Have We Reached the Limits of Chemotherapy for Burkitt Lymphoma?

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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

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

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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

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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.


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