Off-label use of the multiple sclerosis (MS) therapy rituximab (sold as Rituxan in the U.S. and MabThera in Europe) may not be recommended to treat patients with advanced stage childhood cerebral adrenoleukodystrophy (CALD).
A report describing the case of a young boy with advanced CALD revealed that treatment with rituximab failed to prevent the deterioration of motor and cognitive functions, as well as to halt the progression of disease-related inflammatory brain lesions.
The report, “B cell depletion can be effective in multiple sclerosis but failed in a patient with advanced childhood cerebral X-linked adrenoleukodystrophy,” was published in the journal Therapeutic Advances in Neurological Disorders.
People with either CALD or MS show a significant overlap of inflammatory brain lesions in advanced disease stages. Supported by this finding, it has been proposed that therapies designed to prevent pro-inflammatory mechanisms in the central nervous system could represent an effective stragegy for these disorders.
Several immunomodulatory therapies with anti-inflammatory effects have been approved for the treatment of MS. But, to date, such agents have shown to be unsuccessful in CALD patients.
A team at University of Göttingen, in Germany, presented the case of the young boy, who was the son of a healthy father and a mother with mild symptoms of adrenomyeloneuropathy — the adult-onset form of ALD. Pregnancy was complicated by gestational diabetes, while delivery was via C-section due to HELLP syndrome — a life-threatening complication characterized by high blood pressure and proteins in the blood — and at the 36th week of gestation.
At age 2, the boy’s skin was darker compared with his younger siblings, indicating adrenal gland insufficiency. By age 4, he had experienced three severe episodes of gastroenteritis (GI infection) with lethargy and insatiable vomiting. Then, from age 7, his learning and work abilities at school worsened, with subsequent reading difficulties and impaired speech (amnestic aphasia, which refers to failure to say the words one wants to express).
After his brain was evaluated by magnetic resonance imaging (MRI) he was found to have classical CALD patterns, localized white matter lesions affecting the splenium of the corpus callosum (a band of nerve fibers connecting the two sides of the brain). Of note, the white matter contains nerve fibers and makes up about half of the human brain.
According to the Loes score — a way to measure disease severity based on brain abnormalities and mass loss seen on MRI — the boy revealed severe cerebral involvement.
The diagnosis of X-ALD — the most common form of adrenoleukodystrophy — was confirmed by the high levels of very long-chain fatty acids in the blood that he had. At the time he already was experiencing impaired walking and direction difficulties.
Looking back, the clinicians said that the adrenal insufficiency found at age 2 should have led to immediate ALD diagnosis, with hematopoietic stem cell transplant (HSCT) offered upon detection of cerebral involvement. However, the advanced disease reflected by the Loes score and his rapidly progressive clinical course, indicated loss of the myelin protective sheath of nerve cells in both brain and spinal cord, which made HSCT a non-applicable option.
Due to the lack of therapeutic options available, the clinical team decided to treat him with off-label rituximab, once a week over four weeks under compassionate use, when he was 8 years old.
Rituximab an antibody developed and marketed by Roche that was designed to target the CD20 protein and deplete active immune B-cells, which are known to contribute for the pro-neuroinflammatory mechanisms in MS.
After the second infusion, the boy experienced total depletion of B-cells, as determined by peripheral blood cell counts, without signs of adverse reactions. However, he kept showing signs of clinical deterioration.
New MRI scans at two and four months after the first rituximab infusion revealed progressive inflammatory loss of myelin extending to the brain’s frontal lobe. The boy died 18 months after the initial ALD diagnosis and six months after starting treatment with rituximab.
“Our detailed clinical, imaging, and immunological data revealed that rituximab is not effective in advanced stages of X-ALD and consequently should not be applied for compassionate use in these patients,” researchers wrote.
They also commented that rituximab’s lack of effectiveness in advanced CALD, despite effective B-cell depletion, indicates that the role of these cells in inflammatory myelin loss is different in ALD and MS.