Non-Hodgkin's lymphomas, earlier CAR-T for those who do not respond to treatment in large B-cell forms

Progress is being made in the treatment of lymphomas, and in particular large B-cell lymphomas, about one third of the total non-Hodgkin's. If classical treatments do not work in patients with these and other specific forms of the disease, cell therapy can start earlier and change the trajectory of the disease. Thanks to CAR-Ts, lab-engineered cells from the same patient that are reinfused to act directly against the pathological units, a good quality of life and improved chances of recovery have indeed been demonstrated. Even after just one infusion. This is according to the results of the TRANSFORM study, which showed that treatment with CAR-T (lyso-cel) is of particular value in these patients. On this basis, the Italian Medicines Agency (AIFA) has approved the reimbursability of cell therapy with CAR-T, lysocabtagene maraleucel (liso-cel), for the treatment of adult patients with diffuse large B-cell lymphoma (approximately one third of all non-Hodgkin lymphomas), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma and grade 3B follicular lymphoma (FL3B), refractory to first-line chemo-immunotherapy or relapsed within 12 months after completion of first-line chemo-immunotherapy.

The numbers speak for themselves. In Italy, every year, there are an estimated 15,500 new cases of lymphomas: just over 13,000 are non-Hodgkin's, which are far more frequent. These neoplasms of the immune system, which originate from B-, T- or NK-type lymphocytes, can be indolent or aggressive. "They are treatable diseases and in many cases curable, thanks to the availability of numerous therapies that, in recent years, have changed the treatment scenario," explains Paolo Corradini, Professor of Haematology at the University of Milan and Director of the Division of Haematology and Bone Marrow Transplantation at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. About 70% of patients with aggressive lymphomas can be cured and people with indolent lymphomas can achieve a very long disease-free survival of up to 15 years." CAR-Ts fit into these pathways that the haematologist can identify, on a case-by-case basis and based on precise appropriateness criteria. These are truly tailor-made approaches, designed for the individual patient. "These therapies are 'chemo-free', i.e. they do not involve use in combination with chemotherapy, with important advantages for patients," Corradini reports. "Furthermore, in patients refractory to chemotherapy, CAR-Ts can lead to cures when traditional treatments, such as chemotherapy, transplantation, or radiotherapy, do not offer advantages.

Coming to the specifics of liso-cel, treatment with these CAR-Ts is already available in Italy for patients relapsing or refractory to treatment after two or more lines of systemic therapy. Now the situation changes: these treatments can start earlier. "The extension of liso-cel's reimbursability by AIFA concerns patients who relapse after the first line. In this way, treatment with cell therapy is brought forward," says Corradini. In the TRANSFORM study, after a median follow-up of almost 34 months, patients with diffuse large B-cell lymphoma treated with liso-cel continue to show improved event-free survival and progression-free survival. Not only that. The objective response rate improved to 87% compared to 49% with standard therapy. The complete response rate, which in an aggressive disease such as large B-cell lymphoma is a prerequisite for cure, was 74% compared to 43%. This increase in complete response in the experimental arm with lyso-cel translates into improved survival'. According to the experts, in short, we are facing an important step forward in the way of treating large B-cell lymphomas, when they are refractory at onset or relapse early.

On the research front, work is underway to develop allogeneic CAR-Ts, i.e. from donors. This is confirmed by Alessandro Bigagli, Senior Medical Head, Bristol Myers Squibb Italia, who points out that AIFA has also granted liso-cel the status of innovative drug, attributed on the basis of three fundamental criteria: therapeutic need, added clinical advantage, and strength of evidence. 'This recognition guarantees immediate access to reimbursability and automatic inclusion in regional therapeutic registries,' Bigagli said. We were pioneers in cell therapies and continue to transform the therapeutic scenario in haematology, developing solutions that represent a real paradigm shift. Today we are in fact engaged in the development of the second generation of autologous CAR-Ts, produced directly in the patient without the need for extraction and engineering in the laboratory, and studies are also underway on allogeneic CAR-Ts, obtained from healthy donors or pluripotent stem cells'. Objectives: to speed up production times and improve the efficacy and tolerability of treatments, in order to offer new opportunities to an increasing number of patients.