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Chronic myeloid leukemia (CML) accounts for about 15% of adult leukemias, and tyrosine kinase inhibitors (TKIs) have revolutionized the survival
of CML patients.
With the long-term clinical application of TKI drugs, in addition to causing economic burden to patients, the long-term adverse reactions of different TKIs affect the quality of life of
patients.
In recent years, foreign studies have shown that about 50% of patients who obtain a stable deep molecular response (DMR) can successfully stop TKI and obtain no treatment response (TFR).
Nilotinib is a TKI that was used in the first-line treatment
of chronic phase (CP) CML in a 2007 study designed by the GIMEMA CML Working Group (CML 0307 trial).
Recently, the results of the 10-year follow-up of the study were announced, and although TFR was not the original purpose of this clinical trial, the investigators also provide detailed data
on TFR as it gradually becomes a safe option in some patients.
01Research methods
The GIMEMA CML working group initiated a phase II study (NCT00481052) with nilotinib as first-line therapy in 2007, and between June 2007 and February 2008, 73 adults (≥ 18 years) patients newly diagnosed with CP-CML were enrolled in 18 centers in Italy
.
The starting dose of nilotinib is 400 mg twice
daily.
Following the approval of 300 mg of twice-daily nilotinib for first-line treatment of CP-CML in Italy in November 2011, the GIMEMA regimen was revised and then approved by the local ethics committee, and by September 2012, the dose was reduced to 300 mg twice daily for all patients still receiving 400 mg twice daily
.
In addition, the study duration was extended to 10 years and focused on TFR rates, molecular response rates, survival, causes of death, and the type and severity of adverse events, particularly arterial obstructive events (AOEs).
Patient characteristics
The median age of enrolled patients was 51 years (range: 18-83 years), and the baseline characteristics of patients are shown in Table 1
.
Table 1
At the last follow-up, 22 (30.
1%) patients continued to receive the standard dose of 300 mg twice daily nilotinib, 10 (13.
7%) patients received 400 mg once daily nilotinib, and 4 (5.
5%) patients received 300 mg once daily nilotinib
.
Eighteen (24.
7%) patients achieved TFR
after discontinuation of nilotinib.
Fourteen (19.
2%) patients received other TKIs
.
Survival situation
Four patients died, and the 10-year overall and progression-free survival rates were 94.
5% (95% CI: 86 to 97.
9).
Mitigating the situation
The 10-year cumulative incidence of major molecular reactions (MMR) and MR4 was 96% and 83%,
respectively.
The median time to MMR and MR4 was 6 months and 18 months
, respectively.
Overall, 36 (49.
3%) patients continued nilotinib at the last assessment, and 22 (30.
1%) and 14 (19.
2%) patients were in DMR and MMR
, respectively.
There is no therapeutic remission
During the study period, 36 patients (49.
3%) met the minimum discontinuation requirements for ELN (nilotinib treatment duration > 4 years, MR4 or better lasted >2 years), but not all patients tried TFR
.
Overall, 24 (32.
8%) patients (13 women, 11 men) discontinued nilotinib when DMR was stable (Table 2).
Eighteen patients made the decision to discontinue nilotinib specifically for TFR; In the remaining 6 patients, nilotinib
was discontinued due to adverse events.
Table 2
Of the 24 patients who discontinued nilotinib, 18 (75%) had stable TFR before the last assessment (17 DMR stable, 1 MMR stable).
Six (25%) patients confirmed MMR loss (after 3, 3, 6, 7, 13, and 23 months) and resumed treatment, all of whom recovered MMR
.
The estimated 24-month treatment-free survival rate was 72.
6% (95% CI: 48.
3 to 86.
9%)
.
Taking into account the entire enlisted cohort, the TFR stabilization rate was 24.
7% (18/73 patients).
Arterial obstructive events
Overall, 17 (23.
3%) patients developed AOE: 15 patients had one AOE at follow-up and 2 had multiple AOEs, as detailed in Table 3
.
Table 3
Other adverse events
Blood toxicity, liver and pancreas laboratory abnormalities (elevated aspartate aminotransferases, alanine aminotransferases, bilirubin, amylase, and lipase), and other well-known clinical adverse events associated with nilotinib (rash, itching, muscle and joint pain) emerged early in the study, with no new events
recorded in patients taking nilotinib for a long time.
In conclusion, although cardiovascular toxicity remains a concern, first-line treatment with nilotinib induces a stable, treatment-free response
in patients with CP-CML.
Reference sources:
Gabriele Gugliotta, Fausto Castagnetti, Massimo Breccia, et al.
Treatment-free remission in chronic myeloid leukemia patients treated front-line with nilotinib: 10-year followup of the GIMEMA CML 0307 study.
Haematologica.
2022 Oct 1; 107(10):2356-2364.
doi: 10.
3324/haematol.
2021.
280175.
Edited by Quinta
Typesetting: Quinta
Execution: Wenting
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