Insights into Lymphoma Treatment

Dear Colleagues,

Emerging changes in the treatment of different types of non-Hodgkin lymphoma (NHL) are reshaping the therapeutic landscape, driven by advances in precision medicine, immunotherapy, and targeted treatments.

In diffuse large B-cell lymphoma (DLBCL), the development of antibody-drug conjugates (ADCs), chimeric antigen receptor(CAR)-T cell therapy and bispecific antibodies (BiTEs) have  revolutionized the treatment and outcome for patients. Polatuzumab vedotin, an ADC targeting CD79b, has shown promising results in relapsed/refractory DLBCL and, more recently, in newly diagnosed patients, especially those with the ABC subtype and high IPI scores. This has led to its inclusion in first-line treatment.

Furthermore, CAR T-cell therapy, which salvages about 40% of patients with RR DLBCL, has become the preferred second-line treatment in primary refractory/early relapsing patients and the third-line treatment in patients with late relapse, particularly if they are not eligible for transplant. Long-term analyses of CAR T-cell therapy continue to show durable responses.

Bispecific antibodies (BiTEs), which engage T-cells to target lymphoma cells, have recently been implicated in lymphoma, including in DLBCL. CD20/CD3 BiTEs are currently reserved for patients who have failed at least two prior lines of therapy. Recent studies have confirmed that BiTEs are highly effective, inducing durable complete responses and improving the overall survival in about 40% of these heavily pretreated patients, including in those who failed CAR-T cell therapy.

These impressive results have paved the way for the application of both CAR T-cells and BiTEs in earlier lines of treatment. Investigations are underway to determine the role of BiTEs in combination with chemo-immunotherapy in second and first-line treatment, and to explore the potential use of CAR T-cells as a first-line therapy in patients with high-risk disease.

Mantle cell lymphoma (MCL), known for its aggressive nature, has also seen significant advancements. Bruton's tyrosine kinase (BTK) inhibitors have become essential components of treatment regimens, showing substantial benefits in the relapsed setting and more recently in first-line treatment. New noncovalent BTK inhibitors, which overcome resistance to covalent BTK inhibitors, have become crucial for patients who progress when treated with BTK inhibitors; the use of these inhibitors in earlier lines of treatment is therefore being explored. CAR T-cell therapy, providing impressive responses in patients who do not respond to BTK inhibitors, is often considered for those who progress post-BTK inhibitors. However, progression post-BTK is often rapid, necessitating the urgent administration of novel therapies, such as BCL-2 inhibitors, noncovalent BTK inhibitors and BiTEs, which are currently exhibiting favorable results in this setting.

CAR T-cells and BiTEs also appear to be highly effective in patients with relapsed/refractory follicular lymphoma (FL), including those who progress within 24 months. They are currently employed in patients who have not responded to at least two lines of therapy, and their use in earlier lines of treatment is being explored, including combinations of BiTEs with other agents, especially  immunomodulating agents. Targeted therapies, such as the inhibition of EZH2—a commonly mutated protein in FL involved in epigenetic regulation—as well as new BTK inhibitors, have also been shown to provide durable responses in a substantial proportion of relapsed/refractory FL patients, particularly when combined with other anti-FL agents.

The emergence of these highly effective novel agents has continually resulted in a remarkable improvement in patient outcomes. While the role of autologous stem cell transplantation in patients with B-cell NHL is decreasing, the proportion of patients being treated with immunomodulating therapies, CAR T-cells, and recently BiTEs, is increasing.

Overall, the treatment landscape for NHL is rapidly evolving, with an enhanced emphasis on precision medicine and novel therapeutic modalities. These emerging changes hold the promise of improved outcomes and an enhanced quality of life for patients with different types of NHL.

Prof. Dr. Irit Avivi
Guest Editor

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• treatment
• non hodgkin lymphoma
• diffuse large cell lymphoma
• follicular lymphoma
• mantle cell lymphoma
• CAR-T cell therapy
• bispecific antibodies
• BTK-inhibitors
• BCL-2 inhibitors