Among 35 sickle cell patients who received an infusion of Bluebird's LentiGlobin treatment, all had successful engraftment and total hemoglobin levels increased from 8.5 grams per deciliter at the start of treatment to at least 11 grams after six months.
The team behind the nonrandomized open-label HGB-206 study, led by Dr. John Tisdale, chief of the cellular and molecular therapeutics branch of the National Health Lung and Blood Institute, said 25 patients could be evaluated and although they had experienced a median of 3.5 severe vaso-occlusive events prior to the infusion, there were none afterward.
The treatment uses a form of adult hemoglobin A designated T87Q that "provides for more anti-sickling than the normal hemoglobin, and second, it allows us to precisely measure what fraction of the hemoglobin is coming from the gene therapy after the transplant," he said.
"One-time treatment with LentiGlobin led to stable, durable production of HbA-T87Q, with expression of HbA-T87Q in approximately 85% of red cells, a reduction in levels of sickle hemoglobin and in key hemolysis markers, and normalization of total hemoglobin during 54.8 patient-years of follow-up," the researchers concluded.
Hemolysis was reduced based on measures such as reticulocyte counts and lactate dehydrogenase levels, but they didn't quite approach normal levels.
"We are happy with the results but are always looking for ways to improve our therapies," Dr. Tisdale told Reuters Health in an email. "Ultimately, we would like to get to a place where the transplantation procedure is not necessary as this is the most cumbersome aspect of the therapy and the one that is the most difficult for the patient."
"There were no reported strokes after LentiGlobin infusion, including in patients with a history of stroke," the team said.
Three volunteers experienced febrile neutropenia, leukopenia and decreased diastolic blood pressure that may have been related to LentiGlobin therapy, but none of the cases were serious and the problems resolved within a week.
There was one sudden cardiac death, but that was considered to be associated with cardiac fibrosis and other chronic cardiopulmonary organ injury, not the treatment.
The team noted that it remains to be seen whether the benefits of the gene therapy, which the company keeps tweaking to improve performance, will persist for the rest of the person's life.
The beta-thalassemia study results involve 23 patients, all with a non-B0/B0 genotype, and a median follow-up of just under 30 months. Twenty of the 22 people who could be evaluated (91%) achieved transfusion independence, with an average hemoglobin level of 11.7 grams per deciliter.
Before treatment, all had been receiving at least eight transfusions per year.
Seven of the evaluable patients were under 12. The treatment gave six transfusion independence.
Total hemoglobin and hemoglobin-A levels plateaued by 6 months.
The only serious side effect from the treatment, known as beti-cel, was thrombocytopenia, seen in one patient. Others experienced serious adverse events but those "were consistent with those that are typical of busulfan-based myeloablation" needed to prepare for stem cell transplant, said the team, led by Dr. Franco Locatelli of the IRCCS Ospedale Pediatrico Bambino Gesù in Rome.
"The liver iron concentration also decreased over time in patients who had transfusion independence" and those patients were able to stop chelation, they said.
The ongoing single-group open-label phase 3 study is known as HGB-207 or Northstar-2. Beti-cel therapy for beta-thalassemia is licensed under the brand name Zynteglo in the United Kingdom and the European Union. The company has been wanting to charge $1.8 million for the one-time treatment.
Earlier this year, the U.S. Food and Drug Administration forced bluebird to suspend tests of the LentiGlobin therapy after one sickle cell patient who was about 5.5 years into treatment in a phase 1/2 trial developed acute myeloid leukemia (AML). The concern was that the company's BB305 lentiviral vector might be involved. That AML case came immediately after another patient in the HGB-206 study appeared to develop myelodysplastic syndrome (MDS).
A Bluebird team led by Dr. Sunita Goyal reported at the meeting and in the Journal that a subsequent investigation suggested that the leukemia "was unlikely to be related to vector insertion, given the location of the insertion site, the very low transgene expression in blast cells, and the lack of an effect on expression of surrounding genes."
The group did find several somatic mutations that seemed to predispose the patient to AML.
That "suggests that patients with sickle cell disease are at increased risk for hematologic malignant conditions after transplantation, most likely because of a combination of risks associated with underlying sickle cell disease, transplantation procedure, and inadequate disease control after treatment," they said.
In the case of MDS, testing subsequently showed that the patient actually had transfusion-dependent anemia, according to the company's April 20 announcement.
The suspension also affected beti-cel testing and therapy because both beti-cel, which is short for betibeglogene autotemcel, and LentiGlobin use the same viral vector, BB305.
The FDA lifted its hold on the LentiGlobin tests in June.
Both the Tisdale and Locatelli teams said there were no cases of hematologic cancer during follow-up.
Asked about the willingness of sickle cell patients to undergo such an intensive treatment in an era when COVID-19 has revealed the unwillingness of so many people to get vaccinated to avoid falling deathly ill, Dr. Tisdale said this situation is different.
"Part of the reluctance to getting vaccinated for COVID-19 relates to individuals having no knowledge of the potential severity of the disease. That is not the case for patients with sickle cell disease," he said. "These patients have lived their entire lives with a severe disease they were born with, and many have spent much of their lives in the hospital. Through the process, they have become very knowledgeable about their disease. This knowledge improves their ability to make decisions about this and other potential therapies," he said.
SOURCES: https://bit.ly/3rRRbg9, https://bit.ly/30cOvOZ and https://bit.ly/3rTil6C; The New England Journal of Medicine, online December 12, 2021.
By Gene Emery
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