Clinical Advances in Hematology & Oncology

October 2021 - Volume 19, Issue 10

Evolving Strategies for the Management of Transformed Lymphoma

Sonali M. Smith, MD

Elwood V. Jensen Professor in Medicine
Chief, Section of Hematology/Oncology
UChicago Medicine
Chicago, Illinois

H&O  What is transformed lymphoma?

SS  Transformed lymphoma refers to a more aggressive or fast-growing lymphoma that arises from an indolent histology. The most common example of transformed lymphoma is a follicular lymphoma that evolves into diffuse large B-cell lymphoma (DLBCL), or, less commonly, a high-grade B-cell lymphoma with double-hit biology after the indolent disease acquires a MYC rearrangement. In rare cases, follicular lymphoma can transform into high-grade histologies, such as Burkitt lymphoma. Marginal zone lymphoma and lymphoplasmacytic lymphoma can also transform into DLBCL. In the case of chronic lymphocytic leukemia or small lymphocytic lymphoma, transformed disease is known as Richter’s transformation. For unclear reasons, these slow-growing lymphomas can acquire mutations or other genomic hits that lead to a very aggressive phenotype that requires urgent, if not emergent, treatment.

The overall incidence of transformation in indolent lymphomas is low. In the rituximab (Rituxan, Genentech/Biogen) era, the risk of transformation is approximately 2% to 3% per year.

H&O  Are there any risk factors?

SS  It is not always possible to predict whether a certain patient will develop transformed lymphoma. However, the likelihood of transformation depends on several risk factors. In follicular lymphoma, early progression—namely, progression of disease within 24 months—has emerged as an important core prognostic factor. This observation is based on data from the British Columbia Cancer Agency and a Danish registry showing that most patients with follicular lymphoma who experience disease progression within 24 months have transformed disease at the time of re-biopsy. In the British Columbia experience, 75% of early progressors had transformed disease.

Another risk factor was identified through a subanalysis of the PRIMA study, a large clinical trial that enrolled patients with high tumor-burden follicular lymphoma. Patients with a high baseline Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 to 5 had a higher risk of transformation. Their median time to transformation was relatively short, at 9.6 months, which again reflects early progression. A large registry analysis from 2013 coordinated by the University of Iowa and the Mayo Clinic identified several risk factors for transformation: poor performance status, high levels of lactate dehydrogenase, B symptoms, follicular lymphoma of grade 3A or a high FLIPI, loss of beta-2-microglobulin, increased T cells, and mutations in genes such as TP53, PIM1, or beta-2-microglobulin.

H&O  What are the distinguishing characteristics between transformed lymphoma and progressive disease?

SS  Progressive disease is typically defined as an increase in the size or number of lymph nodes or lymphomatous areas of involvement. Patients with progressive disease typically require treatment, and the goal of treatment is to shrink the lymph nodes (ie, achieve remission). It is important to remember that in patients with progression of an indolent disease, such as follicular lymphoma or marginal zone lymphoma, the goal of treatment for progression is disease control, and not cure, since these are incurable diseases. In transformed lymphoma, a biopsy will show a more aggressive histology, typically DLBCL or high-grade B-cell lymphoma, as discussed above. The more aggressive histology warrants more aggressive treatment; ironically, it is possible to “cure” the more aggressive type of lymphoma, whereas the indolent lymphoma will essentially always recur.

H&O  Are there any recent insights into the pathogenesis of transformed lymphoma?

SS  This is a very exciting area. The first Transformed Lymphomas Scientific Workshop was held in early August 2021. This meeting was convened by the Lymphoma Research Foundation, which is the largest advocacy group for lymphoma in the world and an important funding group for lymphoma-related research. The foundation distributes millions of dollars in grant support, offers educational training programs for clinicians who are interested in careers in lymphoma, and, as an advocacy group, provides patient education. In the past, the foundation has convened panels of experts to hold workshops on specific areas of unmet need, and transformed lymphoma is now one of them. At the workshop, there was an entire session dedicated to the biology of transformation.

Using follicular lymphoma as an example, the t(14;18) rearrangement is pathognomonic. Most patients with follicular lymphoma have a t(14;18) rearrangement. This rearrangement is necessary, although not sufficient, for the disease to develop in most cases. Over time, the patient develops increased epigenetic deregulation, which appears to be an early hallmark of lymphoma progression. Eventually, there are adverse mutations, such as the TP53 mutation, beta-2-microglobulin mutations, and PIM1 mutations. There are also changes in the microenvironment. It is not known whether the transformation results from an orderly process or whether there are multiple factors at work simultaneously. The pathogenesis of transformed lymphoma is not known, and work is needed in this area.

