ARTICLE IN BRIEF
Researchers found muscle weakness in 14 percent of the leukemia patients who underwent allogeneic stem cell transplants, suggesting that it is a more common complication than previously thought.
Leukemia patients who undergo allogeneic stem cell transplants may be at significant risk for later developing inflammatory myopathy, even when levels of a common blood biomarker for such disorders is not present, according to a team of South Australian researchers who examined one hospital's records over a ten-year period.
Earlier research reported an estimated 8 percent of stem cell recipients develop neuromuscular complications, but the new study, reported in the September 8 online edition of Muscle & Nerve, found muscle weakness in 14 percent of the research subjects. This represents two occurrences per thousand cases annually.
The scientists retrospectively reviewed all transplant recipients at the Royal Adelaide Hospital in South Australia from 2004 to 2014. More than half (57 percent) of the patients experienced chronic graft-versus-host disease (GVHD) defined as occurring at least 100 days post-transplant.
Onset of muscle weakness varied among the patients, but all had a history of past or concurrent chronic GVHD involving other sites, the researchers reported.
Six patients had biopsy-confirmed inflammatory myopathy, three had GVHD, two patients suffered necrotizing myopathy, and one patient was diagnosed with dermatomyositis associated with anti-MDA5 antibodies — a biomarker of idiopathic inflammatory myopathies, most notably dermatomyositis and polymyositis.
Most patients underwent stem cell transplantation for acute myeloid leukemia, followed by acute lymphoblastic leukemia
Patients with inflammatory myopathy had poor outcomes, the researchers noted, with five out of six patients dying before end of the study period.
“Treating physicians should be vigilant for this as a late complication,” said researcher Julia New-Tolley, MBBS, at the University of Adelaide, in South Australia.
“CK [creatine kinase] levels can be normal in these patients, but this does not exclude the possibility of inflammatory myopathy [IM], and if suspicion for IM is high, muscle MRI and muscle biopsy should be performed,” Dr. New-Tolley told Neurology Today.
“Inflammatory myopathy seems to be under-recognized as a complication post stem cell transplant, therefore the main take home message for neurologists, oncologists, and stem cell recipients is that inflammatory myopathy is a potentially treatable condition that should be considered in the patient presenting with weakness post allogeneic stem cell transplant,” Dr. New-Tolley said.
If clinical suspicion for IM is high, she suggested muscle biopsy or magnetic resonance imaging of muscle. “We are unclear why inflammatory myopathy appears to be predominantly a delayed complication, rather than an acute one, and research into the underlying disordered immune regulation is necessary.”
Although muscle weakness occurred in 32 out of 224 patients and myopathy was confirmed in 19 percent of the cases, CK, a biomarker for autoimmune muscular myopathy, was elevated in only seven out of 20 patients. The authors noted that CK levels were not checked in 38 percent of the cohort who had muscle weakness.
The most common documented cause of weakness among the patients was steroid myopathy in 15 individuals; inflammatory myopathy in six; deconditioning in five patients; neuropathy in two individuals; and single cases of a multiple sclerosis flare, cord compression due to infiltrative disease, and colistin neurotoxicity. The rate of myopathy among the patients at 2.7 percent was somewhat lower other reported rates that have ranged from 3.4 percent to 7.6 percent, however these rates were reported only in patients with chronic GVHD rather than all transplant patients.
Dr. New-Tolley said the study was limited by its retrospective design and by the fact that not all patients with weakness were examined by a neuromuscular expert nor was follow-up standardized.
Most cases of inflammatory myopathy post-transplant are due to chronic graft-versus-host disease, which has been temporally defined as GVHD occurring after 100 days post-transplant. Importantly, there are also differences in the mechanism of immune response between acute and chronic GVHD.
Commenting on the study, Thomas Lloyd, MD, PhD, associate professor of neurology and co-director of the Johns Hopkins Myositis Center in Baltimore, said the most important finding is that inflammatory myopathy is a potential and likely underdiagnosed delayed complication of such transplants.
“While half of the six cases described in the study are likely due to graft-versus-host disease, the other half appear more similar to autoimmune myopathies dermatomyositis or immune-mediated necrotizing myopathy,” Dr. Lloyd told Neurology Today.
“Clinicians should look out for proximal muscle weakness in these patients and, if present, should be evaluated by checking serum CK, electromyography, and/or muscle magnetic resonance imaging to evaluate for myositis. If any of these initial studies are abnormal, further evaluation with autoantibody studies and muscle biopsy should be considered, and patients with inflammatory myopathy should be treated promptly,” he said.
To gain additional insights and better clarify risk, Dr. Lloyd said a prospective study is needed to evaluate allogeneic transplant recipients for early signs and symptoms of weakness.
Mazen Dimachkie, MD, FAAN, professor of neurology and chief of the neuromuscular division at the University of Kansas Medical Center in Kansas City, told Neurology Today that it is important to keep in mind that the most common causes for weakness in allogeneic stem cell recipients are steroid myopathy (47 percent), inflammatory myopathy (19 percent), and deconditioning (16 percent).
Evaluating the ability of such patients to arise from a chair without using their arms may be a valuable bedside tool for clinicians to screen for muscle weakness, he said. In suspected cases, more systematic evaluation should include neurologic clinical evaluation, serum CK, myositis specific antibodies, and electrodiagnostic testing. In some cases, muscle histopathologic assessment is necessary.
Dr. Dimachkie also noted some of the study's shortcomings. “By virtue of its retrospective nature, this study has missing data points. Since the study is from South Australia, it may not be applicable to a variety of gene pools,” he noted.
He called for large, prospective, multicenter international studies to systematically investigate the clinical phenotype and laboratory profile in such cases. “Such a study might be well suited to evaluate in-situ inflammatory cell chimerism in myositis cases and to gain better insight into disease pathogenesis,” he said.