Stem Cell Transplant Successfully Treats Bone Marrow Porphyrias

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by Steve Bryson, PhD |

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A blood stem cell transplant can successfully correct defects in the body’s ability to make heme — a molecule that helps transport oxygen through the bloodstream — in people with bone marrow-based porphyrias, a small study showed.

Thus, in patients with severe porphyrias, stem cell transplants should be considered early on in the treatment plan to minimize organ damage, the researchers said.

The study, “Hematopoietic stem cell transplant for erythropoietic porphyrias in pediatric patients,” was published in the journal Pediatric Blood & Cancer.

Porphyrias are a group of disorders characterized by mutations in genes that encode enzymes needed for heme production, which results in the toxic buildup of heme precursor molecules called porphyrins.

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As heme is produced in the liver and bone marrow, porphyrias can be broadly divided into two groups — liver-based, called hepatic, or bone marrow-based, known as erythropoietic — based on the site of porphyrin accumulation.

Congenital erythropoietic porphyria or CEP is caused by mutations in the UROS gene, which lead to the buildup of a molecule called hydroxymethylbilane in red blood cell precursors in the bone marrow. People with CEP typically have skin photosensitivity (light sensitivity) and hemolytic anemia (red blood cells destruction) and require regular blood transfusions.

Another form of bone marrow-based porphyria is EPP, or erythropoietic protoporphyria, which is  triggered by mutations in the FECH gene. Such mutations can cause damage to the skin and liver due to the resulting accumulation of photoreactive protoporphyrin.

Although most EPP patients only experience painful photosensitivity, in some cases liver damage can be extensive and a liver transplant may be needed. However, damage to the transplanted liver can still occur due to altered protoporphyrin production in the bone marrow.

Given the bone marrow origins of both CEP and EPP, a blood stem cell transplant — also known as hematopoietic stem cell transplant or HSCT — has been suggested as a potential therapy. This type of treatment involves collecting blood cell precursors from a healthy donor that are then infused into a patient’s bone marrow to correct porphyria-associated defects.

Now, researchers at Cincinnati Children’s Hospital Medical Center, in Ohio, reported on HSCT outcomes in four patients with CEP and one with EPP who transplants at their institution between 1999 and 2018.

At the time that they underwent the procedure, the CEP patients had a median age of 1.7 years. Two of the children — Patients 1 and 2 — had confirmed UROS mutations, while the full sibling of Patient 1, identified as Patient 3, also was thought to carry the same mutations.

All four CEP patients underwent myeloablative conditioning, which is a high intensity chemotherapy regimen. It was given immediately before the transplants to help eliminate the patients’ faulty blood cell progenitors and make room for the transplanted stem cells in the bone marrow.

The individual with EPP, identified as Patient 5, was an 18-year-old male with a confirmed FECH mutation. He had received a liver transplant 16 months prior to undergoing HSCT to protect his new liver. This patient also underwent pre-transplant conditioning with a low-intensity chemo regimen.

Following HSCT, none of the participants developed acute graft-versus-host disease — a condition in which the donor stem cells start attacking the recipient’s body within 100 days of the transplant. However, one patient developed limited chronic graft-versus-host disease, a similar condition that takes place more than 100 days after the transplant.

Patient 2 had a history of pneumonia and viral infections, and abnormal development of lung tissue associated with inflammation and scarring (bronchopulmonary dysplasia). On day 45 post-transplant, this patient died of viral pneumonia.

The remaining participants were alive and free of porphyria symptoms at a median follow-up of about 7.5 years (2,765 days).

Engraftment post-transplant is when blood-forming stem cells start to grow and give rise to new healthy blood cells. This occurred at a median of 11 days after the transplant for neutrophils — a type of immune cells — and 19 days following the procedure for platelets, which are small cell fragments needed for blood clotting.

Porphyrin levels in the bloodstream, red blood cells, and urine, measured at follow-up, were significantly reduced compared with levels seen before the transplant. However they were still elevated.

In three patients, blood porphyrin levels dropped from a median of 143 to 9.9 micrograms per deciliter (mcg/dL) (upper normal limit: 0.9 mcg/dL). Porphyrin levels in red blood cells in these same patients decreased from a median of 1,703 to 64 mcg/dL (normal range: 0.2–0.8 mcg/dL).

Only Patient 1 had a urinary test to measure porphyrin levels, which showed a reduction from 11,781 to 632 nanomoles per liter (nmol/L) (normal range: 0–300 nmol/L). Patient 3, who was followed for eight years, had the steepest porphyrin decline immediately following the transplant.

Due to special precautions to avoid light exposure, none of the participants experienced porphyria flares, skin damage, or ulcer formation while in the hospital.

“HSCT effectively corrects the defective bone marrow heme pathway in patients with erythropoietic porphyrias,” the researchers wrote.

“Four of five patients with porphyria are alive after HSCT without symptomatic porphyria manifestations or significant HSCT complications,” they wrote.

The team concluded that new strategies have made HSCT safe for patients — a significant change from prior decades in which the risks of the procedure traditionally outweighed the benefits.

“In patients with severe manifestations of erythropoietic porphyrias, HSCT should be considered and used early to minimize disease morbidity and transplant toxicity,” they concluded.