February 2023, when all patients who entered the TFR phase had completed at least one year of TFR or switched to full-dose phase or entered in survival follow-up or discontinued the study. The primary endpoint of the study is FTFR, defined as the percentage of patients (in both TFR phase and NIL half-dose) in MMR or better at week 96.

Results:Overall, 113 pts were screened and 107 entered in consolidation phase. The baseline characteristics and the clinical outcome of the 107 patients are shown in Tab 1. Specifically, 98/107 (92%) completed the consolidation phase, while 9 pts discontinued permanently (2 due to loss of MMR, 3 due to adverse events (AEs) and 4 due to patient decision). Noteworthy, 89/107 (83%) with sustained DMR entered in the TFR phase, while 9 pts maintained MMR but not sustained DMR (7 entered in NIL half dose follow-up period and were in FTFR at 96 weeks, while 2 discontinued the study before week 96). At 1 year cut-off data, 71/107 pts (66.4%) were in FTFR, meeting the primary endpoint of study. We observed 64/89 pts (72%) who entered in the TFR phase remained in MMR or better after a median duration of 20.4 months (interquartile range [IQR] 1.9-32.4), meeting the main secondary endpoint of the study. The median time to loss of MMR in TFR phase was not reached (Fig 1). The remaining 25/89 pts (28%) had discontinued the TFR phase (21 pts due to loss of MMR, 1 due to AEs and 3 pts for subject/guardian decision). The median time spent in TFR phase until loss of MMR was 3.6 months (IQR 2-19 months). At the cut-off data, 23/24 pts (96%) who restarted NIL after MMR loss regained MMR and MR4 after a median time of 2.7 months (IQR 1.0-5.6) and 4.1 months (IQR 1.2-10), respectively. Notably, 20/24 (83%) who restarted NIL after MMR loss achieved MR4.5 after a median time of 6.4 months (IQR 2.0-16.9). During the TFR phase, all-grade AEs were reported in 64/89 pts (72%). One pt (1.1%) had serious AE (pneumonia). No deaths and disease progressions were observed.

Conclusions: Our findings show that 66.4% pts who entered in consolidation phase achieved FTFR 96 weeks after the start of the consolidation period, and approximately 72% of pts remained disease-free at 1 year after stopping NIL. Overall, our data suggest that de-escalation of NIL before TFR attempt in CML-CP pts with sustained DMR can be a successful dose-optimization strategy.

¹Stagno F. et al., Blood (2022) 140 (Supplement 1): 9614-9616.