ENESTnd ten years and ENESTfreedom five years: Nilotinib long-term medication/discontinuation data update

With the advent of imatinib, a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1, the overall survival of patients with chronic myeloid leukemia (CML) has been greatly improved.

Subsequent second-generation TKIs such as nilotinib and dasatinib further accelerated the molecular remission of CML patients.

However, long-term treatment of TKI may accumulate cardiovascular and musculoskeletal toxicity, affect the quality of life of patients, and also bring a continuous economic burden.
Therefore, withdrawal of TKI is an objective need for some patients.

With the advancement of CML diagnosis and treatment, TKI withdrawal has gradually become possible, and domestic and foreign guidelines have listed treatment-free remission (TFR) as a new goal of CML treatment.

ENESTnd is the first-line registration study of nilotinib.
ENESTfreedom is the first study to evaluate the discontinuation of first-line nilotinib after treatment.
The initial conclusions of these two studies laid the foundation for the first-line nilotinib and the indications for discontinuation.
Recently, two studies have successively published 10-year and 5-year follow-up data in Leukemia, evaluating the long-term outcomes of patients with chronic phase CML (CML-CP) after first-line nilotinib treatment and withdrawal.

What new enlightenment will the long-term data of these core studies bring to the treatment of CML? This article will interpret this.

ENESTnd ten-year data core conclusions The ENESTnd study enrolled 846 newly diagnosed CML-CP adult patients, and they were randomized 1:1:1 to nilotinib 300mg BID, nilotinib 400mg BID, and imatinib 400mg In the three treatment groups of QD, the primary endpoint is the 12-month major molecular remission (MMR) rate, and the 10-year long-term follow-up endpoints are designed, including the cumulative rate of molecular remission, long-term survival, and safety.

① The 10-year cumulative MMR and MR4.
5 rates of the nilotinib group were significantly higher than those of the imatinib group, and the maintenance rate of MMR and MR4.
5 up to ten years was higher than that of the imatinib group.
The tinib group (8.
41 months; 1.
9-115.
9) was shorter than the imatinib group (14.
16 months; 2.
8-95.
6).
The median time to reach MR4.
5: Nilotinib group (37.
65 months; 2.
8-122.
1) Shorter than the imatinib group (41.
63 months; 7.
5-122.
6) Figure 1-1.
Cumulative molecular remission to ten years Figure 1-2.
Molecular remission maintenance at five and ten years ② Nilo The percentage of achieving TFR conditions (deep analytical remission [DMR] for ≥ 2 years) in the tinib group was higher than that in the imatinib group Figure 1-3.
TFR conditions achieved in five and ten years ③ Nilotinib group The observed progression and CML-related deaths were less than the imatinib group Figure 1-4.
Progress and CML-related deaths to ten years ④ Survival outcomes of the nilotinib group and the imatinib group (overall survival [ OS] is equivalent to progression-free survival [PFS]) Figure 1-5.
Ten-year overall survival rate and progression-free survival rate ⑤ The overall frequency of non-hematological adverse events (AE) in the nilotinib group and the imatinib group is similar Grade 3/4 hematological abnormalities (especially lymphocyte and neutropenia) in the imatinib group were more common than fluid retention (pleural effusion, pericardial effusion, and pulmonary edema) and pancreatitis in the nilotinib group.
There was less occurrence (<4%) of any grade of hepatotoxicity in the nilotinib group (48.
4%, 300mg; 53.
1%, 400mg) in the treatment groups than in the imatinib group (17.
5%) in the nilotinib group.
The prolonged period (6.
8%, 300mg; 7.
9%, 400mg) was higher than that of the imatinib group (3.
9%).
Figure 1-6.
The most common non-hematological AEs are shown in Figure 1-7.
Conclusion of cardiovascular events at five and ten years ENESTnd ten-year data are rare second-generation TKI ultra-long-term follow-up data, which helps us understand the long-term benefits and risks of nilotinib in CML-CP patients.
The rate of achieving TFR conditions in the lotinib group is higher than that in the imatinib group, and the cumulative rate of molecular responses is better.
For patients who wish to achieve TFR or expect long-term deep molecular remission, nilotinib treatment may be a better first-line treatment Selection should carefully evaluate the benefit/risk balance of long-term nilotinib treatment, especially for patients with known cardiovascular (CV) risk factors, patients must be informed of the potential risks, and CV comorbidities ENESTfreedom must be closely monitored for five years during treatment Data core conclusions ENESTfreedom study enrolled patients need to be diagnosed with CML-CP, aged ≥18 years, received first-line nilotinib for ≥2 years and reached MR4.
5, enrolled patients received nilotinib consolidation for 52 weeks, can maintain DMR Of patients enter the TFR phase of discontinuation, and the loss of MMR is the standard for restarting treatment. The primary endpoint of the study was the TFR rate (51.
6%) at 48 weeks after discontinuation of the drug.

① A total of 190 patients entered the TFR stage, of which 81 patients (42.
6%) were still in the TFRTFS at the end of five years.
The rate was 48.
2% (95% CI 40.
9, 55.
1).
No patients progressed to the accelerated phase/acute phase (AP/BC ) Or the occurrence of CML-related deaths Figure 2-1.
Treatment-free survival curve after five years of follow-up ② A total of 91 patients restarted nilotinib treatment due to loss of MMR, of which 90 patients (98.
9%) regained MMR and 84 patients (92.
3%) ) Regained MR4.
5 with rapid recovery Figure 2-2.
Regained molecular response in patients who restarted treatment ③ For patients who restarted treatment within 5 weeks after losing MMR, BCR-ABL1IS can decrease rapidly, indicating that the TFR period was once every 3 months The monitoring frequency is safe.
Figure 2-3.
BCR-ABL1IS level decline after restarting treatment ④ TFR rate of patients with different Sokal stratification at the time of diagnosis: low risk 50.
8%, medium risk 38.
0%, high risk 27.
6% ⑤ Any patients in the consolidation phase The incidence of grade AE ​​was 86.
0%, which gradually decreased during the TFR phase (79.
1%, 57.
0%).
In patients with TFR duration >3.
7 years, the incidence of cardiovascular events in the consolidation phase (any grade) was 4.
7%, after the onset of TFR It dropped to 2.
3% within 48 weeks and remained at a low level during TFR.
Conclusion ENESTfreedom's five-year analysis shows that after first-line treatment with nilotinib in CML-CP patients, the TFR rate can be sustained for a long time, and ENESTnd shows a higher rate.
TFR condition achievement rate, patients with TFR as the treatment target may consider first-line nilotinib treatment.
Patients with nilotinib withdrawal for more than 3.
7 years have molecular recurrence, suggesting the necessity of long-term standard molecular monitoring for patients during TFR.
There is a significant overall AE benefit.
Patients who are concerned about long-term toxicity or intolerance of the drug can consider stopping the drug as the treatment target.
The MCC number TAS21033520 is valid for 2022-03-29.
The data is out of date and deemed invalid.

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