Longer treatment duration and history of osteoarticular symptoms predispose to tyrosine kinase inhibitor withdrawal syndrome

Abstract

Summary The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO‐SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO‐SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment [risk ratio (RR) = 1·68 (1·02–2·74)] with a 93‐month cut‐off time, and history of osteoarticular symptoms [RR = 1·84 (1·04–3·28)]. These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre‐existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom?

“…Musculoskeletal pain is a well-recognized side effect of TKI discontinuation. 53,54 Approximately 30% of patients have an increase in musculoskeletal pain or periarticular stiffness, which is usually transient. These symptoms can be managed with non-steroidal anti-inflammatory drugs, and occasionally glucocorticosteroids and acetaminophen.…”

“…Pain is more common in patients with a prior history of musculoskeletal pain and in those who have been on TKI therapy for a long period of time. 53 A small minority of patients need to restart TKI for uncontrolled discomfort. Several mechanisms have been proposed to explain this phenomenon, including activation of other kinase-mediated pathways which had been inhibited by the TKI, such as release of c-kit inhibition, 55 mast cell activation, 56 or bone remodeling effects, 57 but none has been proven yet.…”

Treatment-Free Remission in Chronic Myeloid Leukemia: Lights and Shadows

“… 27 In a systematic review on the efficacy of TKI discontinuation (10 studies, n = 1,601 patients), the weighted mean incidence of TKI WS was 27%, with TKI WS occurring in the early TFR phase. 60 In an analysis of 427 CML patients from the combined cohort of STIM2 and EURO-SKI trials, 61 longer duration of TKI treatment and history of osteoarticular symptoms appeared to be risk factors that predispose patients to TKI WS. A better understanding of the pathophysiology of this complication is needed in order to design strategies that mitigate symptoms and the need to resume therapy.…”

Tyrosine Kinase Inhibitor Therapy Discontinuation for Patients with Chronic Myeloid Leukaemia in Clinical Practice

“…Withdrawal symptoms on TKI cessation were first described in 2014 [48,49] in 15 of 50 Swedish patients in the EURO-SKI study. In a retrospective analysis of STOP-TKI and EURO-SKI data, 23% of 427 patients developed musculoskeletal symptoms on TKI withdrawal [50]. These mainly affected the upper body joints, and required multiple symptomatic treatments in 30% of patients.…”