ARTICLE IN BRIEF
Autologous peripheral blood stem cell transplantation led to marked improvements in nerve conduction and function testing in nine patients with a rare peripheral neuropathy called POEMS.
Transplanting a patient's own blood stem cells appears to repair peripheral nerve damage caused by a rare paraneoplastic syndrome known as POEMS — polyneuropathy, organomegaly, endocrinopathies, monoclonal gammopathy, and skin lesions.
In the Nov. 18 Neurology, Japanese investigators reported that they safely and successfully used autologous peripheral blood stem cell transplantation (PBSCT) in nine patients, all of whom showed marked improvement in nerve conduction and function testing six months after transplantation. Three chair-bound patients regained the ability to walk.
“Autologous peripheral blood stem cell transplantation results in obvious neurologic improvement within six months, presumably by extensive axonal regeneration and remyelination,” according to lead author Satoshi Kuwabara, MD, PhD, chief of undergraduate and postgraduate education in the neurology department at Chiba University in Chiba, Japan.
“At the time of submission in December 2007, our study included nine patients, with a median follow-up period of 20 months ranging from eight to 49 months. Now, 10 months later, the mean follow-up period is 30 months, ranging from 18 to 59 months, and all nine patients are able to walk independently,” he said. “Moreover, during those 10 months, we have treated an additional six patients, so our total is now 15 patients.”
All of the nine patients in the study had substantial sensory and motor deficits prior to treatment. After PBSCT, they had monthly neurologic evaluations, with strength and nerve conduction evaluation and standardized disability rating after three months. All of the patients showed improvement in every area, and none has experienced relapse.
“Today, all the original patients can walk and six of them can run,” Dr. Kuwabara said.
Elevated blood levels of vascular endothelial growth factor (VEGF), indicative of nerve demyelination, are an important biomarker for POEMS. As in previous reports, the Japanese team discovered that VEGF levels in patients fell rapidly within one month of PBSCT, with neurologic improvement evident within three months.
POEMS, a rare multisystemic disorder associated with abnormal plasma cells, has only recently been characterized as a syndrome. Although there is no specific case definition, POEMS patients typically have three or more of five defining characteristics: polyneuropathy, sclerotic bone lesions, skin changes (hyperpigmentation), skin-thickening or hypertrichosis, and endocrine dysfunction. Because the extent of symptoms remains unknown, POEMS is often misdiagnosed, according to Dr. Kuwabara.
POEMS generally appears after age 50, although it has been reported in children as young as 15 years. It is slightly more prevalent in men; Japanese men appear to have a higher incidence, although the reason is unknown.
Dr. Kuwabara said the findings support considering PBSCT as a first-line treatment for POEMS.
In 2003, researchers at Mayo Clinic College of Medicine, in Rochester, MN, published the first study showing neurologic improvement in multiple POEMS patients receiving high-dose chemotherapy and PBSCT.
In 16 patients, treatment resulted in decreased VEGF levels and significant corresponding improvement in nerve conduction and neuropathy impairment scores. However, there was one death (6 percent mortality) and respiratory problems in several patients. In addition, most treated patients required artificial respiration for some period after the transplant procedure.
Principal investigator Angela Dispenzieri, MD, assistant professor of hematology, has continued to successfully use the technique in over 30 patients to date. She agrees that transplantation should be a front-line treatment for POEMS neuropathy, she told Neurology Today in an e-mail.
A pooled review of the medical literature on transplanted POEMS patients, conducted by Dr. Dispenzieri, showed an overall mortality rate of 7.4 percent.
“The [Kuwabara] study supports our findings, in more than 30 patients, that high dose chemotherapy with autologous peripheral blood stem cell support is an effective upfront treatment for patients with POEMS syndrome,” she said. “This paper's major importance is in highlighting these observations to an audience of neurologists, and it will hopefully heighten the awareness of this potentially devastating but imminently treatable disease.”
‘A CONVINCING ARGUMENT’
In an accompanying editorial, Colin Chalk, MD, associate professor of neurology and neurosurgery at McGill University in Montreal, urged neurologists to take note of the findings.
“POEMS is fundamentally a paraneoplastic syndrome, but its pathophysiology is distinctive,” he wrote. “Unlike most paraneoplastic neurologic syndromes (for example, Lambert-Eaton myasthenic syndrome, sensory neuronopathy), which are accidental consequences of a host's immune response to a neoplasm, the manifestations of POEMS appear to be caused by overproduction of a cytokine, vascular endothelial growth factor (VEGF), by the neoplastic plasma cells themselves.”
Although the precise role of VEGF in the syndrome is not completely understood, he noted, standard immunomodulatory therapies generally do not work for POEMS neuropathy. Further, because the neurological sequelae of POEMS resemble those of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) — a far more common disorder that responds well to immunotherapy — neurologists need to be able to tell the two apart, he said.
“Failure to recognize the non-neurologic features of POEMS in a patient with a chronic demyelinating neuropathy may lead to a misdiagnosis of CIDP, and also to long courses of ineffective and expensive treatments.”
Although the study was not “the gold standard” — a randomized, blinded, and controlled trial — its design, the positive findings, and the rarity of the disorder present a convincing argument for considering PBSCT, according to Dr. Chalk.
“As clinical neurologists, we are often forced to make judgments about the value of treatments in conditions for which randomized controlled trials have not been or may never be conducted,” he wrote.
“In such situations, the evidence must be evaluated using less robust but still worthwhile criteria. For example, have data been collected using a prospective protocol, rather than by retrospective chart review? Is the condition's natural history well known and predictable? Were clear, validated, and clinically meaningful endpoints used? Was observer bias minimized, by using objective measures of function and blinded evaluators? Except for the last, the Kuwabara study meets these criteria, lending credence to their claims of efficacy of PBSCT for POEMS neuropathy.”