Impact of Targeted Therapy on Cancer-Related Cognitive Impairment

Cancer-related cognitive impairment (CRCI) is common and distressing among cancer survivors. An understudied area is the impact of targeted therapies, a new generation of cancer therapy. Tyrosine kinase inhibitors (TKIs) are among the first, most prolific, and most successful classes of targeted therapy. TKIs are rapidly expanding, with over 40 FDA-approved TKIs for cancer. We propose to study the impact of targeted therapy on CRCI among patients about to start TKI for chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). These are the ideal models to study the impact of targeted therapy on CRCI because TKI is usually first-line therapy for patients with CML and CLL, patients with hematologic cancers have been understudied in CRCI research, our preliminary data suggests that CRCI is a significant problem for patients with CML and CLL, and these patients also have excellent survival. We propose the first large-scale prospective study to examine the impact of TKIs on CRCI, including potential risk factors and mechanisms. We note three innovative contributions to the field of CRCI. First, we will examine both subjective and objective CRCI using both neuropsychological measures (CANTAB) used in our prior nationwide studies and ecological momentary assessment (EMA). EMA improves the reliability and sensitivity of objective CRCI, and EMA better assesses subjective cognitive lapses. Second, cancer and cancer treatment promote accelerations in biological aging, which is associated with cognitive impairments. We will evaluate whether accelerated epigenetic aging is related to variability in CRCI. Third, we propose to identify modifiable behavioral and modifiable risk factors. This work will inform development of future interventions to prevent or reduce CRCI. We will conduct the first study of subjective and objective CRCI among TKIs recipients for CML and patients with CLL. We will recruit 200 patients about to begin TKIs for CML or CML and 200 controls matched on age, sex, and education with no history of cancer. Participants will be recruited in partnership with the University of Rochester Cancer Center NCI Community Oncology Research Program (NCORP) Research Base and 30 nationwide affiliates treating a large population of CML/CLL patients on TKIs per year. Assessments will occur prior to starting TKIs and 6 and 12 months later and will include a CANTAB battery, cognitive EMA via smartphone, patient-reported outcomes, wrist-worn actigraphy to assess sleep and circadian function, and a saliva sample. We aim to characterize differences in objective and subjective cancer-related cognitive impairment (CRCI) at pre-treatment and longitudinally among patients receiving TKIs for CML and CLL. We will also identify risk factors for CRCI before and during TKI therapy. Lastly, we will identify biobehavioral mechanisms underlying the effect of TKIs on CRCI.