Longitudinal Changes in Cognition in Older Individuals Receiving Lymphoma-Directed Therapy: A Pilot Feasibility Study
Authors: Balitsky Amaris K , Pond Gregory R , Mian Hira , Davies Gwynivere A , Foley Ronan , Fraser Graeme Andrew McCrae , Sussman Jonathan , Kouroukis C. Tom 
Published: December 2024

Introduction: The incidence of non-Hodgkin lymphoma (NHL) in the elderly is increasing. While older patients with lymphoma are considered for treatment with aggressive chemotherapy, they are more susceptible to toxicity and frailty, a complex multi-dimensional syndrome of loss of energy, physical ability, cognition or health.
Objectives: 1. To determine the feasibility of recruiting and measuring cognitive function in older patients with NHL receiving chemotherapy. 2. To estimate the rate of cognitive abnormality and the impact of chemotherapy on cognition longitudinally in older patients.
Methods: A prospective cohort study was conducted in participants ≥65 years with untreated NHL where the intent was to administer aggressive chemotherapy. Key ineligibility criteria included CNS involvement, expected survival less than 6 months, and underlying neurodegenerative disease. A research assistant conducted a battery of baseline measures including: the Geriatric 8 (G8) health status screening questionnaire (frailty), 4-metre walk test and hand-grip strength (physical function), the Cumulative Illness Rating Scale (CIRS) (comorbidities), the geriatric depression scale (depression), the cancer and aging research group (CARG) score (chemotherapy toxicity), the Lee Index ePrognosis (prognosis), and FACT-Lym (health-related quality of life (HRQoL). The selection of questionnaires was based on guidance from the Society of Geriatric Oncology. In addition, measures focusing on cognition were administered: the Montreal cognitive assessment (MOCA) (screen for cognitive dysfunction); Trail making test (TMT) (attention), TMT-A (processing speed), TMT-B (cognitive flexibility); and controlled oral word association (COWA) (verbal fluency). Testing was performed at baseline (prior to initiating chemotherapy), at 6 months (post chemotherapy), and at 12m. Pre-defined criterion of feasibility would be met if 20 pts would be recruited in 12m, and have completed baseline, 6m and 12m assessments.
Results: 20 participants were recruited from October 2022 to November 2023. Of 36 eligible participants, 16 were excluded for, did not consent (8), too sick (6), withdrawal (1), unable to contact (1). As of June 2024, 20 participants completed baseline, 18 completed 6m and 10 completed 12m testing with ongoing 12m follow-up. Reasons for attrition at 6m included death (1) and declined to participate (1). In the study cohort, there were 9 females, mean age was 71.2 (SD 6.3) years. The types of lymphoma were DLBCL (n=12), MCL (1), FL (4) and MZL (3). The chemotherapy regimens were RCHOP (13) and BR (7). Median baseline 4m walk test was 1.1 m/s, 3 used a gait aid, 8 had a CIRS score of 5+, 6 had a frailty score of 15+, 5 had a Lee's 4yr mortality risk of over 20%, and 7 had a CARG chemotherapy toxicity risk of over 60%. Cognitive measures: The mean (SD) MOCA score at baseline and 6 months was 26.8 (3.4) and 26.7 (3.0), with more participants scoring ≤ 26 at 6m (8/18) compared to baseline (4/20). Mean (SD) baseline scores were TMT-A 42.4s (23.6) and TMT-B, 109.5s (55.6). At 6 months, scores improved with mean (SD) TMT-A 37.5s (24.6) and TMT-B 99.5 (74.0). The mean (SD) COWA score at baseline and 6m were 14.8 (5.7) and 15.5 (5.9). HRQoL improved from baseline 126.4 (24.1) to 6m 134.7 (19.9). At 6m, 2 required a dose reduction in their chemotherapy, 1 participant died from progressive disease and 2 participants went on to receive additional therapy.
Conclusions: It is feasible to recruit and conduct a comprehensive cognition assessment in older patients receiving chemotherapy for NHL at baseline and 6m. We plan to update 12m data and conduct an exploratory analysis to assess for change in cognition from baseline to 12m. These results will inform a future clinical trial evaluating cognitive effects in older individuals with NHL undergoing chemotherapy.