Preliminary Report Of The STIM2 Study: A Multicenter Stop Imatinib Trial For Chronic Phase Chronic Myeloid Leukemia De Novo Patients On Imatinib
Authors: Mahon Francois-Xavier , Nicolini Franck E. , Noël Marie-Pierre , Escoffre Martine , Charbonnier Aude , Rea Delphine , Dubruille Viviane , Varet Bruno R. , Legros Laurence , Guerci Agnès , Etienne Gabriel , Guilhot Francois , Dulucq Stéphanie , Rousselot Philippe , Guilhot Joelle 
Published: October 2019

Abstract

Background
In the Stop imatinib study (STIM)1, we previously demonstrated that Imatinib could be safely discontinued in patients with a sustained deep molecular response (DMR) (undetectable BCR-ABLtranscripts (UMRD) for at least 2 years) (Lancet oncology, 2010;11: 1029-1035). Recently, these results were confirmed by the Australasian TWISTER study using criteria of imatinib cessation very similar to those used in the STIM1 study (Blood, 2013; 122:515-22). However in the both studies, half of the patients were previously treated with IFN leading to a non-homogenous cohort of patients. So we conducted prospectively a second trial (STIM2) where cessation of imatinib treatment was proposed for patients in sustained DMR who were treated only with imatinib.

Methods
In this new multicenter, non-randomized STIM2 study (ClinicalTrials.gov, NCT01343173), imatinib was discontinued in CML pts with the same criteria as those we reported previously for the STIM1 i.e. sustained DMR defined as remission lasting more than 2 consecutive years and confirmed on five datapoints of BCR–ABL analyses by quantitative RT-PCR during these 2 years. The UMRD was defined with a sensitivity> to 4.5 log with ≥ 50.000 ABL transcripts amplified as internal control. 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, on 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.

Results
From April 2011 to June 2013, 124 CML pts were included (62 men,62 women) with a median age of 61 years recruited in the 23 French centers. At the last update, the median follow up of the first 124 pts enrolled is 12 months (range 1-25). After discontinuation of imatinib, a molecular relapse occurred in 48 pts (45 relapses during the first 6 months and 3 relapses between 6 and 12 month), and 76 patients were still free of treatment at the last update with DMR. However 41 experienced a BCR-ABL RQ-PCR fluctuation without clear molecular relapse. In this so-called-fluctuation group of patients, 7 were found positive once, 6 twice, 12 patients between 3 and 5 times, 10 patients between 6 and 10 times and 6 patients more than 10 times confirming that BCR-ABL reappearance does not mean automatically clinical relapse.
We confirmed also that all patients were sensitive to a TKI re-challenge. Actually, 33 patients were retreated with imatinib 5 with nilotinib and 3 with dasatinib. The median time to achieve again a CMR from the molecular relapse was 7 months (range 4-16 months) and from re-initiation of TKI was 4 months (range 2-14). 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 STIM2 trial were estimated at 2.8 millions Euros.

Conclusion
We confirm that Imatinib can be safely and prospectively discontinued in pts with DMR of at least 2 years duration in patients only treated with imatinib. To stop treatment it may not require the complete eradication of residual leukemic stem cells since positive fluctuation PCR results do not lead to CML relapse or progression. These intriguing results, even for imatinib treated patients since disease onset (already observed after IFN therapy), are comparable to those reported with the more sensitive PCR on DNA in the TWISTER study and are under investigations in our laboratory.

Disclosures:
Mahon: Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Nicolini:Novartis, Ariad, Teva, BMS and Pfizer: Honoraria from Novartis, Ariad, Teva, BMS and Pfizer. Grants from Novartis. Other. 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.