Modern Treatment Options for Lymphoma

Treatment of lymphoma has evolved a great deal over the past several years and is tailored to the specific subtype of lymphoma. Some lymphomas require immediate treatment (aggressive) while others can be watched and treatment administered only at the time of disease progressoion (indolent). Recent advances have focused on increasing the precision of medicines and activating the body’s immune system to enhance the destruction of lymphoma cells. As a result, the survival of patients with the two most frequent lymphomas (ie, diffuse large B-cell lymphoma and follicular lymphoma), have improved remarkably with the incorporation of rituximab (the first form of immunotherapic agent) as a standard treatment regimen. New insights into the biology of lymphomas provided by studying patterns of the mutational landscape in the cancer cell has further helped improve our ability to target lymphoma-driving abnormalities in the cancer’s genome or biomarker targets on lymphoma cells. Although we can now cure most patients with Hodgkin lymphoma, the past decade has seen advances in our ability to identify patients who are most likely to be cured with less toxic treatment approaches. Unfortunately, our ability to improve the treatment of patients with T-cell lymphoma has not kept pace with the management of those suffering from B-cell lymphomas and Hodgkin lymphoma. Hopefully with the ongoing efforts in studying the various mutations driving T-cell lymphoma, we could begin to improve treatment results over the next decade. 

Historically, the mainstay of treatment for lymphoma has been with conventional chemotherapy. Being a type blood cancer, lymphoma cells are most ‘druggable’ as chemotherapy can be easily carried by the blood stream to the lymphoma cell. The pet peeve with chemotherapy however, is that the cell killing is indiscriminate. Bystander healthy cells are also affected and this accounts for the notorious side effects of traditional chemotherapy like hair loss, nausea, diarrhoea, bleeding and infections. As there is a limit to how much chemotherapy the body can receive, autologous stem cell transplantation was developed to allow the body to receive a way higher dose of chemotherapy without permanently damaging the bone marrow. This procedure has remained a standard treatment for patients with relapsed aggressive lymphomas. Precision cancer medicine on the other hand, uses targeted drugs and immunotherapy engineered to directly attack lymphoma cells with specific abnormalities with the goal of leaving normal cells largely unharmed. Here are just some of the therapies that exemplify the advances being made:

1. Monoclonal antibodies. Rituximab is the prototype while obinutuzumab is a bio-engineered and improved version. These man-made antibodies are designed to attach to CD20, a protein found on many types of B-cells. It is thought to work by attacking targeted cells both directly and together with the body’s immune system. Tafasitamab is a recently approved monoclonal antibody directed against CD19 on the lymphoma cell.
2. Antibody drug conjugate (ADC), a type of precision cancer agent that targets specific proteins on the lymphoma cell surface with an antibody. The antibody is in turn attached to a cancer cell killing agent that is then internalized following attachment of the antibody to the cancer cell and this causes the cancer cell to die when the toxic effect of this ‘smart bomb is unleashed. Important examples in this class includes bretuximab vedotin, polatuzumab vedotin and the very recently approved Loncastuximab tesirine.
3. Checkpoint inhibitors are a new class of medicines that help the immune system recognize and attack cancer. These drugs block PD-1, a protein that inhibits certain types of immune responses. Their application releases the brakes on the immune system, thereby allowing the body to unleash its own army upon the cancer. Pembrolizumab and nivolumab are now standards of care for relapsed cases of Hodgkin lymphoma.
4. BCL-2 inhibitors. The BCL-2 protein is over-expressed in some lymphoma cells and it contributes to a cancer cell’s survival and resistance to standard chemotherapy. Venetoclax is an agent that binds to the BCL-2 protein, thereby disabling its ability to keep cancer cells alive.
5. Bruton tyrosine kinase (BTK) inhibitors are targeted agents that work by inhibiting the enzyme BTK which is needed by the cancer to multiply and spread. BTK inhibitors like ibrutinib and acalbrutinib have now been moved to the frontline standard of care for certain lymphomas that rely on the BTK for growth.
6. Bispecific antibodies like blinatumomab represent an innovative precision immunotherapy approach that helps the body’s immune system target lymphoma cells. These antibodies have two arms; one arm of the drug attaches to a specific protein on the lymphoma cell while the other arm activates immune cells in the patient to kill the lymphoma cell.
7. Chimeric Antigen Receptor (CAR) T-cell therapy is a new type of treatment that utilizes a patient’s own T immune cells to fight certain types of lymphoma. The T-cells are removed from the patient and engineered to recognize specific proteins found on the surface of cancer cells. The T-cells are then infused back into the patient to fight the lymphoma in the body. Tisagenlecleucal is the first CAR-T therapy to be approved by Health Science Authority of Singapore. An ongoing clinical trial now directly compares CAR-T therapy to the standard autologous stem cell transplantation and this may eventually inform if autologous stem cell transplantation will become an obsolete procedure in the future.

With the above-mentioned innovations and many more other treatment options on the horizon in the fight against lymphoma, the prognosis of patients will continue to get better and conventional chemotherapy will eventually become obsolete as it gets replaced by precision medicine.