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Researchers halt promising sickle cell treatment trials

Just when it looked like a new gene therapy for sickle cell disease was headed for success, the company developing the treatment discovered two patients now had cancer and discontinued the trial.

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

Concerned about the diagnoses, the National Institutes of Health halted a similar trial at Boston Children’s Hospital pending further investigation.

It is not clear whether the cancers are linked to experimental gene therapy. But this sudden setback is a disappointment for many experts and sickle cell patients, mostly African Americans, who were hoping a cure was on the horizon.

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

“My other concern is that the black community will once again lose faith or confidence in research studies after it has taken the medical community so long to even regain some degree of confidence,” she added.

It is not yet known what caused the cancers. One possibility is that the deactivated virus used to deliver the gene therapy treatment damaged crucial DNA in hematopoietic cells in the bone marrow of patients. That would be the worst-case scenario, said Dr John F. Tisdale, head of the cellular and molecular therapeutics branch at the National Heart, Lung and Blood Institute.

But it’s also likely 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 altered by gene therapy. Busulfan is known to confer a risk of blood cancer, Dr. Tisdale noted. If it turns out to be the culprit in the Bluebird Bio trials, “we’re back to what we know,” he said.

The disabled lentivirus that Bluebird uses to deliver its gene therapy has been designed with security features. It is believed to be much less risky than the viruses used in gene therapy years ago, which caused cancer in children with immune deficiencies. A lentivirus is also used in a gene therapy trial for sickle cell disease at Boston Children’s Hospital.

The first patient in Bluebird’s trial also developed myelodysplastic syndrome about three years after receiving gene therapy, Dr Tisdale said. An examination revealed that it was caused by busulfan.

The new case “looks a lot like what we saw in the first patient,” said Dr Tisdale. At this point, however, more tests need to be done just to establish that the new patient actually has the syndrome, he said.

Bluebird is completing an analysis to determine if the gene inserted into patients’ DNA has landed near a gene linked to new cancers. Otherwise, busulfan is probably the culprit.

Complicating the issue is that people with sickle cell disease have an increased risk of leukemia, even without treatment. Yet no one would expect two patients in a small trial to contract the disease.

If the gene therapy turns out to be at fault, it’s unclear what the Food and Drug Administration will do.

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

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

Researchers need to be careful when speculating what cancers will mean for Bluebird’s gene therapy, said Dr Michael R. DeBaun, director of the Vanderbilt-Meharry-Matthew Walker Center of Excellence in Sickle Cell Disease. But he said he saw cancer diagnoses as “an uplifting tale of the strange mix between cutting edge science, clinical trials with few participants and the hope of a population that has been largely ignored in the world. medical community.

He is optimistic, however, that there will eventually be enough evidence for patients to make informed choices about curative therapies, including gene therapy and bone marrow transplants.

“At the end of the day, families want to be able to be cured of the disease,” said Dr DeBaun. “They may not engage in the discussion for a cure, but they want to know they have a choice.”

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