The approval of thalassemia gene therapy heralds a new era of medicine

A newly approved gene therapy is changing the lives of patients with beta thalassemia – an inherited blood disorder – by helping to stop or significantly reduce their dependence on blood transfusions, said an expert from the leading global health system, the Cleveland Clinic, on International Thalassemia Day on May 8. .

A gene therapy known as betibeglogene autotemcel, or beti-cel, was approved last August by the US Food and Drug Administration (FDA) as safe and efficacious for adult and pediatric patients with transfusion-dependent beta thalassemia.

Rabbi Hanna, pediatric hematologist-oncologist at Cleveland Clinic Children’s – which is in the process of becoming one of the few certified centers in the world offering gene therapy – said: “This is an important milestone in the treatment of thalassemia because gene therapy uses patients’ own stem cells. hematopoietic to produce healthier red blood cells and cure the blood disorder – or at the very least, significantly reduce the number of blood transfusions needed to manage the condition. Thanks to gene therapy, we can remove the challenges thalassemia patients face and give them the potential to pursue their goals and dreams without the restrictions on blood transfusions or the complications of iron overload.”

Thalassemia, which has two types – alpha and beta – is one of the most common genetic disorders and occurs most frequently in people from the Middle East, Mediterranean countries, North Africa, India, Central Asia, and Southeast Asia.

Beta thalassemia affects the body’s ability to produce hemoglobin, the protein in red blood cells that allows it to carry oxygen throughout the body. Individuals diagnosed with beta thalassemia major develop serious symptoms at a young age, which can be treated with frequent blood transfusions, but the transfusions themselves pose a risk of iron overload with the potential to damage the patient’s liver, heart, and endocrine system.

New gene therapy

The new gene therapy, which tackles this problem, is ideal for teenagers or slightly older patients who have started having complications from blood transfusions, says Hanna.

Hanna said: “The gene therapy includes a short period (four days) of a chemotherapy called busulfan which can impact the fertility of both male and female patients, so it is better to wait until the patients reach their teenage years so they can undergo fertility-preserving treatments, although we have methods to maintain fertility even in pre-pubescent patients. On the other hand, it is best not to leave it on for too long because after years of infusions, the patient’s heart and liver may have been badly damaged from the excess iron. Generally, the healthier the patient is at the start of the gene therapy process, the fewer side effects they will experience.”

Minimally invasive beti-cel treatment is given in three phases over several months, says Hanna. In the first phase, two drugs (G-CSF and plerixafor) are used to stimulate the patient’s bone marrow to produce more stem cells. In the second, blood is drawn for collection of stem cells from the peripheral blood, and these stem cells are sent to a treatment company for gene modification, that is, inserting a gene that allows them to produce unaffected hemoglobin. The modification process takes about two months.

The last phase takes place in the hospital so that the patient can be closely monitored. They receive a single chemotherapy drug once a day for four days, followed by a few days rest, to prepare the body for the modified stem cells to be reinserted via an IV into a vein, similar to an IV.

Within about a month after the modified cell infusion, Hanna notes, most patients will implant the new stem cells and no longer need blood transfusions or other treatments because they will have cells formed in their bone marrow that are capable of producing hemoglobin normally. Even in some exceptional cases where gene therapy does not cure, the patient’s need for blood transfusions will decrease substantially.

Additional advances in treatment

In addition to the new gene therapy treatment, other advances in recent years have greatly improved the quality of life for thalassemia patients, said Hanna.

The drug with the generic name luspatercept-aamt was approved by the FDA in 2019 to reduce patient dependence on blood transfusions. It is given as an injection every three weeks and works by increasing erythroid (red blood cell) maturation and reducing the need for blood transfusions by up to 50% in some patients.

Luspatercept-aamt can also be used to improve outcomes in curative bone marrow transplants, which have become more accessible in recent years thanks to new transplant approaches. Hanna was one of the pioneers of haplo-identical bone marrow transplants, which made non-HLA-identical (human leukocyte antigen) donors possible.

Hanna said the reduction in blood transfusions activated by luspatercept-aamt means patients have better health before bone marrow transplants, and fewer antibodies that could potentially attack the transplanted bone marrow.

“With the wider use of gene therapy and the use of luspatercept-aamt to improve bone marrow transplant outcomes, almost all patients can be cured,” said Hanna.

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