Improving Outcomes of Transformed Follicular Lymphoma

Understanding histological transformation of lymphoma and treatment options.

Histologic Transformation of lymphoma

by Dr. C.H. Weaver M.D. updated 11/2018

Low-grade (slow-growing) lymphoma can sometimes transform (change) into a faster-growing type of lymphoma necessitating a change in the treatment strategy. (1-6)

What is meant by lymphoma transformation?

The histologic transformation (HT) of a lymphoma refers to a biologic event leading to the development of a high-grade, aggressive non-Hodgkin lymphoma in patients with an underlying low grade or follicular lymphoma (FL). Low-grade or follicular lymphomas are typically made up of small, slow-growing cells. As the proportion of larger, faster-growing lymphoma cells increases, the lymphoma begins to behave more like a faster-growing high-grade lymphoma. The process of transformation is important because HT requires a different type of treatment.

In addition to FL other types of low-grade lymphoma transform less frequently. Types of lymphoma that can transform include:

  • Follicular lymphoma
  • Small lymphocytic lymphoma/chronic lymphocytic leukemia (this transformation is called Richter syndrome)
  • Marginal zone lymphomas
  • Waldenstrom’s macroglobulinemia and other lymphoplasmacytic lymphomas

When does transformation happen?

Transformation can happen at any time after diagnosis and occasionally a low-grade lymphoma will have already transformed by the time it is diagnosed. This is evident when a newly diagnosed individual has a mixture of high-grade and low-grade lymphoma cells.

Transformation is most common in FL and every year, they transform in about 2-3% of individuals. The National LymphoCare Study evaluated the outcomes of 2652 patients with transformation of follicular lymphoma and found that at a median follow-up of 6.8 years, 14.3% patients lymphomas transformed following the initial FL diagnosis. (6-8)

Why does transformation happen?

Lymphomas transform when mutations (genetic changes) cause lymphocytes to divide in an abnormal way or to stay alive when they shouldn’t (apoptosis). Mutations tend to increase over time, which is why transformation generally becomes more likely as time goes on. Most lymphomas don't transform and there is currently no definite way to predict in advance which lymphomas are likely to transform into a faster-growing type.

Does treatment reduce the risk of transformation?

Some but not all clinical studies suggest that early treatment of a lymphoma may reduce the risk of transformation. In the National LymphoCare study patients initiating treatment at diagnosis had a reduced risk of transformation compared to those managed with a “watch and wait” strategy.

The risk of transformation was similar in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone). Maintenance rituximab however was associated with a reduced transformation risk.

Can transformed lymphomas be treated?

Historically, FL that transformed to diffuse large B-cell lymphoma (DLBCL) portended a poor prognosis with a reported average overall survival of 1 to 2 years. (1-5) This may be changing with more modern therapies. A more recent analysis of the National Comprehensive Cancer Network (NCCN) non-Hodgkin lymphoma outcomes database reported 2- and 5-year survival rates of 68% and 49%, respectively with several different treatment approaches. (1)

High Dose Chemotherapy Treatment for Transformed NHL

​Patients with transformed follicular lymphoma may achieve a significantly higher rate of long-term survival when treated with high-dose therapy with stem cell transplantation, according to a study published in the Journal of Clinical Oncology.

High-dose treatment (chemotherapy and/or radiation) kills more cancer cells than standard dose treatment. However, more healthy cells are also killed in the process, including stem cells. Stem cells are immature cells produced in the bone marrow (spongy material inside large bones) that develop into the 3 types of blood cells: red blood cells, which carry Oxygen to tissues; platelets, which aid the blood in clotting; and white blood cells, which fight infection. The low levels of blood cells caused by high-dose treatment are “rescued” by the infusion of stem cells into the patient following therapy. The stem cells are collected from the patient prior to treatment.

Researchers analyzed data from the European Bone Marrow Transplant Lymphoma Registry involving patients with transformed follicular lymphoma. The patients in this group were still responsive to chemotherapy (chemosensitive). They received treatment with high-dose therapy and stem cell transplantation. Approximately 3 months following treatment, 62% of patients had a complete disappearance of their cancer and 15% showed a partial disappearance of cancer. Five years following treatment, over half of the patients were still alive, and 30% of patients had no return of disease.

These results are important as they indicate a marked long-term improved survival for patients with transformed chemosensitive follicular lymphoma treated with high-dose therapy versus standard dose therapy. The researchers conducting this trial suggest that this group of patients should at least be offered this treatment option by their physicians. Patients with follicular lymphoma may wish to speak with their physician about the risks and benefits of receiving high-dose therapy or participating in a clinical trial evaluating other promising treatments.(9)


  1. Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 1995;13(7):1726-1733.
  2. Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 2004;22(8):1454-1459.
  3. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol 2008;26(32):5165-5169.
  4. Incidence of transformation to aggressive lymphoma in limited-stage follicular lymphoma treated with radiotherapy. Ann Oncol 2013;24(2):428-432.
  5. Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 1997;15(4):1587-1594.
  6. The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann Oncol 2006;17(10):1539-1545.
  7. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 2007;25(17):2426-2433.
  8. Journal of Clinical Oncology, Vol 19, No 3, pp 727-735, 2001)

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