H&O  What are the traditional treatment approaches for transformed lymphoma?

SS  The treatment of transformed lymphoma in large part depends on the prior therapies used for the indolent component. Some patients do not receive treatment for indolent lymphoma; rather, they undergo observation. If these patients develop transformed lymphoma, they will receive treatments such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), depending on the histology.

Among patients who receive treatment for their initial disease and then relapse quickly, therapy for transformed lymphoma can include a stem cell transplant, enrollment in a clinical trial, or a newer option, such as chimeric antigen receptor (CAR) T-cell therapy. The treatment for transformed lymphoma might be their second, third, or fourth line of treatment overall. The selection of treatment will vary based on the earlier treatments the patient has received. Data regarding treatment sequencing are limited.

H&O  What is the treatment goal for transformed lymphoma?

SS  The treatment goal in transformed lymphoma is to put the aggressive component into remission indefinitely. Treatment aims to cure the aggressive component. It is not possible to cure the indolent component, so the goal is to delay its return. When the indolent component does return, the hope is that it can be managed with traditional treatments.

H&O  Are there any novel treatment strategies for transformed lymphoma?

SS  Currently, treatment of transformed lymphoma is typically adopted from the approach to DLBCL. All of the treatments under development in DLBCL are also being evaluated in patients with transformed lymphomas. Such treatments include bispecific antibodies and CAR T-cell therapies. In the last 2 years, 4 new regimens were approved for relapsed/refractory DLBCL: polatuzumab vedotin-piiq (Polivy, Genentech), bendamustine (Ben­deka, Teva), and rituximab; tafasitamab-cxix (Monjuvi, MorphoSys/Incyte) and lenalidomide (Revlimid, Celgene/Bristol Myers Squibb); loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics); and selinexor (Xpovio, Karyopharm Therapeutics). It is possible to also use these treatments in patients with transformed lymphoma.

H&O  Are there any other promising areas of research?

SS  There are many gaps in the knowledge and much work to be done. My hope is that as treatment options for DLBCL improve, there will be more treatments for transformed lymphoma. Unmet needs include the ability to predict which patients will transform and how to prevent the transformation. Some researchers have suggested that rituximab decreases the risk of transformation. There may be other ways.

H&O  Do you have any other recommendations regarding the treatment of patients with transformed lymphoma?

SS  It is important for patients to obtain a second opinion and to consider receiving treatment in a tertiary care center. There are many ongoing clinical trials, and there is significant room for improvement in this field. Patients can also visit the Lymphoma Research Foundation website or consult other advocacy groups to obtain more information and guidance.


Dr Smith has served as a consultant to Adaptive, ADC Therapeutics, Gilead, MBX, MorphoSys, Janssen, BMX, Karyopharm, Genentech, TG Therapeutics, and Celgene in the past 2 years. She has received institutional funding for clinical trials from Epizyme, Genentech, Novartis, Celgene, Portola, Karyopharm, Acerta, Pharmacyclics, TG Therapeutics, and Forty Seven.

Suggested Readings

Al-Tourah AJ, Gill KK, Chhanabhai M, et al. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(32):5165-5169.

Chin CK, Rodriguez MA, Qing Y, et al. Impact of maintenance rituximab in patients with de novo transformed indolent B cell lymphoma. Leuk Lymphoma. 2020;61(12):2985-2989.

Freeman CL, Kridel R, Moccia AA, et al. Early progression after bendamustine-rituximab is associated with high risk of transformation in advanced stage follicular lymphoma. Blood. 2019;134(9):761-764.

Gleeson M, Hawkes EA, Peckitt C, et al. Outcomes for transformed follicular lymphoma in the rituximab era: the Royal Marsden experience 2003-2013. Leuk Lymphoma. 2017;58(8):1805-1813.

Link BK, Maurer MJ, Nowakowski GS, et al. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol. 2013;31(26):3272-3278.

Madsen C, Pedersen MB, Vase MO, et al. Outcome determinants for transformed indolent lymphomas treated with or without autologous stem-cell transplantation. Ann Oncol. 2015;26(2):393-399.

Méndez M, Torrente M, Sánchez-Beato M, et al. Transformed follicular lymphoma in the rituximab era: a report from the Spanish Lymphoma Oncology Group. Hematol Oncol. 2019;37(2):143-150.

Mir F, Barrington SF, Brown H, et al. Baseline SUVmax did not predict histological transformation in follicular lymphoma in the phase 3 GALLIUM study. Blood. 2020;135(15):1214-1218.

Smith S. Transformed lymphoma: what should I do now? Hematology (Am Soc Hematol Educ Program). 2020;2020(1):306-311.