The news comes from Frankfurt, where the annual Congress of the European Hematology Association (EHA) is underway, that a 6-year-old Italian boy with beta-thalassemia will receive autologous cell therapy next Tuesday which will allow him to grow without having to have blood transfusions as patients with this blood disease are usually forced to do. This is the second Italian pediatric patient, but the studies already conducted on adult patients have shown very promising results presented, in fact, at the EHA Congress which sees the participation of over 10,000 haematologists.
Studies in patients with beta-thalassemia and sickle cell disease
Our country is among those with the highest incidence of thalassemia patients in the world. In fact, an estimated 7,000 people are affected by beta-thalassemia, of which about 73% suffer from transfusion-dependent thalassemia, the most serious form. These patients need 1-3 bags of blood or more per month and are particularly fragile: 85% have, in addition to beta-thalassemia, other pathologies due to complications of the disease or related to therapy. Data from three phase 3 clinical trials (Climb-111, Climb-121 and 131) evaluating the efficacy and safety of the cell therapy called exa-cel (from the abbreviation of exagamglogene and autotemcel) in patients with beta-thalassemia and sickle cell disease. The shared data concern 83 patients (48 with beta-thalassemia and 35 with sickle cell disease), who were administered exa-cel with follow-up up to three and a half years later. Italy is the country that has recruited the largest number of thalassemia patients.
Free from transfusions
89% of treated beta-thalassemia patients went transfusion-free for at least 6 to 12 consecutive months with a mean hemoglobin of at least 9 g/dL. The median duration of transfusion independence is 20.5 months with a maximum of about three years. “The increases in total hemoglobin – he explained at the press conference Frank Locatelli, professor of Pediatrics at the Catholic University of the Sacred Heart in Rome and director of the Department of Pediatric Hematology and Oncology at the Bambino Gesù Pediatric Hospital – have already occurred in the first few months and have persisted over time. In the analysis of all patients who received exa-cel, mean total hemoglobin was above 11g/dL at month 3 and above 12g/dL at month 6 onwards with a pancellular distribution of fetal hemoglobin”. Results that sound even more encouraging, if one considers the seriousness of the subjects enrolled: “Of the 48 patients with beta-thalassemia who had received exa-cel at the time of the analysis – Locatelli underlined – more than half have genotypes (that is, the ) associated with severe disease, i.e. beta-zero/beta-zero, or other severe beta-zero-like genotypes”.
No seizures for 94% of patients with sickle cell disease
The results presented on sickle cell anemia, of which around 2-3 thousand cases a year in Italy, are also very promising. Of the 35 patients who received exa-cel, 94% had no vaso-occlusive crises (recurring in these patients) for at least 12 consecutive months. The average absence duration of these crises was almost 19 months, with a maximum of three years. “All patients treated with this therapy – explained Locatelli – managed to avoid hospital admissions related to these crises for at least 12 consecutive months. Elevations in fetal hemoglobin and total hemoglobin occurred early in the first few months and were sustained over time. In the analysis of all patients who received exa-cel, mean fetal hemoglobin was greater than 30% of total hemoglobin at month 3 and then remained at approximately 40% during follow-up.
The study on children
The results presented at the Eha Congress refer to an adult population, but exa-cel is also being tested on children aged 2 and over: “At Bambin Gesù – Locatelli recounted with a smile that brings out all his enthusiasm – we have already experimentation started. Last week we infused the therapy into a 7-year-old girl and, next Tuesday, it will be the turn of a 6-year-old boy”. Will they be able to grow up free from the obligation of transfusions? “We really hope so and the results presented at the EHA bode well. The impact on the quality of life of these young patients and their families is truly enormous”.
A joint research
Exa-cel represents the first potential treatment to emerge from the joint research program between Vertex and Crispr Therapeutics. It is an autologous cell therapy, ex vivo, genetically modified with Crispr/Cas9, being evaluated for patients with beta-thalassemia or sickle cell disease, in which the patient’s own hematopoietic stem cells are modified to produce high levels of fetal hemoglobin in red blood cells. “The fetal one – the hematologist of the Bambin Gesù Hospital in Rome explained to Repubblica.it – is the form of hemoglobin that carries oxygen, naturally present during fetal development, which is replaced by hemoglobin in the adult type form after birth. It is an extraordinary mechanism, it is as if the hands of the biological clock were brought back to the fetal age”.
The gene editing technique in these studies
But how is this type of therapy administered? “The stem cells of the patients enrolled in these studies – replied Locatelli – are collected from their peripheral blood and modified using the Crispr/Cas9 technique. The modified cells, exa-cel, are then re-infused into the patient as part of a stem cell transplant, a process that involves, among other things, treatment with specific drugs. Patients are initially monitored to determine when the modified cells begin producing mature blood cells, a process known as engraftment. Then the patients continue to be monitored to observe the impact of exa-cel on different parameters of evaluation of the disease and on safety”.
From research to clinical practice
The first results of these ongoing studies were published two years ago in the New England Journal of Medicine and exa-cel has received Food and Drug Administration Regenerative Medicine Advanced Therapy, Fast Track, Orphan Drug, and Rare Pediatric Disease designations for both beta-thalassemia and sickle cell disease. In Europe, exa-cel has obtained the designation of an orphan drug from the European Commission and the designation of priority drug from the EMA, to which the application for marketing authorization was submitted. The expectation for the arrival of this new therapy is strongly felt not only among patients, but also by clinicians, who are especially concerned about the complications that can affect thalassemia patients. Just recently a study, published in theAmerican Journal of Hematology, showed that the most frequent complications in patients are endocrine (19.2%), hepatic (14.5%), malignant tumors (13.1%), cardiopulmonary (12.1%) and musculoskeletal (10.3%) complications ). “These data demonstrate that, despite the increased survival of thalassemia patients, there is still some way to go. The progress made in the treatment of the disease is to be celebrated, but it is our duty to try to further improve the quality of life of these patients”, he underlined during an event recently held in the Chamber of Deputies Gianluca Forni, director of the thalassaemia and congenital anemia center of the Galliera hospital in Genoa.