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by Dr. C.H. Weaver M.D. updated 2/2022

​Low-grade (slow-growing) lymphoma's and chronic lymphocytic leukemia (CLL) 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), often referred to as "Richter's transformation" 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 transformed lymphoma's require a different type of treatment.

In addition to FL other types of low-grade lymphomas 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 Rituxan 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 improved 2- and 5-year survival rates with several different treatment approaches.1

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Adding the BCL-2 precision medicine Venclexta (venetoclax) to a combination chemotherapy regimen significantly improves outcomes in Richter’s syndrome. Venclexta selectively blocks the BCL-2 “survival” protein that allows cancers to resist treatment. When added to a chemo regimen called R-EPOCH the Venclexta combination has yielded the highest rate of complete responses and the longest median overall survival rate to date according to a publication in the journal BLOOD.

Researchers theorized that Venclexta could render Richter’s syndrome cancer cells more sensitive to chemoimmunotherapy with the standard treatment regimen R-EPOCH. To test this hypothesis, they launched a phase 2 trial in which 26 patients were treated with R-EPOCH followed by increasing doses of Venclexta added in the second treatment cycle. Patients then received up to five cycles of VR-EPOCH in 21-day intervals followed by Venclexta maintenance therapy.

Results showed that 50% of patients achieved a complete response, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial responses; altogether, the overall response rate was 62%. The average duration of survival without disease progression was 10.1 months, and median overall survival was 19.6 months.12,13

High Dose Chemotherapy Treatment for Transformed NHL

​Patients with transformed lymphomas may achieve a significantly higher rate of long-term survival when treated with high-dose therapy and stem cell transplantation, according to an early 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.9 Patients with transformed lymphomas should consider being evaluated at a cancer center focused on developing newer treatment strategies. CAR-T cell therapy, improved stem cell transplant techniques and "mini" or "reduced intensity allogenic stem cell transplants are all being used to improve the outcome of individuals with transformed lymphomas .


  1. Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS)
  2. Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 1995;13(7):1726-1733.
  3. 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.
  4. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol 2008;26(32):5165-5169.
  5. Incidence of transformation to aggressive lymphoma in limited-stage follicular lymphoma treated with radiotherapy. Ann Oncol 2013;24(2):428-432.
  6. Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 1997;15(4):1587-1594.
  7. 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.
  8. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 2007;25(17):2426-2433.
  9. Journal of Clinical Oncology, Vol 19, No 3, pp 727-735, 2001)
  10. Al-Sawaf O, Robrecht S, Bahlo J, et al. Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials. Leukemia. 2021;35(1):169-176. 
  11. Rogers KA, Huang Y, Ruppert AS, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol. 2018;180(2):259-266.
  12. Davids MS, Rogers KA, Tyekucheva S, et al. A multicenter phase II study of venetoclax plus dose-adjusted R-EPOCH (VR-EPOCH) for Richter’s syndrome [ASCO abstract 8004]. J Clin Oncol. 2020;38(15)(suppl).