When non-Hodgkin’s lymphoma returns

Breakthrough research: Major advancements in the understanding of diffuse large B cell lymphoma has led to many new therapies developed to treat it, including CAR-T cell therapy, which is being researched in this French pharmaceutical lab. — AFP

LYMPHOMA is a type of cancer that originates from lymphocytes, a type of white blood cell.

It can be broadly classified to two main groups: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma.

In 2020, non-Hodgkin’s lymphoma was the 11th most common cancer in terms of new cases worldwide and ninth in Malaysia, according to the International Agency for Research on Cancer (IARC).

Around 40% to 50% of all non-Hodgkin’s lymphomas in Malaysia comprise diffuse large B cell lymphoma, an aggressive version of the cancer.

Patients often present enlarged lymph nodes and constitutional symptoms like unintentional weight loss, night sweats and unexplained fever.

Sometimes the disease may affect other organs apart from the lymph nodes – this is called extra-nodal disease.

The course of the disease is aggressive and swift, necessitating immediate treatment.

Currently, initial treatment of newly diagnosed diffuse large B cell lymphoma is a combination of immunotherapy (monoclonal antibody) and chemotherapy.

Chemotherapy has been used for the treatment of this cancer type for over 40 years.

Immunotherapy, on the other hand, is a newer treatment approved by the US Food and Drug Administration (FDA) in 2006.

The combination of immunotherapy and chemotherapy has led to improved outcomes for patients, compared to chemotherapy alone, with an estimated cure rate of approximately 50% to 60% of patients.

Relapsing or refractory disease

Unfortunately, about 30% to 40% of patients will either relapse after initially responding to treatment or are unable to achieve remission with initial therapy (known as refractory disease).

Patients with relapsed or refractory diffuse large B cell lymphoma generally have a poor prognosis.

Without any treatment, their estimated median survival time is approximately three to four months.

The current treatment for patients with relapsed or refractory disease is salvage chemotherapy – a different regimen from the initial chemotherapy – followed by autologous haematopoietic stem cell transplantation (ASCT).

Approximately half the patients respond to salvage chemotherapy, and out of these, only half are able to undergo ASCT.

Of those who underwent transplantation, only 30% to 40% have the progression of their cancer halted, i.e. their condition reported as stable, after three years.

In fact, analysis of real world data from 126 haematology/oncology institutions in the United States for the period of 2010 to 2016 showed that only 13% of patients who had salvage chemotherapy actually underwent ASCT.

In addition, the elderly and patients with other medical conditions may not be able to undergo these treatments.

Those unresponsive to current salvage treatment regimens have a median survival time of five to seven months.

Clearly, there are unmet needs with regard to many patients with the current treatment regimens for relapsed or refractory diffuse large B cell lymphoma.

Promising new treatments

Thankfully, there have been major advancements in understanding the biology of this non-Hodgkin’s lymphoma.

Hence, a plethora of novel therapies for relapsing or refractory disease are either currently or will soon be approved and available.

They include:

> Monoclonal antibodies and antibody-drug conjugates

New and enhanced monoclonal antibodies against diffuse large B cell lymphoma cells have been developed.

Some have been conjugated with chemotherapy molecules or other cytotoxic (cell-killing) molecules, and are known as antibody-drug conjugates (ADCs).

Unlike conventional monoclonal antibodies, ADCs target and deliver the chemotherapy more selectively to lymphoma cells.

This allows for greater specificity in the killing of the lymphoma cells than conventional salvage chemotherapy.

> Bispecific T cell engagers (BiTES)

These are modified antibodies designed to mobilise the body’s T lymphocytes to the lymphoma cells and thus kill them.

T lymphocytes are a type of white blood cells, which are part of our immune system.

Hence, these medications utilise the patient’s own immune system to selectively eliminate lymphoma cells.

> Small molecule inhibitors

Recent breakthroughs in the understanding of lymphoma biology have underscored the importance of interactions between lymphoma cells and the surrounding non-cancerous cells (known as the “microenvironment”), as well as the immune system in promoting the survival and proliferation of the lymphoma cells.

Certain medications – broadly termed as immunomodulatory agents – can alter the microenvironment and immune system, leading to increased cancer cell death.

Small molecular inhibitors target certain signalling pathways inherent in the lymphoma cells.

Therefore, they tend to have less effect on non-cancerous cells and are more selective in eliminating lymphoma cells.

> Chimaeric Antigen Receptor T (CAR-T) cells

CAR-T cell therapies manipulate the patient’s own T lymphocytes so that they express modified receptors – the chimaeric antigen receptors – that can recognise and target lymphoma cells for killing.

Unlike BiTEs, this treatment involves genetic modification of the patient’s own T lymphocytes via a virus carrier in order for the T lymphocytes to express CARs.

Other new therapies include immunomodulatory agents, epigenetic-modifying drugs, immune-checkpoint inhibitors and CAR-Natural Killer Cells (CAR-NK).

These treatments can be used in combination, with synergistic effects, with some combinations even being chemotherapy-free.

Optimistic future

Indeed, it is a harrowing experience for patients, caregivers and family members, as well as us doctors, when diffuse large B cell lymphoma cells recur or remain recalcitrant to standard chemotherapy.

For example, in our medical centre, an elderly gentleman with this cancer who had achieved remission after initial standard immunotherapy and chemotherapy, relapsed a few years later.

He underwent standard salvage chemotherapy and ASCT.

Unfortunately, in less than a year, the disease relapsed again.

Usually, this means a poorer prognosis, and due to his age, further “aggressive” chemotherapy is not a good option.

He subsequently had an immunotherapy plus immunomodulatory agent combination therapy, and all his signs and symptoms disappeared (i.e. complete remission).

Hence, there is indeed much optimism that with recent breakthrough advances in lymphoma therapeutics, the prognosis of relapsed or refractory diffuse large B cell lymphoma will improve.

Early treatment for relapsed disease, team effort and cooperation among patients, doctors and patients’ family members or caregivers are also crucial in ensuring successful treatment outcomes.

Dr Edmund Chin is a consultant clinical haematologist at Universiti Malaya Medical Centre, Kuala Lumpur. For more information, email starhealth@thestar.com.my. The information provided is for educational purposes only and should not be considered as medical advice.

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