Relapsed-Refractory Follicular Lymphoma and Personalized Medicine

Follicular lymphoma is a personalized disease in itself, which makes it difficult to apply averages to its treatment. It is established that it occurs far more frequently in the elderly.

This is thought to be due to biological differences in the tumor cells occurring in the elderly compared to younger patients.

These may include various cytogenetic modifications, immune factors including variations in the types and functional status of various immune cells, such as macrophages and T-cells of different classes in the non-malignant parts of the tumor.

The rate at which these tumors transform into more aggressive types is also largely unpredictable, as is their likelihood of relapse or their initial response to chemotherapy or immunotherapy.

Even so, it is known today that even in the higher-risk elderly patients, a regimen of appropriately dosed drugs can help them achieve remission rates comparable to those found in younger age groups. This requires an initial complete evaluation of elderly patients who have relapsed or whose tumors are refractory to treatment. The accuracy of this study will help tailor the immunochemotherapy plan for each patient.

Factors which change treatment strategy

Various factors to be taken into consideration include the overall slow growth of the tumor, the risk of transformation of the cells into a diffuse large B-cell type of lymphoma, the age and the presence of comorbidities in the patient, the stage and grade of the tumor, nutritional status, and ability to care for oneself.

There are various scales used to make a full and clinically useful assessment of patients before beginning treatments. One which is used in older people is the Comprehensive Geriatric Assessment (CGA), which incorporates the important features of many testing tools such as the ADL and IADL scale to assess the patient’s ability to carry out activities of daily living, Charlson’s and CIRS-G scales for comorbidity evaluation, and the Mini Mental State Assessment for mental status, as well as nutritional and economic assessments, which help to identify those in need of financial and social help. The Geriatric Depression Scale is another tool that is made use of in the CGA to identify depression, which occurs in a fifth of people over 70 years. The CGA differentiates the elderly into the fit, unfit and frail categories to help identify those who could potentially undergo a chemoimmunotherapy regimen with curative intent, and spare those who would not be able to tolerate such therapy and produce customized treatment schedules for the latter. Any type of personalized medicine must include the risk factors in the patient concerned, the symptoms, and the patient’s own wishes and beliefs.

Another approach to help tailor therapy to the type of disease includes PET and MRD based criteria.

Treatment regimens

Secondary regimens for relapsed or refractory FL includes choosing from the following drugs to be used alone or in combination:

• Chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone
• Radiation
• Monoclonal antibodies such as rituximab
• Radioimmunotherapy utilizing radioactive molecules to a monoclonal antibody to irradiate the lymphoma cells carrying CD20 antigen on their surfaces, making use of the body’s own immune responses and of radiation therapy. These drugs include ibritumomab tiuxetan or Zevalin, and 131I tositumomab or Bexxar. They are suitable especially for older people who cannot tolerate high doses of chemotherapeutic agents.
• Bendamustine has shown great advantages in the adverse effect profile without any loss of overall survival or progression-free survival rates
• Autologous or allogeneic stem cell transplant following high-dose chemotherapy especially for FL which undergo transformation in younger patients
• Newer drugs under study include:
  • Idelalisib which is a phosphatidyl-inositol-3-kinase inhibitor
  • Lenalidomide which is an immunomodulator designed for use alone or in addition to chemotherapy or rituximab

How to tailor treatment to the patient

There are many avenues of treatment for a relapsed or refractory FL. Among these options, the ideal treatment for older patients should be short, capable of outpatient administration and effective, with the lowest possible toxicity.

The first retreatment of a relapsed or refractory FL in these patients results in an average successful survival of 3-5 years. Younger patients will probably do better in this situation with high-dose chemotherapy and cell transplantation, which may even result in a cure or at least many years free of the disease.

On the other hand, if an elderly patient has advanced stage FL, but low tumor burden, some researchers suggest it may be best to watch and wait for indications to treat such as the onset of symptoms or if there is a large tumor burden. Other studies are in progress, which seem to indicate that carefully designed maintenance regimens may be beneficial even in elderly or frail without increasing the rate of other illnesses or secondary malignancy.

If the relapse occurs after the use of one chemotherapy regimen, it should be treated with another to prevent cross-resistance, based on the safety. For instance, bendamustine could be substituted for CHOP. Again, if CD20 antibodies achieved remission for 6-12 months after treatment, salvage could start with rituximab, while if the patient is refractory to rituximab, newer CD20 antibodies such as obinutuzumab might be added to chemotherapy for a higher response rate of 93-96%.

References

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224805/
• http://www.lymphoma.org/atf/cf/%7B0363cdd6-51b5-427b-be48-e6af871acec9%7D/FOLLICULARRE2010.PDF
• https://www.texasoncology.com/types-of-cancer/non-hodgkins-lymphoma/follicular-lymphoma/relapsed-follicular-nhl
• http://www.ascopost.com/issues/september-10-2016/early-relapse-in-follicular-lymphoma-clinical-trial-data-may-guide-management-decisions/
• http://www.esmo.org/Guidelines/Haematological-Malignancies/Newly-Diagnosed-and-Relapsed-Follicular-Lymphoma