ReviewPeripheral neuropathy in hematologic malignancies – Past, present and future
Introduction
Peripheral neuropathy (PN) commonly affects the lives of many patients with hematologic malignancies. Although the etiology can be disease-related, it is most often produced as a treatment-related side effect. Neurotoxic treatments (including proteasome inhibitors, immunomodulatory drugs and vinca-alkaloids) are often used in the treatment of multiple myeloma, lymphomas and leukemias (Table 1). PN occurring during anti-neoplastic treatment can lead to dose reduction, delay or treatment cessation, while persisting symptoms post-treatment can adversely impact patients’ quality of life [1,2].
PN produces sensory, motor, autonomic nerve dysfunction, or combinations, leading to pain, loss of sensation, functional disability and increased falls risk [3]. Treatment-induced PN is most consistently assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Neuropathy Sensory subscale. This outcome measure is a clinician based grading scale that scores a patient’s symptoms from grade 0–4 (no symptoms to life threatening symptoms). However, the NCI-CTCAE has been known to under report symptom severity [4], while also lacking interobserver reliability [5] and responsiveness [6]. Despite these shortcomings, the NCI-CTCAE grading scale persists as the most commonly used measure of PN in clinical trials. This feature is reflected throughout this review with the incidence reported using this outcome measure (with mild symptoms denoted grade 1, moderate symptoms grade 2 and severe symptoms grade 3).
With the survival rates of hematologic malignancies steadily increasing [7], a research emphasis on treatment-residual side effects is necessary to ensure cancer survivors maintain high quality of life after completion of cancer treatment. The aim of this review is to provide an update of neurotoxic treatments used in hematologic malignancies, mechanisms producing PN in the clinical setting and treatment and rehabilitative strategies.
Section snippets
Search strategy and quality grading
The search strategy identified articles written in English through searches of the National Center for Biotechnology Information/PubMed database, the Cochrane Library and clinical trial registries using search terms ‘neuropathy’ and ‘neurotoxicity’ with multiple terms including ‘bortezomib’, ‘carfilzomib’, ‘ixazomib’, ‘proteasome inhibitor’, ‘thalidomide’, ‘lenalidomide’, ‘pomalidomide’, ‘immunomodulatory drugs’, ‘vincristine’, ‘vinca’, ‘vinca-alkaloids’, ‘brentuxumab vedotin’, ‘vedotin’,
Disease-related neuropathy
The etiology of PN experienced by patients with hematologic malignancies can be disease-related (Table 3). Multiple myeloma and Waldenström macroglobulinemia are associated with paraproteinemic PN [9,10]. In patients with treatment-naïve multiple myeloma, the prevalence of pre-existing PN ranges from 7.2% to 54% [11,12] with the variance largely depending on outcome measures used. Further studies have suggested more than 80% of pre-treated myeloma patients demonstrate subclinical sensory
Bortezomib
Proteasome inhibitors are actively used in the treatment of multiple myeloma, inducing apoptosis of cancer cells [17] by inhibiting the 26S proteasome, disrupting protein regulation and preventing proteasomal degradation of ubiquitinated proteins in cancer cells [18]. Bortezomib is the first generation proteasome inhibitor approved for clinical use and is effective for the treatment of both newly diagnosed and relapsed or refractory multiple myeloma [19,20]. PN is a common toxicity of
Immunomodulatory drugs
Immunomodulatory drugs are commonly used in the treatment of multiple myeloma. Thalidomide is a synthetic derivative of glutamic acid with the ability to inhibit tumor necrosis factor alpha (TNFα) production [54], and also possess anti-angiogenic [55] and immunomodulatory properties [56]. Lenalidomide and pomalidomide were synthesised with the purpose of increasing efficacy (TNFα inhibition capability) [57] while minimising the toxicities associated with thalidomide.
Vinca-alkaloids
Vinca-alkaloids are a class of chemotherapy derived from the periwinkle plant, and are commonly used for the treatment of Hodgkin and non-Hodgkin lymphomas [77]. The four main vinca-alkaloids in clinical use are vincristine, vinblastine, vinorelbine and vindesine.
