Ahead of World Thalassemia Day [May 8], global health system Cleveland Clinic’s main campus has become one of only a few centers worldwide authorized to offer three novel gene therapies for treating individuals with sickle cell disease and beta thalassemia, significantly improving their quality of life and in most cases achieving a functional cure.
Sickle cell disease and beta thalassemia are inherited blood disorders caused by abnormalities in hemoglobin, the red protein responsible for transporting oxygen in the blood. In sickle cell disease, a genetic mutation causes abnormal hemoglobin to clump together so that the red blood cells become sickle shaped. Beta thalassemia, on the other hand, affects the body’s ability to produce hemoglobin. India and countries in the Middle East and Africa are among those with a higher prevalence for both diseases.
“These new therapies are well-tolerated, transformative and could enable individuals to live free from the often-debilitating effects of these diseases and their traditional treatments such as frequent blood transfusions, which carry the risk of iron overload and organ damage,” says Rabi Hanna MD, a hematologist-oncologist and director of the pediatric blood and bone marrow transplant program at Cleveland Clinic Children’s.
Both sickle cell disease and beta thalassemia are associated with lifelong complications, multi-organ damage and comorbidities that impact quality of life, ultimately leading to a shortened lifespan. Until now, the only curative treatment was an allogeneic blood or marrow transplant, and finding a suitable donor was often difficult and therapy could be complicated by Graft rejection or Versus Host disease (GVHD) due to immune interaction between donor and recipient (patient). In contrast, the new therapies work by extracting, a patient’s own blood-producing stem cells then modifying or adding genes that produce functionally normal red blood cells and reinfusing these blood-producing stem cells, thereby eliminating the need for a matching donor and the need to use immune suppression medications, while minimizing the risk of rejection and GVHD complications.
Cleveland Clinic will treat children and adults using one of three new therapies that act by either adding to or replacing defective genes in stem cells. The newest therapy, exagamglogene autotemcel [Casgevy], treats both sickle cell disease and beta thalassemia in children age 12 or older in addition to adults. Approved in January this year for treating sickle cell disease, and in December 2023 for transfusion-dependent beta thalassemia, this is the first medicine approved in the U.S. that uses the gene-editing tool CRISPR, which earned its inventors the Nobel Prize in chemistry in 2020.
The other two available therapies are lovotibeglogene autotemcel [Lyfgenia], approved by the FDA in December last year and used to treat patients with sickle cell disease who are aged 12 or above, and betibeglogene autotemcel [Zynteglo] approved in 2022 for the treatment of children and adults with transfusion-dependent beta thalassemia.
“The clinical trials showed remarkable success for this once-in-a-lifetime therapy, with a functional cure rate – defined as either transfusion-free survival in thalassemia patients or pain-free survival in sickle cell disease patients, – well above 90%. However, prospective patients should be aware that this is a treatment journey involving several phases, which is also why so few centers have the comprehensive and specialized expertise needed to provide the treatment,” Dr. Hanna says. “We are working with some hospitals in other regions so that international patients can undergo some of the preliminary phases in their own countries before completing the treatment at our facilities.”
The initial preparation phase, lasting two to three months, focuses on preparing the body for stem cell collection by reducing any inflammation in patients’ bone marrow. Certain medications may be given, or stopped, and patients may have additional blood transfusions. Next, the patient will visit our facility for one or more cycles of stem cell collection, with the extracted cells sent to an external company for gene modification. In this step, a gene capable of producing normal hemoglobin is either added to or replaces the faulty gene in the extracted cells. The modified cells then undergo quality assurance testing, which takes a further two months. Towards the end of this period, patients will have chemotherapy over a period of a few days to destroy their remaining bone marrow, making room for the repaired cells that will be infused back into their body.
In the last stage, involving a hospital stay of around four to six weeks, the infused cells will engraft while the patient is carefully monitored for any adverse effects. “We use one medication, Busulfan, as the chemotherapy to get rid of the old bone marrow and create space for the new modified stem cells. This is basically an autologous transplant – one using the patient’s own cells – so patients do not need to take drugs to suppress their immune systems and there is no risk of graft-versus-host disease where donor bone marrow or stem cells attack the recipient,” explains Dr. Hanna.
According to the World Health Organization, approximately 5% of the world’s population carries trait genes for hemoglobin disorders, mainly sickle-cell disease and thalassemia, although this does not mean they will necessarily develop the disease. It is estimated that 300,000 babies with severe hemoglobin disorders are born each year.
Cleveland Clinic’s Global Patient Services (GPS) department helps patients from abroad to make medical appointments and travel arrangements to receive novel treatments. Among other considerations, the department helps to overcome language barriers and assist with cultural requirements.
