Long Term Follow-Up After Imatinib Cessation For Patients Indeep Molecular Response: The Update Results Of The STIM1 Study
Authors: Mahon Francois-Xavier , Rea Delphine , Guilhot Joelle , Guilhot Francois , Huguet Françoise , Nicolini Franck E. , Legros Laurence , Charbonnier Aude , Guerci Agnès , Varet Bruno R. , Etienne Gabriel , Reiffers Josy , Rousselot Philippe 
Published: October 2019

Abstract

Background
Imatinib treatment significantly improves survival in patients with CML. We previously demonstrated that Imatinib could be safely discontinued in pts with deep molecular response (DMR) i.e., with undetectable minimal residual disease (UMRD) of at least 2 years (Lancet oncology, 2010;11: 1029-1035).Around 40% of CML patients with stable DMR on imatinib for at least 2 years are likely to remain in a prolonged treatment-free remission (TFR) after treatment is stopped and this rate has been safely confirmed by the recent Australasian TWISTER study (Blood, 2013; 122:515-22).

Methods
In this multicenter STIM study, imatinib (of >3 years duration) was prospectively discontinued in CML pts with who were in DMR with UMRD sustained for at least 2 years (ClinicalTrials.gov,NCT00478985). The UMRD was defined with a sensitivity> to 4.5 log with ≥ 50,000 ABL transcripts amplified as internal control). Importantly, the molecular relapse was defined as positivity of BCR–ABL transcript in quantitative RT-PCR confirmed by a second analysis point indicating the increase of one log in relation to the first analysis point, at two successive assessments, or loss of MMR at one point. Quantitative RT-PCR for BCR–ABL transcripts from peripheral blood was performed every month during the first year and every 2 months thereafter. Beyond 2 years, molecular biology FU was performed every 3 months.In cases of molecular relapse, the treating physician was recommended to reintroduce TKI treatment.

Results
From July 9, 2007, to Dec 17, 2009, 100 pts (48 male, 52 female) with CML (51 pts previously treated with IFN) and a median age of 63 years (range 29–80) were recruited in the STIM trial. Eight years after the first inclusion, the median follow-up of the STIM study is now 50 months (range 9-72) with a mean of 51 months. Sixty-one patients met the definition of molecular relapse: 58 relapses occurring during the first 7 months and 3 late relapses at month 19, 20 and 22, respectively). No other molecular relapse was observed at the last update (July 2013). However, 4 extra-hematological deaths were observed: 1 case in DMR after 9 months of imatinib cessation (due to myocardial infarction) and 3 cases belonging to the molecular relapse group (due to respectively stroke, mesothelioma, and gastric carcinoma). So, considering the death in DMR without any relapse (n = 1) as a competing event the cumulative incidence of molecular relapse remains 60%. Among the 58 patients alive, we confirmed that all patients were sensitive to TKI re-challenge, and were re-treated with imatinib (n=48), nilotinib (n=5) and dasatinib (n=5). One patient stopped again for side effects. A Second attempt of TKI discontinuation was proposed for 15 patients in sustained DMR and 5 cases of molecular relapse were reported at the last update after this second attempt of TKI cessation.
Among the initial 38 patients alive who are still in DMR without any treatment the median follow up is 54 months (range : 24- 71).Taking into account the cost of imatinib and the number of months without treatment in the total study population at last analysis, the savings within the STIM trial were estimated at 5.5 millions Euros.

Conclusion
Imatinib can be safely discontinued in pts with a DMR of at least 2 years duration and we continue to recommend proposing discontinuation only in clinical trials with close molecular monitoring. In spite of the fact that we did not observed other molecular relapse beyond 2 years a long-term follow-up of the different cessation studies will be necessary to affirm cure. Because the life expectancy of de novo CML is now closed to the healthy population, the long-term medical costs and quality of life have become very important and depend on the possibility to cease safety TKI in long term.

Disclosures:
Rea: Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Etienne:novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Rousselot:BMS, Ariad, Pfizer: Honoraria from BMS, Ariad, Pfizer. Grants from BMS Other.