Retro-Prospective Observational Study on the Risk of Progression in Chronic Phase-Chronic Myeloid Leukemia (CML) Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation (TFR-PRO)
Authors: Gambacorti-Passerini Carlo , Alvarez-Larrán Alberto , Assouline Sarit E , Pregno Patrizia , le Coutre Philipp D , Saussele Susanne , Antolini Laura , Druker Brian J. 
Published: February 2021

Background
More than 50% of CML patients treated with ABL tyrosine kinase inhibitors (TKIs) obtain during treatment a Deep Molecular Response (DMR), defined as the presence of BCR-ABL1 transcript levels lower than 1/10000 (or MR4). Treatment discontinuation (TD) in CP-CML patients with stable DMR has proven successful in approximately half of cases, with relapse free survival (RFS) of 48-61% at 3 years. TD proved a safe option, since virtually all patients leukemia regains optimal control with TKI rechallenge, and treatment-free remission (TFR) is usually attempted outside clinical trials.
The occurrence of tumor progression, i.e. the progression to Accelerated Phase/Blast Crisis (AP/BC) has been considered a rare event. However, reports document at least six cases of disease progression after TD, some of which were fatal. These observations raise concerns about the safety of TKI discontinuation, since now we can no longer consider this practice as completely immune from the risk of disease progression, a condition which dramatically changes the patient situation and perspective. Nevertheless, a precise quantification of the risk of progression in this setting has not been determined.
Study Design and Methods
The TFR-PRO project will monitor approximately 3000 CML patients in long term treatment and with stable and minimal residual disease (MR4 or better) followed at 28 centers in 5 different countries (US, Canada, Italy, Germany, Spain). Each center is expected to enroll approximately 100 patients. A total of 30000 person years will be collected.
The following variables will be measured: time adjusted rates (TAR) of molecular relapse and of progression to AP/BC; progression free and overall survival; incidence of Serious Adverse Events (SAEs) and evaluation of Quality of Life indicators.
Primary Objective
To quantify the risk of progression to AP/BP, expressed as TAR, after TKI discontinuation in CML patients who undergo a first or subsequent TKI discontinuation attempt.
This value will be compared to that obtained in a similar population of patients with the same characteristics who do not discontinue TKI treatment.
Patients eligibility includes a history of at least 4 years of TKI treatment and at least 18 months of DMR. Events developing in patients after the end of discontinuation and TKI resumption will be considered linked to the discontinuation if they will develop within 36 months from the end of discontinuation. This rule will apply also to subsequent TD attempts. In case of a second or subsequent discontinuation attempt after the failure of a previous one (for molecular relapse), patients must have re-achieved a DMR with TKI therapy resumption and must keep DMR for at least 18 months before another TD.
Collection of data will be retrospective and prospective, as each center will collect the data for 24 months. Patients who become eligible before the opening of this study will contribute to the retrospective cohort, while those who will enter after it will contribute to the prospective cohort. Patients who will become eligible before the opening of this study but will continue after it, will contribute to both cohorts.
Sample size calculations were obtained assuming a contrast between risks of progression to AP or BP of 0.001% under treatment versus 0.1% under discontinuation (Figure 1). Study group classification will be defined as a binary non reversible time-varying factor where eligible patients are divided into two groups at the beginning of the follow-up depending on the presence or absence of discontinuation, and in the latter case may start discontinuation during the follow-up and thus change dynamically the study group classification.
Descriptive statistics on the main end-point will be obtained by the "Simon-Makuch" version of the Kaplan-Meier curves and log-rank test. Exponential model will be used for the calculation of confidence intervals on rates. Flexible Poisson model and Cox model will be used for data analysis adjusting for potential prognostics factors. The dynamic nature of the study group classification will be handled by left truncation.
The study was opened on July 24th. Eligible patients belonging to the prospective cohort will be entered in TFR-PRO between August 1st, 2020 and August 1st, 2021 while those in the retrospective cohort will be entered by November 1, 2020. Total duration of the study will be of 24 months.

Disclosures
Gambacorti-Passerini: Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Pregno:Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. le Coutre:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Saussele:Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Druker:EnLiven: Consultancy, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Henry Stewart Talks: Patents & Royalties; Iterion Therapeutics (formerly Beta Cat Pharmaceuticals): Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Research Funding; McGraw Hill: Patents & Royalties; Merck & Co: Patents & Royalties; Millipore (formerly Upstate Biotechnology): Patents & Royalties; MolecularMD (acquired by ICON): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Oregon Health & Science University: Patents & Royalties; Patient True Talks: Consultancy; Pfizer: Research Funding; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Aptose Therapeutics Inc. (formerly Lorus): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Patents & Royalties.