December 1, 2023

Just as a new gene therapy for sickle cell disease appeared to be on the rise, the company that developed the treatment discovered that two patients now have cancer and stopped the study.

One patient treated five and a half years ago developed myelodysplastic syndrome, a form of cancer that is often a precursor to leukemia, reported Bluebird Bio, while another developed acute myeloid leukemia.

It is not clear whether the cancers are related to experimental gene therapy. But the sudden setback is a disappointment for many sickle cell patients, mostly African Americans, who had hoped a cure was in sight.

“It feels like sickle cell disease can never get a break,” said Dr. Melissa J. Frei-Jones, a researcher at the University of Texas Medical School at San Antonio.

“My other concern is that after it has taken so long for the medical community to regain any level of trust, the black community will lose confidence in research studies,” she added.

It is not yet clear what caused the cancers. One possibility is that the disabled virus that was used to deliver gene therapy damaged critical DNA in blood-forming cells in patients’ bone marrow. That would be the worst case scenario, said Dr. John F. Tisdale, director of the Cell and Molecular Therapeutics Division at the National Heart, Lung and Blood Institute.

However, there’s also a likelihood that both cancers were caused by a powerful drug, busulfan, which is used to cleanse the bone marrow to make room for new cells that have been modified by gene therapy. Busulfan is known to carry a risk of blood cancer, noted Dr. Tisdale. If this turns out to be the culprit in Bluebird Bio’s trials, “We’re back to what we know,” he said.

The disabled lentivirus that Bluebird uses to conduct its gene therapy was designed with safety features in mind. It is considered to be far less risky than the viruses used years ago in gene therapy that caused cancer in children with immunodeficiency. A lentivirus is also being used in a gene therapy study for sickle cell disease at Boston Children’s Hospital.

The first patient in Bluebird’s study developed myelodysplastic syndrome about three years after gene therapy, said Dr. Tisdale. An investigation found that it was caused by busulfan.

The new case “looks very similar to what we saw in the first patient,” said Dr. Tisdale. However, more tests will need to be done at this point to see if the new patient actually has the syndrome, he said.

Bluebird will perform an analysis to see if the gene that was added to the patient’s DNA ended up near a gene linked to the new cancers. If not, then Busulfan is the likely culprit.

The question is complicated by the fact that people with sickle cell disease are known to have an increased risk of leukemia even without treatment. Still, no one would expect two patients to develop the disease in a small study.

If gene therapy turns out to be to blame, it’s not clear what the Food and Drug Administration will do.

Sickle cell disease itself is degenerative and debilitating, causing episodes of severe pain and damage to tissues and organs over time, disabling patients and significantly shortening their lifespan, said Dr. David A. Williams, hematologist at Boston Children’s Hospital.

The risk of gene therapy could be offset by the benefits of treatment that could alleviate that terrible burden, he and other experts said.

Researchers need to speculate cautiously about what the cancers will mean for Bluebird’s gene therapy, said Dr. Michael R. DeBaun, director of the Vanderbilt Meharry Matthew Walker Center of Excellence for Sickle Cell Disease. But he said he sees cancer diagnoses as “a cautionary story about the strange mix of cutting-edge science, clinical trials with few participants, and hopes for a population that has been largely ignored by the medical community”.

However, he is optimistic that at some point there will be enough evidence for patients to make informed decisions about curative therapies, including gene therapy and bone marrow transplants.

“Ultimately, families want the disease to be cured,” said Dr. DeBaun. “They may not be discussing a cure, but they want to know that they have a choice.”