Relapsed/Refractory Follicular Lymphoma Causes

Follicular lymphoma (FL) is an indolent tumor of the lymphatic system, which may often remain inactive for years before undergoing transformation into an aggressive tumor.

After treatment, a high percentage of FL patients fail to respond, and these tumors are categorized as refractory lymphomas. Some respond with an initial positive change, but then develop signs of recurrent tumor, called relapsed follicular lymphoma.

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What causes patients to enter either of these categories is still unknown; however, older people above the age of 60 years at diagnosis are known to have a much higher risk of relapse and transformation. Other possible factors include an advanced stage at diagnosis, large tumors, the involvement of the bone marrow, and other symptoms, among other blood parameters. These symptoms have been incorporated into the FL International Prognostic Index (FLIPI), which was widely used to classify patients at risk of relapsed or refractory FL.


With the advent of the monoclonal antibody rituximab, which has proved effective in the treatment of FL, the revised version, FLIPI 2, is now in use, which uses other parameters such as the beta-2 microglobulin levels, the size of the largest lymph node, signs of involvement of the bone marrow, and the reduction in the hemoglobin level.

Therapy with chemical or immunological agents is associated with toxicity to the heart, kidneys, mucous membranes, or nervous structures in elderly people, prompting discontinuation before the appropriate time or accounting for greater hesitation to begin therapy in this patient category.

Most chemotherapy is meant to target fast-growing cells, which means that some slow-growing cells within FL are likely to escape annihilation and may eventually proliferate enough to cause a relapse of the tumor after primary treatment.

Interfollicular CD4-positive T cells and CD-68 positive macrophages also respond well to the use of rituximab with conventional chemotherapy because of better antibody-dependent cytotoxicity, which will mean lower rates of relapse.


The poor response in elderly patients is somewhat expected as a result of the high proportion of patients who are above 60 years of age. It is also difficult to treat these patients with full-scale chemotherapy because of higher rates of adverse effects that are serious enough to stop treatment. This is partly due to the increased incidence of comorbidity and poorer interaction between the tumor and the host.

The fact that the immune function deteriorates in most people with age is also likely to be responsible for the higher rates of DNA damage, which is not repaired promptly and adequately, along with lower humoral and cellular immunity levels. This may explain why FL in this age group is typically more aggressive and often shows a more complex pattern of differentiation, which makes the prognosis worse.

It is already known that individuals who are immunocompromised, such as those with certain infections, diseases, or chemical exposures, have a higher rate of FL. This may hold true for the tumor cells, which eventually cause relapse or fail to respond to treatment.

It is also established that a higher number of cytogenetic abnormalities is associated with a higher tumor grade and therefore a greater risk of relapse or refractory tumor cells. This may be related to the accumulation of many random mutations with age.

Studies have shown that the presence of genes that code for T cell markers and macrophage markers are associated with a favorable outcome, and conversely, those which are associated with macrophages and dendritic cells, or either, predict a poor outcome. These are reflective of the non-malignant sections of the tumor and may provide directions for future prognostic immunohistochemical testing.

The interactions between these T-cell subsets along with other immune cells and the tumor cells may regulate the differentiation and growth of the latter. Host genetic factors are also important in determining how these interactions are driven, with regard to the composition and functional status of the immune cells within the tumor.



Further Reading

Last Updated: Apr 10, 2021

Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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