Chemotherapy-related cognitive decline, often called “chemo brain,” is a significant concern for patients with non-Hodgkin’s lymphoma (NHL). It manifests as problems with memory, attention, processing speed, and executive function, which can severely affect quality of life. Novel therapies are being explored to reduce or prevent this cognitive decline, aiming to improve both survival and life quality for NHL patients.
Chemotherapy causes cognitive decline through multiple mechanisms. It can directly damage brain cells, disrupt neural connectivity, and induce systemic inflammation that affects the brain. Additionally, metabolic disturbances and oxidative stress triggered by chemotherapy contribute to neurotoxicity. These effects combine to impair brain structure and function, leading to cognitive symptoms. The complexity of these mechanisms means that a single approach is unlikely to fully prevent cognitive decline, so novel therapies often target multiple pathways.
One promising avenue involves precision medicine approaches that deliver chemotherapy more selectively to cancer cells, sparing healthy brain tissue. For example, antibody-drug conjugates (ADCs) are engineered molecules that attach chemotherapy agents to antibodies targeting specific cancer cell markers. This targeted delivery reduces off-target toxicity, including neurotoxicity, potentially preserving cognitive function. Recent preclinical studies have shown striking efficacy of such ADCs against aggressive cancers with reduced side effects, suggesting a future role in NHL treatment to minimize cognitive harm.
Another strategy focuses on modifying chemotherapy regimens and combining them with neuroprotective agents. High-dose methotrexate-based chemotherapy delivered through blood-brain barrier disruption techniques has shown effectiveness with less neurotoxicity in certain lymphoma types. Adjusting doses and timing, and using drugs that protect neurons or reduce inflammation, may help mitigate cognitive side effects. Clinical trials are ongoing to optimize these combinations and identify which patients benefit most.
Beyond pharmacological approaches, non-invasive neuromodulation techniques like transcranial magnetic stimulation and cognitive rehabilitation therapies are being investigated. These aim to enhance neural plasticity and repair cognitive networks damaged by chemotherapy. Early evidence suggests that integrating such interventions into cancer care can improve cognitive outcomes and functional independence.
Routine cognitive screening and multidisciplinary care involving oncologists, neurologists, and neuropsychologists are critical for early detection and management of chemotherapy-related cognitive decline. Personalized treatment plans based on biomarkers and neuroimaging may soon allow clinicians to predict which patients are at higher risk and tailor interventions accordingly.
Future research priorities include large-scale, longitudinal studies to map cognitive trajectories in NHL patients receiving chemotherapy and novel therapies. Randomized controlled trials are needed to validate neuroprotective strategies and establish standardized outcome measures. Translational efforts should focus on biomarker development to guide clinical decisions and enable precision-guided interventions.
In summary, novel therapies hold promise to reduce chemotherapy-related cognitive decline in non-Hodgkin’s lymphoma by targeting cancer cells more precisely, protecting neural tissue, and enhancing brain repair mechanisms. While challenges remain, advances in targeted drug delivery, neuroprotection, and supportive care are paving the way toward treatments that not only extend life but also preserve cognitive health.
