Early intervention and careful management are critical in the treatment of peripheral neuropathy
Peripheral neuropathy is a common occurrence in patients with hematologic diseases, whether from the disease itself or the chemotherapy used to treat the disease, and often has debilitating and long-lasting effects. Neuropathy can substantially affect overall quality of life and, to date, has few effective treatment options.
For some patients, neuropathy symptoms may fade with time; for others, the condition is permanent or continues to worsen after completing chemotherapy.
Due to the debilitating nature of neuropathy, prevention, early communication about signs and symptoms, and strategic management are essential to limiting its effects.
“The best treatment for neuropathy is to prevent it from happening, sadly, because a lot of the pharmacologic treatments are not that effective,” explained Ramy Sedhom, MD, an oncologist and palliative care physician fellow at Memorial Sloan Kettering Cancer Center in New York.
Dr. Sedhom and other specialists in palliative care and hematology/oncology spoke with ASH Clinical News about the management and prevention of peripheral neuropathy in patients with hematologic disorders, including how neuropathy affects cancer treatment and when to get the neurologist involved.
What Causes Peripheral Neuropathy?
Peripheral neuropathy is a broad term used to describe the more than 100 forms of a condition that involves damage to the peripheral nervous system, according to the National Institute of Neurological Disorders and Stroke.1 It is estimated that more than 20 million people in the U.S. are affected by peripheral neuropathy, and it can be either acquired or genetically inherited.
Each form of the condition has a distinct prognosis and symptom profile, making it difficult to draw universal conclusions about its causes or effective management.
Neuropathy is caused by “a huge range” of factors, including metabolic issues, genetic disorders, immune system problems, and treatments, Susanna Park, PhD, an associate professor at the University of Sydney in Australia, told ASH Clinical News. “In the context of hematology and oncology, most cases of neuropathy are treatment-related, although with hematologic malignancies, peripheral neuropathy is also caused by the underlying disease.”
Common chemotherapy drugs known to damage the peripheral nerves include bortezomib, carfilzomib, cisplatin, brentuximab vedotin, vincristine, interferon, ixazomib, lenalidomide, methotrexate, pomalidomide, cytarabine, and thalidomide, according to the Leukemia & Lymphoma Society.2
“It’s a real challenge to understand because the field of chemotherapy is pretty broad,” said Noah Kolb, MD, an associate professor in the department of neurology at the University of Vermont College of Medicine. “When we talk about chemotherapy-induced peripheral neuropathy as a whole, we are actually talking about several kinds of drugs and several different mechanisms of action.”
Dr. Kolb believes this is one reason why the condition “has remained such a mystery.” The exact path of physiology differs between each drug or therapeutic class.
Common Neuropathy Symptoms
Peripheral neuropathies are classified according to the types of nerves that are damaged: motor, sensory, or autonomic. Most forms of neuropathy affect all three types of nerve fibers to some degree; others primarily affect one or two types. The symptoms a patient experiences depend on the types of nerves involved.
A patient who has damage to the sensory nerves may experience tingling in the hands, feet, or legs; pain, numbness, sensitivity to touch, burning, or difficulty feeling hot or cold.
Motor nerve damage can cause weak or sore muscles, loss of balance, or difficulty swallowing. These symptoms can make it challenging to walk or complete everyday tasks like buttoning a shirt or opening a jar.
Damage to the autonomic nerves – which control organs to regulate unconscious activities, such as breathing, digesting food, and heart and gland functions – could result in constipation or diarrhea, difficulty urinating, dizziness, irregular heartbeat, or excessive sweating.
“In general, most patients tend to develop neuropathy in the middle or end of their course of chemotherapy,” Dr. Kolb said of chemotherapy-induced neuropathy. “It’s often maximal around the end of their chemotherapy.”
However, sensory loss can progress for several months after cessation of treatment, a phenomenon called “coasting.” These symptoms alleviate with time for some patients, but others continue to experience the effects for the rest of their lives.
Who’s at Greatest Risk?
“There is a lot of variability in terms of the development and severity of neuropathy,” said Dr. Park, noting that researchers have been looking into individual risk factors.
