Intensive combination chemotherapy is associated with high cure rates in younger patients with Burkitt lymphoma, as reflected in the 5-year overall survival rates of 75% to 85% reported across clinical trials.1 However, due to the toxicity of traditional treatment approaches, substantial gaps remain in the management of this condition in older individuals and those with certain comorbidities. An emerging body of genomics research has helped to elucidate the pathogenesis of Burkitt lymphoma, and additional research has explored novel treatment regimens.
Jennifer Crombie, MD, and Ann LaCasce, MD, from the department of medical oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, and Kieron Dunleavy, MD, professor of medicine, director of the Lymphoma Program, and co-director of the Microbial Oncology Program in the Division of Hematology and Oncology at the George Washington University Cancer Center in Washington, DC, each of whom authored recent papers regarding the treatment of Burkitt lymphoma in adults, provided their perspectives on managing this highly aggressive lymphoma.1,2
What are some of the most notable recent developments in the understanding and management of Burkitt lymphoma?
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Drs LaCasce and Crombie: Burkitt lymphoma is a highly chemosensitive disease with high cure rates with multiagent chemotherapy. Although intensified regimens were the first to yield high success rates, their use has been restricted to younger, fit patient populations. More recently, the infusional [dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R)] regimen has resulted in impressive outcomes, particularly in patients without [central nervous system (CS)] involvement, with an improved toxicity profile.3
While MYC rearrangements are the defining molecular hallmarks of Burkitt lymphoma, recent integrated genomic analyses have provided insight into additional drivers of disease pathogenesis. These findings provide the rationale for additional preclinical studies of targeted therapeutic strategies.
Dr Dunleavy: We have recently developed less-intensive therapies than those that have been used traditionally for Burkitt lymphoma; the newer therapies are less toxic but highly effective. These are especially important for older and immunocompromised patients who have difficulty tolerating the standard regimens. The [National Cancer Institute (NCI)] tested the DA-EPOCH-R regimen in a small group of patients with Burkitt lymphoma about a decade ago. This demonstrated excellent results, and the NCI cooperative groups recently confirmed these findings in a large multicenter study of more than 100 patients.3
Also, our understanding of the molecular biology of this disease has advanced significantly, and numerous novel critical genomic aberrations have been identified. Importantly, these findings pave the way for testing of targeted approaches in Burkitt lymphoma.
What are some of the remaining challenges in managing Burkitt lymphoma in adults?
Drs LaCasce and Crombie: Although many of our patients with Burkitt lymphoma have favorable outcomes with aggressive chemotherapy, options for patients with primary refractory or relapsed disease are extremely limited, and the majority of these patients do not survive. Conducting clinical trials in this highly aggressive disease is extremely challenging. We suggest that these patients be referred whenever possible to tertiary care centers for consideration of any available studies.
Another challenge is managing older patients with high-risk disease, including baseline CNS involvement and/or extensive bone marrow disease. We know that these patients have poor outcomes with frequent progression of disease or relapse in the CNS. The use of intrathecal chemotherapy only for CNS prophylaxis, as used in [DA-EPOCH-R], is associated with high failure rates. Administering high doses of methotrexate or cytarabine, the most effective CNS-directed drugs, is associated with significant suppression and risk of renal failure. These drugs are not feasible for elderly patients.
Dr Dunleavy: Managing toxicity of various standard treatments is a huge challenge, especially in older and immunocompromised patients, and less-toxic, effective approaches are needed. Tumor lysis syndrome (TLS) is a challenge in some patients who have high amounts of disease, and prophylaxis and close monitoring of electrolytes including renal function should be considered. CNS involvement is a major challenge, as this portends an inferior outcome. How best to approach patients with CNS disease at diagnosis has not been worked out very well, so this is a critical area for development of novel approaches that hopefully will improve outcomes in this group.
What are other key points to consider for clinicians treating these patients?
Drs LaCasce and Crombie: Due to the aggressive nature of Burkitt lymphoma, patients often present with rapidly progressive disease and require urgent care. It is important for clinicians to be aware of the high risk for TLS, which can occur spontaneously or with treatment initiation, and the need for prophylaxis and possibly inpatient admission for close monitoring. For patients with comorbidities or a particularly high risk of [developing] TLS, prephase therapy can also be implemented to mitigate risk.
Dr Dunleavy: A correct diagnosis is critical. Burkitt lymphoma and diffuse large B-cell lymphoma can have a similar appearance histologically, so having these cases reviewed by a hematologist with expertise in diagnosing lymphoid diseases is ideal. Also, for patients without CNS involvement, CNS prophylaxis is typically administered because of risk for CNS spread. There is a lot of debate regarding the benefit of this and how exactly it should be done in terms of drug, dosing, and administration modality, so this area needs more investigation.
What are additional needs in this area in terms of research or otherwise?
Drs LaCasce and Crombie: With highly aggressive chemotherapy, outcomes are good but resistance does emerge, and these therapies are associated with morbidity and mortality. Further investigation into the biology of the disease to inform identification of potential targeted agents is definitely needed. In addition, given that the endemic form of this disease occurs in Africa, developing safe and effective regimens for resource-poor settings is a priority.
Dr Dunleavy: Treatment approaches for children with Burkitt lymphoma are quite different than those for adults. As lymphoma specialists, and with the help of organizations like the Lymphoma Research Foundation, we are focusing a lot of our efforts on unmet needs for adolescents and young adults with lymphoma. One important need is for adult and pediatric lymphoma physicians and researchers to work together to figure out how to advance treatment and understanding of Burkitt lymphoma biology in pediatric and adult patients simultaneously. Crosstalk and collaborations are important to advance this field and improve outcomes for our patients.
References
- Crombie JL, LaCasce AS. The treatment of Burkitt lymphoma in adults. Blood. Published online November 10, 2020. doi:10.1182/blood.2019004099
- Dunleavy K. Approach to the diagnosis and treatment of adult Burkitt’s lymphoma. J Oncol Pract. 2018;14(11):665-671. doi:10.1200/JOP.18.00148
- Roschewski M, Dunleavy K, Abramson JS, et al. Multicenter study of risk-adapted therapy with dose-adjusted EPOCH-R in adults with untreated Burkitt lymphoma.. J Clin Oncol.
