Another commonly used class of drugs in hematologic malignancies is vinca-alkaloids, which are frequently used for treating Hodgkin and non-Hodgkin lymphomas. The 4 main agents in clinical use are vincristine, vinblastine, vinorelbine, and vindesine, and they vary in their risk of neurotoxicity. Vincristine is the most neurotoxic of the vinca-alkaloids, and induces a distal sensory peripheral neuropathy in anywhere from 18% to 70% of adult patients and often requires dose reduction. Vinblastine has been associated with lower risk for peripheral neuropathy compared with vincristine, but even so, peripheral neuropathy has been reported in 12% to 56% of patients, and up to 12% of patients report severe peripheral neuropathy.

Vedotin-containing immunoconjugates are an emerging class of therapies for the treatment of lymphomas. Peripheral neuropathy is a common side effect of brentuximab vedotin, an antibody-drug conjugate consisting of a specific antibody targeting CD30, and generally manifests as sensory neuropathy. The development of peripheral neuropathy appears to be dose-dependent and cumulative, suggesting that dose modification could be a preventive approach for some patients. Polatuzumab vedotin, another drug in this class, has also been associated with peripheral neuropathy, with one open-label study reporting an incidence of 42% and additionally showing peripheral neuropathy to be dose-dependent. 

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Research Needed for Prevention Strategies

The researchers pointed out that vinca-alkaloids are a key component of treatment regimens for childhood hematologic malignancies. Given the significance of long-term vinca-alkaloid peripheral neuropathy, they have the potential to have a significant effect on quality of life. Unfortunately, noted Dr Park, there are currently no proven preventive strategies for peripheral neuropathy during treatment.


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“The current recommendation is limited to close monitoring and treatment modification to prevent the development of severe and persistent nerve damage,” she said. “There are a number of trials currently investigating possible neuroprotective strategies, including exercise intervention and pharmacologic agents. However, the results of these studies are yet to be known, and larger-scale randomized control trials will need to be conducted to further examine the efficacy of these interventions.”

Recognizing patients who are at higher risk of developing peripheral neuropathy has also been difficulty. Studies on genetic risk factors for treatment-related peripheral neuropathy have provided insights into the potential underlying mechanisms, but there is still no true consensus on genetic risk factors. To date, there has been a high degree of variation in studies, as well as a lack of replication.

Some potential clinical risk factors have been investigated, and higher cumulative dose and increased number of treatment cycles appear to be associated with greater risk for peripheral neuropathy. Results from a few small studies suggest that age and diabetes may also play a role in the development of peripheral neuropathy among patients receiving bortezomib, but these findings have not been replicated in larger studies. Among children receiving vincristine, obesity, white race, and older age may be clinical risk factors for peripheral neuropathy.

“Limited evidence exists regarding risk factors for peripheral neuropathy development,” said Dr Park. “Higher cumulative dose is typically associated with higher risk of developing neuropathy, as is pretreatment neuropathy.”

She added that pharmacogenetic studies have suggested that polymorphisms in certain genes, such as CYP3A5, may be associated with different risk profiles. “However, well-phenotyped clinical studies are still needed to confirm these associations,” she concluded.

Reference

  1. Li T, Timmins HC, Lazarus HM, Park SB. Peripheral neuropathy in hematologic malignancies — past, present and future [published online January 17, 2020]. Blood Rev. doi:10.1016/j.blre.2020.100653