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Introduction: Kinase inhibitors (KI) rapidly changed treatment paradigms in CLL and ibrutinib currently enters clinical standards in previously untreated patients. Thus, the prevailing "treat-untilprogression" concept will lead to very long treatment durations or a need for drug cessation. However, explored stopping rules largely rely on MRD negativity, rarely achieved with KI. Outcomes in lineages after KI are reported mostly on patients that received immediate salvage treatment. However, in real-life experiences a large proportion of discontinuations of KI in CLL treatment happen due to toxicity and patient decisions rather than progression and often happen in meaningful clinical remission due to the KI, but without achieving MRD negativity. Their fate in a treatment-free observation setting is unknown. Methods:We here report a first real-world cohort of CLL patients that had received ibrutinib or idelalisib in different lines of treatment, that had achieved measurable response, suffered toxicities or made decisions to stop therapy and remained in unmaintained (i.e. untreated) observation after discontinuing the kinase inhibitor. Retrospective analyses from chart review in 7 academic centres were performed.Results: We report on 54 patients, treated with either ibrutinib (n = 29) or idelalisib (n = 25). Median age was 74 years at the start of the novel drug and the median number of treatments prior to KI was 1 (range 0 to 6). The median duration on KI was 8 months before stopping due to toxicity (n = 49) or patient's decision (n = 5). Expectedly, the most important toxicities leading to drug cessation were cardiac events, infection and bleeding for ibrutinib and gastrointestinal events, as well as skin and hepatic toxicity for idelalisib. FISH cytogenetics were available in 51 and mutation states in 42 patients.Twenty patients had del17p and 13 had del11q. Eleven patients stopped treatment in CR and 43 achieved PR. Median PFS after treatment cessation was 9.4 months, median TTNT was 12 months and OS was 62% at a median observation time of 27 months. PFS and TTNT at 2a were 19 and 27%, respectively. No differences were observed between the two drugs in PFS and TTNT, but the idelalisib cohort had a significantly better OS (median n.r. vs 20 mo, p = .002) in our cohort. PFS, TTNT and OS were not significantly different by FISH risk, while unmutated IgVH predicted earlier progression, but not OS. Despite low numbers in some groups, the type of toxicity had no apparent large effect on outcome. While the line of treatment did not affect PFS or OS, achievement of CR showed better PFS, but not OS.Conclusion: Treatment cessation in CR or PR after kinase inhibitor treatment is associated with limited median PFS, but some patients experience prolonged treatment free intervals. Exploratory analyses point to clinical response quality and mutational state as predictors of PFS. OS from stop of kinase inhibitor was respectable for this elderly cohort, suggesting available salvage options.Introduction: The FoRT trial was a prosp...