Prevalence and Clinical Significance of Restless Legs Syndrome in Patients with Chronic Myeloid Leukemia and Its Impact on Quality of Life and Disease Course

Introduction: Restless legs syndrome (RLS) is a sensorimotor disorder characterized by the urge to move the legs, typically occurring during rest or at night. While there are few studies evaluating the prevalence of RLS in Philadelphia negative myeloproliferative neoplasms (MPNs), no study has yet investigated the relationship between chronic myeloid leukemia (CML) and RLS. The aim of our study was to assess the prevalence of RLS in CML and to investigate the impact of RLS on the disease course and quality of life (QoL) in patients (pts) with CML.

Methods: CML pts visiting our outpatient clinic consecutively between January and August 2023 were invited to participate in the study. Demographic data, disease risk scores, comorbidities, tyrosine kinase inhibitor (TKI) therapies, molecular responses, and follow-up data of pts were documented retrospectively. RLS was assessed with the International Restless Legs Syndrome Study Group Rating Scale. Anxiety was measured by the Beck Anxiety Inventory, depression by the Beck Depression Inventory, fatigue by the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, hopelessness by the Beck Hopelessness Scale, QoL by the European Organization for Research and Treatment of Cancer QoL Questionnaires (QLQ-C30 and CML-specific QLQ-CML24), and sleep quality by the Pittsburgh Sleep Quality Index. Electromyographic evaluations and neurological exams were conducted on pts diagnosed with RLS.

Results: One hundred and sixty-four pts were included. The median age at diagnosis was 41 years (range, 7 - 76 years), and 86 pts (52.4%) were male. At the time of analysis, all pts were receiving TKI therapy; 129 pts (78.7%) were on imatinib, 34 pts (20.7%) were receiving second-generation TKIs, and one (0.6%) on ponatinib. The median follow-up was 11 years (range, 2 - 24 years). RLS was detected in 33 pts (20.1%). Among pts with RLS, two had iron deficiency and six had peripheral neuropathy by electromyography, all of whom had type 2 diabetes. Comparative analysis between pts with and without RLS revealed no significant differences regarding sex, age at diagnosis, risk scores, TKI therapy distribution and duration, or comorbidities. Additionally, there were no significant differences in hopelessness scale scores and EORTC QLQ-C30 summary scores. Satisfaction with care and social life scores were also comparable between groups.

Pts with RLS exhibited significantly worse sleep quality (p=0.016), higher levels of anxiety (p<0.001), depression (p=0.005), and fatigue (p<0.001), along with increased symptom burden, negative impacts on worry/mood, interference with daily life, and issues related to body image compared to those without RLS (all p<0.001). The need for TKI dose reduction was observed in 18.1% of pts with RLS and 17.6% of those without RLS due to hematological and non-hematological toxicities (p=0.933). Molecular responses were comparable between the two groups, with 12.1% major molecular response (MMR) and 87.9% deep molecular response (DMR) (MR^4.0 or deeper) rates in pts with RLS versus 18.3% MMR and 70.2% DMR rates in those without RLS (p=0.196). Multivariate analysis revealed that pts with a high CML24 symptom burden score had an increased risk for RLS (OR=1.077).

Conclusions: International data indicate that the prevalence of RLS in normal population ranges from 7.2% to 11.5%, while reported prevalence rates in Turkey vary between 3.2% and 5.5%. In our study, the prevalence of RLS was increased among CML pts when compared to normal population. Furthermore, the presence of RLS exacerbates anxiety, depression, and fatigue, while deteriorating sleep quality and overall QoL measures. RLS does not appear to impact molecular responses. It seems that the presence of RLS in CML pts is primarily associated with the disease itself rather than the duration or type of TKI therapy, and it is likely influenced by unique factors inherent to CML. None of our pts discontinued TKI therapy, so maybe in pts with RLS and a stable DMR, it would be reasonable to attempt treatment-free remission which would additionally help use to assess the potential impact of TKI therapy on RLS generation. In addition, examining other factors contributing to the pathogenesis of RLS among CML pts is crucial for a comprehensive understanding. Our study represents a pioneering effort in the literature, providing the first insights into these mechanisms and laying the groundwork for future research.

No relevant conflicts of interest to declare.