While allogeneic hematopoietic stem cell transplant (HSCT) is a feasible approach for people with adrenoleukodystrophy (ALD), it should be performed before the onset of neurological manifestations to effectively stop disease progression, a case report illustrates.
The study, “The experience of allogeneic hematopoietic stem cell transplantation in a patient with X-linked adrenoleukodystrophy,” was published in the journal Transfusion and Apheresis Science.
An allogeneic HSCT uses healthy blood stem cells, or hematopoietic stem cells — which can generate all types of blood cells in the body — to replace diseased or damaged bone marrow. Allogeneic means the stem cells come from a genetically similar donor, usually a close relative of the patient.
This transplant is regarded as the only approach able to prevent the progression of ALD — or X-ALD. It is best performed early in the disease course, researchers say.
A team at Hacettepe University, in Turkey, presented the case of a 31-year-old man diagnosed with ALD in 2007. His was the third case of this disorder in the family. Two siblings had died from childhood cerebral ALD.
The patient was started on diet and Lorenzo’s oil to stop disease progression, but began showing hyperactivity and impulsivity by 2014. His gait disturbance and visual acuity also became aggravated.
An initial plan to conduct an allogeneic HSCT was refused by the patient and his family, because his brother had died after the procedure.
The patient had a low level of morning cortisol, and a subsequent test confirmed adrenal insufficiency — a shortage of steroid hormones, mainly cortisol and aldosterone. That led to the start of treatment with prednisolone, the researchers said.
A brain magnetic resonance imaging (MRI) scan showed changes compatible with ALD. Over the following three years, the patient developed MRI lesions in the superior cerebellar peduncles, which connect the cerebellum with the midbrain. Lesions also developed in the fourth ventricle — a communicating network of cavities, containing cerebral spinal fluid — the optical pathways, and the internal capsules. These contain all fibers going to and coming from the cerebral cortex.
The patient also had an increased, or worsening Loes score — a way to measure disease severity based on brain abnormalities and mass loss seen on MRI.
The rapid changes seen on MRI, and the increased Loes score, made the patient and his family agree to undergo HSCT from an HLA-matched sibling. HLAs are molecules found on the surface of most cells in the body.
The clinicians used a conditioning regimen of reduced intensity to lessen toxicity, and reduce the risk of mortality. It contained fludarabine (30 mg/m2/day for six days), busulfan (4 mg/kg/day one week to five days before HSCT), phenytoin (to prevent seizures), granulocyte colony stimulating factor (5 μg/kg twice daily for 5 days), and anti-thymocyte globulin (5 mg/kg/day) given four days to the day before transplant in January 2018.
The patient stayed on antiviral prophylaxis against herpes simplex, varicella zoster, and Pneumocystis jirovecii through at least six months after the procedure. He also was given medication to prevent graft-versus-host disease (GvHD) — an immune reaction between the body and the donated tissue and cells.
The Loes score increased from 9 to 10 at three months after HSCT. In November 2018, the man was hospitalized due to nausea, vomiting, elevated liver enzymes — including alanine aminotransferases and aspartate aminotransferases — and leukopenia, which refers to a decreased level of white blood cells. His total level of bilirubin — a marker of liver damage — increased to 11.8 mg/dL during follow-up.
The man became more impulsive, and his visual acuity decreased. He showed bilateral optic atrophy, or shrinkage. A bone marrow biopsy was reported as hypocellular, meaning it showed reduced peripheral blood count.
Graft-versus-host-disease was deemed as the cause of the increase in liver enzymes. The patient therefore underwent a liver biopsy, which revealed minimal hepatocellular injury and cholestasis, or reduced bile flow. No activity of macrophages — key immune cells — was detected in either the bone marrow or the liver.
The patient then had a good response to treatment with methylprednisolone (2 mg/kg per day). The steroid decreased levels of liver enzymes, lessened leukopenia, eased neurological symptoms, and decreased visual loss.
“In conclusion, alloHSCT is effective and feasible in the treatment of X-ALD patients,” the researchers said, adding that the “use of reduced intensity conditioning regimen…allows us to reduce procedure-related toxicity and prevent mortality while achieving a curative effect.”
The team emphasized, however, that “these patients should undergo alloHSCT in the early stage of disease in order to get good survival.”
“Early diagnosis of these patients is important,” the clinicians said.