For example, older patients and those with higher body mass index typically experience more severe neuropathy. Other factors, such as diabetes, alcohol abuse, vitamin deficiencies, and viral infections may increase the likelihood that patients with hematologic disorders develop the condition.
Dr. Sedhom added that neuropathy resulting from disease is often accompanied by comorbidities such as previous poor diabetic control, cardiac issues, or vision problems that suggest a systemic health condition.
There is general agreement, according to Dr. Kolb, that neuropathy can be more severe in chemotherapy-induced settings if the patient has some form of nerve damage before treatment begins.
Genetic factors also could play a role in neuropathy’s development. “On an individual patient basis, we are trying to unpack what those might be, but there’s still more work to do to understand the specifics of what defines an individuals’ risk,” Dr. Park said.
In 2015, scientists at St. Jude Children’s Research Hospital in Memphis, Tennessee, found that children with acute lymphocytic leukemia (ALL) were more likely to develop peripheral neuropathy while taking vincristine if they had inherited a particular single-nucleotide polymorphism (SNP) in the promoter region of both copies of the CEP72 gene.3 Of the 321 children and adolescents included in the study, 60.8% of those wo were homozygous for the SNP developed peripheral neuropathy, compared with just 23.4% of those who had one copy of the variation.
Also, patients who were homozygous for the SNP were more than twice as likely to experience serious, disabling, or life-threatening peripheral neuropathy. At the same time, these patients were found to have a higher cancer cell sensitivity to vincristine.
“This finding suggests that it might be possible to lower the vincristine dose in these patients, without compromising the likelihood of cures,” corresponding author William Evans, PharmD, said in a press release announcing the findings.4
In another study, researchers examined peripheral neuropathies among 816 patients with chronic lymphocytic leukemia (CLL), 19 of whom (2.2%) suffered from peripheral neuropathy during a median follow-up of 99 months.5 According to the results, 90% of the peripheral neuropathy cases were identified after CLL diagnosis and about half were sensory axonal peripheral neuropathy.
While some of the patients’ cases could be attributed to preexisting diabetes or nerve injury from treatment administration, there were 12 cases with no clear underlying cause. Researchers found the presence of chronic inflammatory demyelinating polyradiculoneuropathy (an autoimmune disease in which the body attacks the myelin sheaths) was higher than in the general population. Those who developed peripheral neuropathy also had high-risk cytogenetic abnormalities, a higher percentage of monoclonal proteins, and a higher likelihood of expressing the negative prognostic markers CD38 and ZAP70 at the time of diagnosis.
Grading and Assessing Neuropathy
The tool most often used by clinicians to grade or assess the severity of neuropathy is the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), but experts say the grading system has its limitations. Notably, it wasn’t specifically created for the evaluation of neuropathy.
“The problem is that the categories for neuropathy [in the CTCAE] are broad enough that they don’t pick up many of the smaller differences that are important with these disorders,” Dr. Kolb said. “I think that decisions can be made on such a person-by-person basis that it’s hard to make generalizations based on those very broad categories.”
Dr. Park agreed, calling for improved assessment tools that account for patient-reported symptoms and that could be used in concert with the broader clinical grading scales. “We know that patients typically will report greater pain severity than clinicians, so several studies are looking at the crossover between clinician-reported and patient-reported scales,” she said.
Sorely Lacking in Treatment Options
Regardless of how neuropathy develops, there are few effective interventions.
“There are two potential ‘holy grails’ of chemotherapy-induced neuropathy research that we all wish we could figure out: the drug to prevent it and the drug to fix it,” Dr. Kolb explained. “As a researcher in this area, I am frustrated that we don’t have any broadly applicable answers yet, but it’s not for lack of trying. We still need that breakthrough.”
Tanya Lehky, MD, chief of the electromyography section in the National Institute of Neurological Disorders and Stroke, added that once chemotherapy-induced neuropathy presents, “you really don’t have options to treat it. You can check to make sure that there is no underlying problem like a B12 deficiency, diabetes, thyroid disease, or vitamin E deficiency, but you can’t even really mitigate it.”
Early research has suggested that interventions such as cryotherapy, acupuncture, or exercise during chemotherapy could improve neuropathy symptoms, but has not shown overwhelming evidence of improvement in patient outcomes.
