Burkitt lymphoma (BL) is a fascinating disease from which many groundbreaking medical and oncologic lessons have been learned. Since the Irish surgeon Denis P. Burkitt, MD, FRCS, FRS, first described rapidly enlarging jaw and facial tumors in Ugandan children in 1958,1 the study of BL has led to numerous seminal discoveries, including the recognition of Epstein-Barr virus (EBV) as a tumor-initiating virus2,3 and MYC as a bona fide oncogene.4 Early clinical observations noted that BL was predominantly confined to geographic regions along equatorial Africa that were holoendemic for Plasmodium falciparum, which led to our current understanding of its relationship with malaria.5,6 Most importantly, the treatment of BL has underscored the profound curative potential of cytotoxic chemotherapy and transformed a uniformly fatal condition into a highly curable condition, even with widespread disease.
Mark Roschewski, MD
The Role of Chemotherapy
The chemosensitivity of BL was first demonstrated by Dr. Burkitt himself, who showed that single-agent administration of methotrexate, cyclophosphamide, or vincristine was capable of inducing durable remissions, although this occurred more commonly in patients with limited-stage disease.7 Subsequent studies established that highly dose-intensive combination chemotherapy regimens cure more than 90% of children and adolescents with BL.8-12 Even children with high-risk features, including involvement of the central nervous system (CNS) and/or bone marrow, may be reliably cured with additional agents that cross the blood-brain barrier and intensive intrathecal chemotherapy.13
The fundamental lessons learned are that chemotherapy is almost universally effective for young patients with BL, and potential treatment resistance can be largely avoided with further intensification of chemotherapy in this patient population. These studies also led to the conventional wisdom that highly dose-intensive chemotherapy regimens are required to cure BL and that the acute toxicities and late effects of therapy are necessary and justifiable risks.
Yet the success of chemotherapy has been more modest for adults with BL and for patients who receive therapy in resource-poor areas, where the cure rates are lower.14 In large part, this is related to the profound myelosuppression associated with highly dose-intensive chemotherapy regimens designed to reach high peak drug concentrations. These regimens are often poorly tolerated in older patients or those with comorbid conditions and require intensive supportive care resources to prevent therapy-related complications. Still, prospective clinical trials in adults with BL demonstrate cure rates of 65% to 80%,15-17 but the regimens often require dose modifications and are largely infeasible in areas that lack adequate supportive care resources. Indeed, developing a chemotherapy regimen that is highly effective for BL and tolerated by patients of all ages has been an unmet clinical need for decades.
Clinical Trial Findings
When I first joined the National Cancer Institute in 2012, my mentors Kieron Dunleavy, MD, and Wyndham Wilson, MD, PhD, had already initiated a pilot study testing the infusional chemotherapy regimen dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) for adults with BL deemed unsuitable for more dose-intensive regimens.18 They hypothesized that the prolonged drug exposure time of dose-adjusted EPOCH-R would be effective in rapidly proliferating BL tumor cells and obviate the need to achieve high peak drug concentrations. The impressive results of their initial study of 30 patients suggested that dose-adjusted EPOCH-R was highly effective in BL and associated with less toxicity than conventional BL regimens.
These findings were subsequently validated in a multicenter study of 113 adults with BL treated with risk-adapted, dose-adjusted EPOCH-R, including those with low-risk disease who received just three cycles of therapy.19 In this study, the regimen was equally effective across age groups, and comorbid conditions such as the presence of concomitant HIV infection did not influence outcomes. At 5 years of follow-up, all patients with low-risk disease and more than 80% of patients with high-risk disease remained in remission. The problem of identifying a tolerable yet effective BL regimen for adults of all ages appeared to have a solution.
The treatment of BL has underscored the profound curative potential of cytotoxic chemotherapy and transformed a uniformly fatal condition into a highly curable condition, even with widespread disease.— Mark Roschewski, MD
Tweet this quote
Recently, the first results of a randomized study that compared dose-adjusted EPOCH-R with the conventional BL regimen of R-CODOX-M/R-IVAC (rituximab plus cyclophosphamide, ifosfamide, etoposide, high-dose cytarabine, and methotrexate/rituximab plus etoposide cytarabine, and ifosfamide) in adults with BL were reported.20 Patients were between the ages of 18 and 75 and had at least one high-risk feature, although patients with CNS involvement were excluded. The study targeted 260 patients to adequately compare the regimens but enrolled only 89 patients and terminated the study prematurely due to a slow rate of accrual.
From the patients who were enrolled, a greater number of them discontinued therapy with R-CODOX-M/R-IVAC for excessive toxicity, and the rates of infectious complications were higher. Overall, the rates of complete metabolic remission were similar in both arms (65% vs 66%), and no difference in survival was observed between the two groups. Unfortunately, these results did not definitively answer the clinical question regarding the optimal front-line treatment approach in adults with BL and raise important questions about the best way for the field to move forward.
Lessons to Learn
What are the most important lessons for us to learn from these recent data? Perhaps, we have simply reached the limits of what can be achieved with chemotherapy for BL. In children and young adults, the cure rate is so high that the next logical question will likely revolve around identifying patients who can be treated with less therapy. In adults, the major unmet needs are to improve therapy for patients with disease involving the CNS, prevent relapse in the CNS, and avoid treatment-related mortality (which often manifests as early toxic death).
