Treatment- Free Remission in Chronic Myeloid Leukemia -Experience of a Single Brazilian Private Institution Using Imatinib Copies

Introduction: In addition to the best possible overall survival, discontinuation of the tyrosine kinase -inhibitor (TKI) treatment [treatment free response (TFR)] without observing a recurrence of the disease has become a standard part of chronic myeloid leukemia (CML) care. Evidence of several studies suggest that patients who have achieved a sustained stable deep molecular response (DMR) as MR4 and MR4.5 can be safely discontinued with close monitoring without relapse, despite BCR/ABL1 DNA remaining detectable.

In Brazil, CML patients have received almost exclusively Imatinib as first-line treatment and since 2013, only generics and copies of imatinib mesylate have been used in first-line throughout the whole Public Health System and in several institutions within the private system. However, in both scenarios there is a limit coverage of PCR exams/ year which allows for adequate monitoring but it is not sufficient for the implementation of TFR safely in eligible patients

Aims: To report a Brazilian single institution Imatinib discontinuation trial and to evaluate factors impacting treatment -free response (TFR) and treatment free survival (TFS)

Methods: From 2020 -2021 , 26 eligible patients were invited to participate in a single arm trial of Imatinib discontinuation (DIP). Inclusion criteria: age > 18 years, chronic phase, minimum of 04 years of Imatinib therapy, deep molecular response sustained > or = 02 years (confirmed by 04 tests in the last two years, defined MR4.0 or MR 4.5 and a confirmatory exam at the moment of the screening). Atypical transcripts were excluded. After discontinuation, patients were monitored by RT- PCR monthly in the first year, every two months in the second year and every three months since the third year. Criteria for Imatinib re-initiation: loss of MMR confirmed by two exams, loss of cytogenetic response, loss of hematologic response, disease progression. TFR was calculated from the date of discontinuation until first event: loss of MMR, Imatinib reintroduction, death any cause or last follow up. TFS was calculated from the date of imatinib discontinuation until reintroduction or last follow- up (censoring deaths not related to CML). The costs of exams were provided by own founds of our institution.

Results: From 26 patients, 20 patients agreed to consent inform to discontinuation of imatinib. 06 patients declined despite information because their insecurity about TFR. Twelve patients (60%) presented MR4 . Median age was 52.3 years old and 13 (65%) were female. Median time diagnosis to discontinuation of imatinib 8.04(4.6-15.5) years. Twelve (60%) patients sustained TFR. Seven patients of twelve had presented MR 4 and five had MR 4.5 in the screening, respectively . (p=0,85) .It means 58,3% of the total of patients with MR 4 and 62,5% with MR 4.5 . In this interim analysis the median time of follow up was 14.5 (2.7-18.8) months. One patient died due to COVID19 with major molecular response (MMR). Eight (40%) lost MMR and imatinib was restarted. In this group the median time until MMR loss was 7.24 (2.1-13.8) months.

At this moment, 07 patients (87,5 %) recovered MMR . In addition , in this group 06 patients (75%) achieved the same level of MR with reintroduction of imatinib with median 5.2 (3.7-6.3) months. Regarding adherence, 4 (20%) had some absences in monthly medical consultations and 1(5%) missed follow-up. Fifteen tests (6.14%) were performed to confirm MR loss, however only in 8 tests (53.3%) were confirmed. In fact, 04 patients (33,33%) still in TFR because of the double confirmatory test. There was no transformation to advanced phases.

Gender, age at de diagnosis , age at discontinuation, Sokal , BCR-ABL trasncripts type , duration of Imatinib therapy , duration of MR 4.0 or MR4.5 did not affect TFR.

Withdrawal syndrome occurred in 05 patients (25%) ; 04 patients with grade 1 and 01 patient with grade 2, had been used corticosteroid for few days.

Conclusions: Despite the small number of patients included and short time of follow-up, the preliminary results of this trial demonstrated the feasibility and safety of Imatinib discontinuation , even using Brazilian copies, and the results were similar of that presented in another trials . The confirmatory exam to establish the loss of TFR was useful and safe. Adhesion of a discontinuation is one of the most important keys of the success of TFR.

Bellesso:AstraZeneca: Research Funding.