Pharmacologic interventions also have met with only limited success.
Despite data showing better outcomes with duloxetine, Dr. Sedhom sees more patients in the palliative care clinic who have been prescribed gabapentin, which is more easily accessible and more frequently covered by insurance.
He also cautioned that pharmacologic interventions have been found to be more effective for negative symptoms of neuropathy, such as numbness or sensitivity to hot or cold, but not for positive symptoms like the pins-and-needles sensation that many patients experience.
The literature also suggests that patients would need to be on much higher doses than are routinely prescribed in order to experience an effect, but that could lead to unwanted side effects.
“It’s a tough balance when it comes to pharmaceutical management, which is why we often say prevention is the best treatment,” Dr. Sedhom added.
“Even in situations where we feel like there may or may not be effective therapy and patients are pleading with us, we try to advocate and be on their side and say, ‘OK, let’s try it,’” he said. “That is likely what drives much of the ineffective treatment of neuropathy and greater use of pharmacologic agents that we know don’t work.”
Peripheral Neuropathy Across Hematologic Malignancies
In the setting of hematologic malignancies, neuropathies can be related to the disease itself, as in patients with monoclonal gammopathy of unknown significance (MGUS) or plasma cell disorders such as multiple myeloma, POEMS syndrome, and Waldenström macroglobulinemia. These individuals often have a higher rate of the complication at disease presentation.
More often, however, neuropathies occur as the result of a treatment for the hematologic malignancy. For example, the first-generation proteasome inhibitor bortezomib, which is routinely used to treat myeloma, is often accompanied by bortezomib-induced peripheral neuropathy (BIPN), an adverse reaction that is linked to numbness and painful paresthesia.6
In the lymphoma setting, Nina Wagner-Johnston, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, Maryland, said patients often develop peripheral neuropathy after using vinca alkaloids, such as vincristine or vinblastine, or the newer antibody drug conjugate brentuximab vedotin.
Chemotherapy is not the only treatment associated with peripheral neuropathy. Patients who develop chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation can experience peripheral nerve symptoms, although the mechanisms behind this connection are poorly understood. In a 2016 study published in Bone Marrow Transplantation, no patients who were referred to analysis for neuromuscular complications had preexisting neuropathy or an underlying disorder that could cause it, yet it was observed in 92.6% of patients.7 Approximately two-thirds of patients developed axonal sensorimotor symptoms and 71% had an abnormal finding on the quantitative sensory testing.
Dr. Lehky told ASH Clinical News that the results of this study were similar to those she’s observed in unpublished data: 68% of patients with chronic GVHD described weakness, 81% reported cramps, and 68% had sensory symptoms.
In a 2020 study, Ola Landgren, MD, PhD, a hematologic oncologist at the University of Miami Health System, and colleagues assessed the prevalence of peripheral neuropathy in patients with MGUS and found that, in addition to the condition being underrecognized in clinical practice, peripheral neuropathy was associated with a 2.9-fold risk of developing amyloid light-chain (AL) amyloidosis.8
Because of this risk, when Dr. Landgren sees a patient with a plasma cell disorder who has an M-spike or elevated light chain levels, he must first rule out AL amyloidosis by assessing for gastrointestinal symptoms, shortness of breath, cardiovascular issues, or foam in the urine suggestive of protein leakage. He also checks kidney function, B-type natriuretic peptide, and troponin; if abnormalities are found, he advances to an electrocardiogram and urine analysis before moving to an abdominal wall fat pad biopsy or possibly kidney biopsy to exclude a disease that needs extra attention.
When starting treatment, even after AL amyloidosis is ruled out, BIPN remains a concern.
Dr. Landgren emphasized the importance of early intervention because severe and long-lasting neurologic complications are often irreversible if they progress too far. He said that modern thinking sets the bar for intervention at CTCAE grade 3 or higher, but about half of patients with a plasma cell disorder will have grade 2 neuropathy. These symptoms can be “horrid” and need to be addressed, he added.
“We have to think more granularly about this when it comes to neuropathy,” Dr. Landgren said.