Vincristine is the most neurotoxic of the vinca-alkaloids, resulting in PN being a prominent dose-limiting side effect. It induces a distal sensory PN in 18%-70% of adult patients [78,79]. Motor involvement can also occur, manifesting
Brentuximab vedotin
Brentuximab vedotin is an antibody-drug conjugate consisting of a specific antibody targeting CD30, and a microtubule disrupting agent monomethyl auristatin E (MMAE) linked through a protease-cleavable linker [100]. It has demonstrated efficacy across several CD30-expressing lymphomas including Hodgkin lymphoma, systemic anaplastic large cell lymphoma and CD-30 positive peripheral T-cell lymphoma [101,102]. PN is a prominent side effect of brentuximab vedotin, typically presenting as a sensory
Platinum
Platinum compounds including cisplatin and oxaliplatin are commonly associated with PN and utilised across a range of solid tumors. In the treatment of solid tumors, cisplatin-induced PN is strongly associated with cumulative doses of >300 mg/m2 [3,116]. In the setting of hematologic malignancies, there is a lack of specific information regarding PN in association with platinum treatment. Cumulative cisplatin doses in hematologic cancer regimens are often lower than in solid tumours and
Neuropathy outcomes post-treatment
The recovery and reversibility of PN post-treatment varies across neurotoxic treatments used in hematologic malignancies. BIPN is commonly described as reversible in the majority of patients. Typically, PN resolves or improves in a substantial majority of patients, as assessed by conventional grading scales. One series demonstrated that 88% of PN events completely resolved in 2.4 months, with 94% resolving to at least a grade 1 in a median of 2.6 months [120]. Another study found that 79% of PN
Role of genetic risk factors
The search for genetic risk factors for treatment related PN has provided insights into the potential mechanisms underlying the development of peripheral nervous system dysfunction. Overall, single nucleotide polymorphisms (SNPs) in genes associated with drug transport and efflux, neural development and repair, microtubule systems and genes associated with inherited peripheral neuropathies have been linked to treatment related PN in hematologic malignancies. However, there remains little
Current options in treatment and prevention
Although treatment-induced PN remain a common side effect among numerous hematologic malignancy treatments (Table 5), there remains a lack of strategies adopted for its treatment and prevention. Despite a number of clinical trials currently investigating possible treatment and prevention interventions (Table 6), recommendations are limited to regular monitoring with neurologic evaluation and dose modification or treatment cessation to prevent severe and permanent nerve damage [18]. In
Conclusions and future directions
Treatment related peripheral neuropathy is a common side effect in the treatment of hematologic malignancies. Despite the development of newer and novel analogues which are associated with reduced toxicity, PN remains an important consideration in managing patient quality of life and maximizing function. Improved understanding of the mechanistic bases underlying neurotoxicity will assist in the development of targeted neuroprotective approaches. Standardized and objective assessment strategies
Practice points
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Peripheral neuropathy (PN) remains a common toxicity associated with treatment for hematologic malignancy.
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Detailed clinical assessment (including baseline and during treatment) is required to monitor the development of toxicity and enable implementation of dose reduction guidelines.
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Improved assessment tools, including use of objective measures of PN and patient-reported outcomes, are required in clinical studies and clinical trials of neuroprotection.
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Further collaboration with neurologists and
Research agenda
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Examination of mechanisms for individual agents is required to guide development of neuroprotective therapy.
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Detailed studies with objective assessment tools are needed to clarify PN risk, particularly with newer agents.
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The development of better assessment tools to quantify PN in the clinical setting and a standardized set of clinical trial outcome measures.
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Better understanding of risk factors, including genetic risk factors, which may lead to individual patients having a higher risk of severe
Funding
This work was supported by the National Health and Medical Research Council of Australia [#1080521, 1148595] and the Cancer Institute of New South Wales [14/TPG/1-05].
Declaration of competing interest
Professor Lazarus is a consultant and promotional speaker for Seattle Genetics and Bristol-Myers Squibb and a consultant for Celgene Corporation.
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