Bortezomib helps girl avoid liver transplant rejection, return of PFIC2

Cancer treatment started after other approaches failed to help 10-year-old

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A young girl, sitting at a table, is shown drawing on a piece of paper.

Bortezomib, an anticancer medication, prevented a recurrence of progressive familial intrahepatic cholestasis type 2 (PFIC2) after a liver transplant by helping a young girl to avoid rejecting the organ, according to a report from Korea.

The report, “Successful Use of Bortezomib for Recurrent Progressive Familial Intrahepatic Cholestasis Type II After Liver Transplantation: A Pediatric Case with a 9-Year Follow-Up,” was published in the journal Pediatric Gastroenterology, Hepatology & Nutrition.

Progressive familial intrahepatic cholestasis comprises a group of rare genetic diseases marked by impaired production and/or secretion of bile, a digestive fluid, by liver cells. An impaired flow leads to cholestasis, or slowed or stalled bile flow, that can result in the toxic buildup of bile in the liver.

Symptoms typically begin early in childhood and include intense itching and jaundice, or yellowing of the skin and whites of the eyes.

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The kidney and its bile ducts are highlighted in this close-up illustration.

New study finds PFIC3 marked by increased inflammation in liver

Girl given transplant at age 1 to prevent liver disease progression with PFIC2

PFIC2 is a severe and treatment-resistant condition in newborns caused by a mutation in both copies of the ABCB11 gene. This gene provides instructions for producing bile salt export pump (BSEP), a protein that transports (pumps) bile salts from liver cells (hepatocytes). When BSEP is faulty or missing, bile acids accumulate within the liver to toxic levels and leak into the bloodstream.

Given its typically rapid progression to cirrhosis, in which the liver is irreversibly scarred, and its medication-resistant nature, a liver transplant “remains the only therapeutic option for end-stage PFIC type II in Korea,” the researchers wrote.

However, the transplanted organ can be rejected by a patient’s immune system, causing the disease to come back. When rejection is caused by self-reactive antibodies against the BSEP that are produced by the transplanted liver cells, the disease’s return is likely.

Scientists described the case of a 10-year-old girl with PFIC2 whose treatment with bortezomib — an injectable medication for multiple myeloma and a form of lymphoma, marketed as Velcade and available in generic forms — effectively prevented liver transplant rejection and disease recurrence.

Bortezomib works by blocking the proteasome, enzyme complexes within cells that break down damaged or unwanted proteins. This results in an accumulation of unwanted proteins that can kill cells, particularly the immune cells that produce antibodies.

Scientists also noted that bortezomib “has been used … for antibody-mediated rejection after solid-organ (liver, kidney, or heart) transplantation.”

The girl underwent a liver transplant for PFIC2 at age 1 and started on immunosuppressive treatment with tacrolimus and prednisolone to avoid organ rejection. At age 10, however, she began experiencing severe itching, jaundice, abdominal pain, and weight loss.

Physical examination revealed a swollen liver, and lab tests showed elevated liver enzymes, a sign that the liver may be inflamed or damaged, and high levels of bile acids in the blood.

A computed tomography scan showed no obvious abnormalities in the liver’s blood vessels or intrahepatic bile ducts, which carry bile inside the organ.

“Genetic testing confirmed the original diagnosis,” the scientists wrote. The girl carried a known mutation, called C.1416T>A, in both ABCB11 gene copies that produces a shortened, faulty version of BSEP.

Corticosteroids, rituximab, and other treatments failed to help the child

A liver biopsy to closely examine a tissue sample then revealed severe cholestasis and tissue scarring. The buildup of an immune molecule called C4d also suggested “recurrent BSEP deficiency after transplant and mild acute cellular rejection,” the researchers wrote.

She was treated with high-dose corticosteroids for two months, but they failed to control her cholestasis.

Suspecting the presence of self-reactive antibodies against BSEP, her doctors next opted for rituximab, a medication that depletes antibody-producing cells, and other treatments helping to remove or inactivate harmful antibodies from the bloodstream. These efforts also failed to ease the cholestasis symptoms.

The girl then received four doses of bortezomib over about 1.5 weeks. Within two weeks of treatment, her liver function began to improve, as indicated by lower levels of bilirubin, a bile pigment that causes jaundice.

Other markers of liver damage were seen to have stabilized two months later. A liver biopsy that followed six months of bortezomib treatment “demonstrated complete resolution of the recurrence,” the scientists wrote. Her BSEP levels had increased, whereas those of C4d had decreased.

Over nine years of follow-up, her BSEP levels remained constant, and her bile acids and bilirubin levels were normal. She experienced a moderate episode of rejection, which was treated with intermittent high-dose corticosteroids, but she had no complications, such as serious infections.

“This case represents the first use of bortezomib for treating BSEP deficiency recurrence after liver transplantation in a child with [PFIC2],” the scientists wrote. “The short-term response was rapid and successfully maintained throughout the long-term (9 years) follow-up.”

For this patient, “bortezomib was a safe and effective treatment,” they added, but “further evaluation is needed to confirm the safety and efficacy of bortezomib in [other] pediatric patients.”