Editorial note: Acute Lymphoblastic Leukemia (ALL) is a malignant neoplastic disease that originates from B-cell or T-cell lymphocytes and proliferates abnormally in the bone marrow. In recent years, immunotherapy has made significant strides in the field of ALL, including breakthroughs in treatments such as Chimeric Antigen Receptor T-cell (CAR-T) therapy, bispecific antibodies, and antibody-drug conjugates (ADC). The 50th European Society for Blood and Marrow Transplantation (EBMT) annual meeting took place in Glasgow, UK, from April 14 to 17, 2024. At the conference, Professor Peter Bader from the Department of Stem Cell Transplantation, Immunology, and Intensive Care Medicine at the University Hospital Frankfurt, Germany, delivered a special report on the current application of CAR-T therapy in ALL patients. Hematology Frontier invited Professor Bader to share the latest progress and challenges in CAR-T therapy in the field of ALL with a wide audience.
“Oncology Frontier – Hematology Frontier“: Could you please start by summarizing the current state of ALL treatment?
Professor Bader: ALL is the most common malignant disease in childhood, and clinical treatment generally has a good prognosis. However, a minority of patients experience relapse, and the prognosis for these patients is poorer, with some patients not showing improvement even after transplantation. If a patient relapses after transplantation, treatment becomes even more difficult. In such cases, patients typically undergo CAR-T cell therapy.
In principle indeed, ALL first is the most frequent malignant disease in childhood, and it has an excellent prognosis. However, a few patients do relapse, and the ones who relapse have a poor prognosis, some them don’t improve with transplantation. If patients are relapsing post-transplantation, then it is even more difficult to treat. These are mostly the patients we are treating with CAR T-cells.
“Oncology Frontier – Hematology Frontier”: In recent years, various CAR-T products have been launched. Could you provide an overall evaluation of the effectiveness of CAR-T therapy in ALL and its clinical value?
Professor Bader: As a pediatrician, I focus on the treatment of pediatric hematological malignancies. In fact, the first successful applications of CAR-T cell therapy were in children. Professor Carl June, known as the “father of CAR-T”, developed CAR-T products targeting the CD19 antigen. The success of treating the first child in 2012 was truly astounding. This therapy was subsequently taken over and commercialized by pharmaceutical companies, leading to the approval and market launch of the first CAR-T cell product, Tisagenlecleucel (commonly known as tisa-cel), in Europe and North America. In recent years, China has also developed many CAR-T cell therapy products and achieved great success. Currently, China has developed CAR-T products targeting CD19 with outstanding efficacy, used to treat ALL patients.
I am a pediatrician, so I would really like to focus on the pediatric field. Indeed, the first patients treated successfully were children. This was a product at the time generated in Philadelphia by Carl June against the CD19 antigen. This was spectacular back in 2012 when the first child was successfully treated. Tis treatment has been taken over and engaged by the pharmaceutic industry, leading to the licensing of the first product called KYMRIAH (tisagenlecleucel) in Europe and North America. This was followed by much activity in China as well. You have a lot of products with excellent capabilities and effectiveness now available to treat patients with CD19-positive ALL, which has been a great success.
“Oncology Frontier – Hematology Frontier“: How do you view the safety issues associated with CAR-T therapy?
Professor Bader: The key to this question lies in whether we compare CAR-T therapy with allogeneic bone marrow transplantation or total body irradiation, or if we compare it with intensified chemotherapy regimens. In my view, CAR-T cell therapy is one of the less toxic treatments available for these severely ill patients to date. Some of our patients can be discharged from the hospital after a 2-3 week stay and can return to normal life. In contrast, patients undergoing allogeneic transplantation cannot achieve such a rapid recovery.
The point is always whether you want to compare with allogeneic bone marrow transplantation or total body irradiation, or whether you want to compare this to intensive chemotherapy. In my eyes, CAR T-cell therapy is one of the less toxic treatments used to treat these severely ill patients. Some of them are treated as in-patients for two or three weeks, and are then discharged and go back to normal life, which is not the case after allogeneic transplantation.
“Oncology Frontier – Hematology Frontier“: How can CAR-T therapy be improved to minimize the risk of relapse as much as possible?
Professor Bader: It is still challenging to say definitively how best to reduce the risk of relapse. As I mentioned in my talk, it partly depends on whether we are discussing first-line treatment for these patients or treatment after relapse following allogeneic transplantation. From another perspective, if we use autologous CAR-T cell therapy, the risk of relapse may be higher; for patients who relapse early after allogeneic transplantation, using allogeneic CAR-T cell therapy might help reduce the risk of relapse.
To minimize the risk of relapse, it is difficult to say. As I mentioned in my presentation, this depends a little bit on whether you are talking about treating patients up-front, or whether you are talking about treating patients who relapse after allogeneic transplantation. If you are using autologous CAR T-cells, the product will be different. I could imagine that for the patients who relapse early after allogeneic transplantation, an allogeneic CAR T-cell product may be helpful.
