The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukaemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. Results from a five-year update further confirm the durability and safety of TFR for patients receiving second-line nilotinib.
“The 5-year update of the ENESTop confirms that even CML-CP patients receiving the second-line TKI nilotinib, after previous failure of imatinib, can stop the TKI after sustained deep molecular remission and remain treatment free in 42.9% of cases due to persistent molecular response. The update shows once more that TFR success is higher in patients with a longer TKI treatment and a longer duration of stable deep molecular response. The future could teach us if reduced molecular monitoring the first years after TKI stop can be recommended without compromising optimal response to restarting the TKI.”
Treatment-free remission (TFR) – stopping tyrosine kinase inhibitor (TKI) therapy without loss of response – is an emerging treatment goal in chronic myeloid leukaemia (CML). The phase II ENESTop study therefore evaluated TFR in patients with chronic-phase CML with sustained deep molecular response following second-line treatment with nilotinib. Eligible patients had received ≥3 years of treatment (including >4 weeks of imatinib followed by ≥2 years of nilotinib) and had achieved MR4.5 (BCR-ABL1IS ≤ 0.0032%) while on nilotinib. Patients without confirmed loss of MR4.5 after one year of consolidation treatment could attempt TFR. After one year of nilotinib consolidation, 126 patients attempted TFR. In the primary analysis, 57.9% (73/126) of patients remained in TFR 48 weeks after stopping nilotinib. Patients with a loss of major molecular response (MMR, BCR-ABL1IS >0.1%) or confirmed loss of MR4.0 (BCR-ABL1IS >0.01% in two consecutive assessments) during TFR reinitiated nilotinib treatment.
By data cut-off (January 29th 2020), 52 patients had completed at least five years of TFR and 74 discontinued the TFR phase. Of these, 59 patients resumed nilotinib while 15 discontinued the study. The MR4.5 rate at five years after starting TFR was 37.3% (47/126), as compared with 53% at week 48. Eleven patients with MR4.5 at five years had a temporary loss of MR4.5, while 36/126 (28.6%) maintained stable MR4.5 for five years. The estimated treatment-free survival (TFS) rate at five years was 49.4% (95% CI: 40.3-57.9).
Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR4, 98.3% regained MMR. The only patient who did not regain MMR stopped retreatment at 19.7 weeks and withdrew from the study. Furthermore, 56 (94.9%) patients regained MR4.0 and 55 (93.2%) regained MR4.5 by the time of the cut-off date. The median time to regain MR4.5 was 2.9 months. Baseline characteristics between patients who resumed nilotinib due to loss of MMR (N= 34) or confirmed loss of MR4.0 (N= 25) were comparable. However, patients with loss of MMR had a longer interval between CML diagnosis and achievement of MR4.5 (58.9 vs. 47.4 months) and a shorter median time from achievement of MR4.5 until TFR entry (27.9 vs. 40.1 months). In patients with confirmed loss of MR4.0, all 25 regained MR4.0 and 24 (96.0%) regained MR4.5 within the first 48 weeks of nilotinib re-initiation. In patients with loss of MMR, 97.1% regained MMR and 91.2% regained MR4.0 and MR4.5 within the first 48 weeks of nilotinib re-initiation.
There were no cases of disease progression or death due to underlying CML. A general trend towards decreasing rates of adverse events (AEs) was observed during the TFR phase, from 86.0% in the first twelve months to 49.1% in the fifth twelve months among patients who remained in TFR after the fourth twelve months. The musculoskeletal pain AE rate was high during the first twelve months of TFR (52.6%) but by the fifth twelve months of TFR was lower (8.8%) than during consolidation (10.5%). In patients reinitiating nilotinib (N= 59), the rate of all-grade AEs was higher than during consolidation treatment (94.9% vs. 77.9%), with a cumulative increase in cardiovascular events with longer nilotinib exposure. Overall all-grade AE rates were similar between patients re-initiating nilotinib due to loss of MMR (94.1%) or confirmed loss of MR4.0 (96.0%), with the most common AEs being hypertension (26.5% vs. 32.0%), arthralgia (20.6% vs. 8.0%), constipation (11.8% vs. 20.0%) and hyperglycaemia (26.5% vs. 0%).
Overall, these results confirm the durability and safety of TFR for patients with chronic phase CML receiving second-line nilotinib. The majority of patients requiring nilotinib re-treatment rapidly regained MMR, MR4.0 or MR4.5. However, cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.
Hughes TP, Clementino NCD, Fominykh M, et al. Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update. Leukemia. 2021;35:1631-42.