Tackling Burkitt lymphoma in older patients: novel strategies and the promise of targeted agents

Current “standard” approaches to patients with Burkitt lymphoma (BL) involve the use of intensive multi-agent chemotherapy regimens that originated from early leukemia studies, principally conducted in pediatric populations. Although these regimens are highly effective and result in cure in a large proportion of younger patients with BL, they are associated with considerable treatment-related toxicity [1,2]. While this toxicity is usually tolerable and does not typically compromise the outcome of younger patients, the case is different in older and immunocompromised patients [2]. Though the literature relating to the treatment of these groups is scant and they are underrepresented in BL clinical trials, intensive therapies are often not feasible at all. The associated high rate of treatment-related mortality and serious morbidities really preclude their use in certain age groups [3]. When they are administered, patients are often unable to complete scheduled doses of therapy, and this can translate into an inferior outcome and lower cure rates.

In an attempt to improve the tolerability of these treatments, trials have been conducted using “dose-modified” Burkitt regimens, and in particular, doses of methotrexate have been reduced. However, even with dose-modified and dose-reduced BL regimens, in most studies, older patients continue to have a poor outcome [1]. This is important to consider in BL therapeutics, as most newly diagnosed patients in the USA are 40 years or older, and a significant proportion have human immunodeficiency virus (HIV)-associated BL [4]. The inferior survival of these groups with “standard” regimens due to poor tolerability highlights the need for investigating and developing new approaches and novel agents that maintain high cure rates but reduce treatment-related toxicity.

In this edition of Leukemia and Lymphoma, Kasamon and colleagues report on the results of their brief, anthracycline-sparing, intensive cyclophosphamide (BASIC) approach for patients aged 30 years or older with untreated HIV-negative BL [5]. The approach consisted of two cycles of therapy that included cyclophosphamide, vincristine, rituximab, prednisone, methotrexate and intrathecal cytarabine, followed by intensification with high-dose cyclophosphamide and rituximab. This was a pilot initiative, aimed at patients with poorer-risk disease for whom novel approaches are needed, considering their poor outcome with standard therapy. The 3-year event-free survival (EFS) and overall survival (OS) of 52% and 57%, respectively, are encouraging, given the fact that the median age was 53 years and their analysis included many poor-risk patients. However, treatment-related mortality was still very problematic (five of 21 patients), and this emphasizes the need to continue to investigate approaches associated with less toxicity in BL.

Other approaches that are under investigation at present include using the dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) regimen. Based on its efficacy in diffuse large B-cell lymphoma and its ability to overcome highly proliferative tumors, it was tested in BL [6,7]. While it demonstrated very high efficacy, it was well tolerated across all age groups, in both HIV-negative and -positive patients, and is currently being tested in a multicenter trial. In terms of identifying new targets for novel rational drug development in BL, recent studies have provided very helpful insights into the biology of this lymphoma [8–10]. While cMYC deregulation has long been established as a hallmark of BL, other genetic changes and cooperating events with cMYC have not been well understood. Recently, high throughput RNA sequencing and RNA interference screening in tissue from patients with BL and BL cell lines have identified new pathways in BL that cooperate with MYC [8]. Seventy percent of sporadic BL cases had mutations affecting the transcription factor TCF3 or the ID3 gene, which encodes a protein that blocks TCF3 action. Importantly, TCF3 activated the phosphatidylinositol-3-OH (PI3) kinase pathway, suggesting that PI3 kinase inhibitors may have activity in BL. In 38% of sporadic cases, mutations of another gene – CCND3 – were found. CCND3 encodes cyclin D3 and this then promotes cell cycle progression through an interaction with a kinase called CDK6 in BL cells. The identification of these critical pathways and targets in Burkitt lymphomagenesis paves the way for developing and testing new agents that may one day provide effective alternatives to intensive therapy, particularly for older and immunocompromised patients.

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