An underexplored path forward in the treatment of BL would be to identify genetic or epigenetic subgroups with unique therapeutic vulnerabilities that can be exploited with novel targeted agents or immunotherapy.— Mark Roschewski, MD
Tweet this quote
A retrospective series of 30 centers in the United States has shown that the rate of primary treatment resistance in adults with BL is approximately 15%, and the treatment-related mortality is 10%—outcomes that are worse than those reported on prospective clinical trials.21 It seems implausible that intensification of chemotherapy in adults will reduce the rate of treatment resistance without increasing the rate of early toxic death.
An underexplored path forward in the treatment of BL would be to identify genetic or epigenetic subgroups with unique therapeutic vulnerabilities that can be exploited with novel targeted agents or immunotherapy. Early work in this regard has suggested that the EBV status of the tumor best subdivides BL into genetic subtypes that are independent of age and the traditional epidemiologic variants.22 More recent data presented at the 2022 American Society of Hematology Annual Meeting & Exposition in New Orleans demonstrated that the methylation profile of BL tumors can also be used to identify two distinct epigenetic subgroups with differences in both clinical and molecular features—a finding that also appears to be independent of age.23 The next breakthough lesson we need to learn in BL is how to integrate these biologic differences into the next wave of clinical trials testing novel targeted agent combinations and immunotherapy approaches that are effective for treating and preventing CNS disease.
Dr. Roschewski is Senior Clinician and Clinical Director of the Lymphoid Malignancies Branch of the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland.
DISCLOSURE: Dr. Roschewski reported no conflicts of interest.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
REFERENCES
1. Burkitt D: A sarcoma involving the jaws in African children. Br J Surg 46:218-223, 1958.
2. Epstein MA, Barr YM: Cultivation in vitro of human lymphoblasts from Burkitt’s malignant lymphoma. Lancet 1:252-253, 1964.
3. Epstein MA, Achong BG, Barr YM: Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1:702-703, 1964.
4. Dalla-Favera R, Bregni M, Erikson J, et al: Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci U S A 79:7824-7827, 1982.
5. Kafuko GW, Burkitt DP: Burkitt’s lymphoma and malaria. Int J Cancer 6:1-9, 1970.
6. Robbiani DF, Bothmer A, Callen E, et al: AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 135:1028-1038, 2008.
7. Magrath I: Towards curative therapy in Burkitt lymphoma: The role of early African studies in demonstrating the value of combination therapy and CNS prophylaxis. Adv Hematol 2012:130680, 2012.
8. Patte C, Philip T, Rodary C, et al: Improved survival rate in children with stage III and IV B cell non-Hodgkin’s lymphoma and leukemia using multi-agent chemotherapy: Results of a study of 114 children from the French Pediatric Oncology Society. J Clin Oncol 4:1219-1226, 1986.
9. Murphy SB, Bowman WP, Abromowitch M, et al: Results of treatment of advanced-stage Burkitt’s lymphoma and B cell (SIg+) acute lymphoblastic leukemia with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and cytarabine. J Clin Oncol 4:1732-1739, 1986.
10. Magrath I, Adde M, Shad A, et al: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14:925-934, 1996.
11. Ribrag V, Koscielny S, Bosq J, et al: Rituximab and dose-dense chemotherapy for adults with Burkitt’s lymphoma: A randomised, controlled, open-label, phase 3 trial. Lancet 387:2402-2411, 2016.
12. Minard-Colin V, Aupérin A, Pillon M, et al: Rituximab for high-risk, mature B-cell non-Hodgkin’s lymphoma in children. N Engl J Med 382:2207-2219, 2020.
13. Frazer JK, Li KJ, Galardy PJ, et al: Excellent outcomes in children and adolescents with CNS+ Burkitt lymphoma or other mature B-NHL using only intrathecal and systemic chemoimmunotherapy: Results from FAB/LMB96 and COG ANHL01P1. Br J Haematol 185:374-377, 2019.
14. Gopal S, Gross TG: How I treat Burkitt lymphoma in children, adolescents, and young adults in sub-Saharan Africa. Blood 132:254-263, 2018.
15. Mead GM, Barrans SL, Qian W, et al: A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial). Blood 112:2248-2260, 2008.
16. Diviné M, Casassus P, Koscielny S, et al: Burkitt lymphoma in adults: A prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol 16:1928-1935, 2005.
17. Kelly JL, Toothaker SR, Ciminello L, et al: Outcomes of patients with Burkitt lymphoma older than age 40 treated with intensive chemotherapeutic regimens. Clin Lymphoma Myeloma 9:307-310, 2009.
18. Dunleavy K, Pittaluga S, Shovlin M, et al: Low-intensity therapy in adults with Burkitt’s lymphoma. N Engl J Med 369:1915-1925, 2013.
19. 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 38:2519-2529, 2020.
20. Chamuleau M, Stenner F, Chitu D, et al: R-CODOX-M/R-IVAC versus dose-adjusted-EPOCH-R in patients with newly diagnosed high-risk Burkitt lymphoma: First results of a multi-center randomized HOVON/SAKK trial. EHA 2022. Abstract LB2370. Presented June 12, 2022.
21. Evens AM, Danilov A, Jagadeesh D, et al: Burkitt lymphoma in the modern era: Real-world outcomes and prognostication across 30 US cancer centers. Blood 137:374-386, 2021.
22. Thomas N, Dreval K, Gerhard DS, et al: Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma. Blood. October 6, 2022 (early release online).
23. Thomas N, Dreval K, Gerhard DS, et al: DNA methylation-based Burkitt lymphoma epitypes have distinct molecular and clinical features. 2022 ASH Annual Meeting and Exposition. Abstract 721. Presented December 12, 2022.
