Scientific and medical research has truly revolutionized the treatment of a wide range of diseases over the past twenty years. However, the development of a new drug has been and remains particularly long and expensive – the cost of bringing a new drug from discovery to changing patients’ lives in the real world remains in the billions of dollars, and the process can take a decade or more. One of the welcome responses to this challenge is the initiative of doctors and researchers worldwide to harness innovative scientific tools to find new uses for existing drugs for various diseases. These studies promise to save substantial parts of the cost of developing a new drug and to offer patients new hope more quickly.
These initiatives have produced a wealth of research indicating the potential of using certain drugs for different diseases. However, most discoveries do not mature into approved treatments for patients. The recent European approval for combining an existing drug in the treatment protocol for patients with a rare lymphoma is a true breakthrough in care and demonstrates the potential of this approach. The combination spares a significant group of patients from aggressive treatment and the negative consequences of autologous stem cell transplantation. The approval process also highlights the challenging path such initiatives must take to gain regulatory approval and bring good news to patients.
The European approval was granted for the combination of a drug called Imbruvica (Ibrutinib) as part of first-line treatment for relatively young patients with Mantle Cell Lymphoma (MCL) who are candidates for autologous stem cell transplantation, following the impressive results of the TRIANGLE study. The study was initiated by the European MCL Network, an independent organization of researchers in Europe that has led a series of clinical trials for treating the disease, in which I participated. MCL is a rare subtype of lymphoma that develops in certain B lymphocytes and is diagnosed in about 80 new patients each year in Israel.
The recent success of the European network, whose research has greatly contributed to advancing MCL treatment since its establishment over 20 years ago, highlights the great value of such initiatives in improving the management of rare diseases. The economic incentive to develop new drugs for diseases affecting a small number of patients each year is still limited, despite various governmental and public initiatives to encourage the development of new treatments for these patients.
One reason why drug development for rare diseases is particularly challenging is the need to find enough patients to participate in research. The European network, which includes dozens of doctors and researchers from 15 countries, successfully recruited 870 patients who participated in the three arms of the TRIANGLE study, with Prof. Ofer Shpilberg, director of the Hematology Institute at Assuta Ramat Hahayal, leading the study in Israel. The network was formed because MCL is a rare disease, and the only way to find new combinations and conduct clinical trials is to join forces with many countries, allowing for a large number of patients, which made this study possible – the largest in the world so far for this rare disease.
MCL usually progresses relatively quickly. In most patients, the disease presents with enlarged lymph nodes along with symptoms such as fever and weight loss, and it can affect various organs, primarily the digestive system, with the development of polyps in the colon. Sometimes the disease affects the production of red and white blood cells in the bone marrow, leading to anemia and recurrent infections. Without treatment, there is a life-threatening risk. However, there is a group of patients in whom the disease progresses slowly, and they can live for years without needing treatment.
Until recently, the standard treatment for young patients was a combination of chemotherapy with a biological drug, followed by autologous stem cell transplantation, and then prolonged therapy to stabilize the protocol’s effect and prevent the cancer cells from recurring. Autologous stem cell transplantation is a very intensive treatment in which the patient receives very high-dose chemotherapy to eliminate as many tumor cells as possible. But, due to the high dose, the bone marrow is also destroyed. Therefore, before treatment, stem cells are collected from the blood, and after treatment, they are reinfused to allow the bone marrow to recover.
This protocol indeed showed good results in patient treatment. However, stem cell transplantation is a process accompanied by severe side effects. The transplant requires at least a month of hospitalization and carries significant morbidity and mortality risk. The TRIANGLE study included three arms: the first was a control group receiving standard treatment including stem cell transplantation, the second received standard treatment including transplantation plus Imbruvica, and the third received standard chemotherapy and biological treatment plus Imbruvica, but without stem cell transplantation.
The study results showed that not only did the addition of Imbruvica significantly improve overall survival and progression-free survival in the two arms compared to the control group, but there was also no significant difference between the two arms that included Imbruvica. This means that young MCL patients receiving chemotherapy and biological treatment together with Imbruvica do not need to undergo the difficult process of autologous stem cell transplantation to gain the maximal benefit of the treatment.
This is big news and a revolution. The combination of an existing drug in the regimen has transformed treatment for young MCL patients. This news was first published at the end of 2023, and only in the summer of 2025 did it receive its first regulatory approval from the European Commission. The European MCL Network is the body that promoted and improved treatment for this rare disease, and as part of this academic process, it even succeeded in convincing European regulatory authorities to include Ibrutinib in first-line treatment, thereby adopting the new treatment standard. This success can serve as a model for further initiatives in rare diseases. Identifying gaps in treatment and uniting a large number of researchers from different countries is the way to advance optimal treatment in various diseases, especially rare ones such as MCL, and thus bring good news to patients more quickly.
Dr. Avraham Avigdor, Director of the Hematology Institute and Co-Director of the Hematology and Stem Cell Transplantation Division at Sheba Medical Center – Tel Hashomer, and member of the European network, who participated in the study