He advocated for close monitoring of patients and dose reduction or therapy-switching if a patient experiences more severe neuropathy.
While many of the newer drugs for myeloma may have lower risks of neuropathy, Dr. Landgren noted that these agents require greater attention to detail and expertise in their use than the average private practice doctor has.
Altering Chemotherapy Plans
The clinicians who spoke with ASH Clinical News stressed that the best strategy to managing chemotherapy-induced peripheral neuropathy is early intervention once symptoms appear. “If the treatment isn’t stopped or the dose isn’t reduced at this point, then the nerve pain can progress to motor neuropathy and functional impairment,” Dr. Wagner-Johnston warned.
To determine the best strategy for an individual patient, clinicians must evaluate his or her prognosis and unique needs through a risk-benefit analysis.
“If your goal for a patient is cure, the risk-benefit ratio may be offset and you are willing to take a little bit more risk to reach that goal,” Dr. Wagner-Johnston explained. “If your goal is entirely palliative, then you’re probably not willing to risk as much because comfort comes into play.”
She recommended having open conversations with patients, setting expectations, and then assessing their status and side effects at each cycle. In the treatment of both ALL and Hodgkin lymphoma, Dr. Wagner-Johnston said it is unlikely that oncologists would deviate from the frontline standards of care, but neuropathy symptoms could factor into selecting future treatment paths.
The challenge, the experts agreed, is that patients may not always be upfront about their symptomology. They may fear that reducing doses or stopping chemotherapy could compromise their cancer treatment.
For this reason, Dr. Wagner-Johnston added, clinicians should encourage patients to continuously communicate with members of the care team, including nurses and advanced practice providers, about their symptoms. “We must stress the importance of sharing those symptoms early to prevent peripheral neuropathy symptoms from intensifying,” she said.
When to Call the Neurologist
Hematologists and oncologists are equipped with a limited number of tools for assessing and managing neuropathy. In cases where a patient has a sudden onset or unusual distribution of symptoms, referral to a neurologist is warranted.
Dr. Kolb explained that neurologists can perform electrical studies to evaluate nerves in patients who have neuropathy before starting chemotherapy, which can help oncologists craft an informed treatment approach.
A multidisciplinary approach combining oncologists’ expertise in controlling cancer and neurologists’ expertise in controlling neuropathic pain can also minimize the occurrence of neuropathy.
“An integrated approach where the two of them are working together … is really advantageous,” Dr. Kolb said. “Different patients have different goals as it pertains to what they want from their cancer treatment and how important neuropathy is to them and that’s where having a cancer expert and a neuropathy expert together can be really helpful.” —By Jill Sederstrom
- National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet. Updated March 16, 2020. Accessed April 26, 2021. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet.
- Leukemia and Lymphoma Society. Side-Effect Management: Managing Peripheral Neuropathy. May 2020. Accessed April 26, 2021. https://www.lls.org/sites/default/files/National/USA/Pdf/Publications/FF12_Side_Effect_Mgt_Peripheral_Neuropathy_2020_FINAL.pdf.
- Diouf B, Crews KR, Lew G, et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA. 2015;313(8):815-823.
- St. Jude Children’s Research Hospital. Inherited gene variation leaves young leukemia patients at risk for peripheral neuropathy. February 24, 2015. Accessed April 26, 2021. https://www.stjude.org/media-resources/news-releases/2015-medicine-science-news/inherited-gene-variation-leaves-young-leukemia-patients-at-risk-.html.
- Briani C, Visentin A, Salvalaggio A, et al. Peripheral neuropathies in chronic lymphocytic leukemia: a single center experience on 816 patients. Haematologica. 2017;102(4):e140-e143.
- Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood. 2008;112(5):1593-1599.
- Bilic E, Delimar V, Desnica L, et al. High prevalence of small- and large-fiber neuropathy in a prospective cohort of patients with moderate to severe chronic GvHD. Bone Marrow Transplant. 2016;51(11):1513-1517.
- Rögnvaldsson S, Steingrímsson V, Turesson I, et al. Peripheral neuropathy and monoclonal gammopathy of undetermined significance: a population-based study including 15,351 cases and 58,619 matched controls. Haematologica. 2020;105(11):2679-2681.