Burkitt lymphoma: click here to add to CAR-T? Free

In this issue of Blood, Samples et al report real-world outcomes from CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in patients with relapsed Burkitt lymphoma (BL).¹ 

The rarity of relapsed BL is highlighted by the paucity of cases, namely 31 patients identified from 18 US/Spanish centers over 5 years. There was heterogeneity in patient, disease, prior therapy, and bridging characteristics, as well as CAR-T product delivered. In addition, only those infused were analyzed due to real-world data collection constraints, and median follow-up was short (4.7 months). Notwithstanding these limitations, aptly acknowledged by the authors, the results are disappointing. Long-term benefit was limited despite responses in 58% (complete response [CRs] in 42%) of patients. No partial responses were durable and 54% of patients with CRs relapsed or died, but the majority of sustained CR cases achieved disease control prior to CAR-T delivery. Nonrelapse mortality (NRM) was high at 19% and median overall survival was 6 months. All 3 patients who underwent allografting after achieving a CR from CAR-T relapsed within 74 days. Notably, and similar to other CAR-T studies, this was not an intention-to-treat analysis and infused patients were likely a favorable group, remaining fit with stable or bridging-responsive disease. If the denominator included those not collected, or collected but not infused, the genuine measure of CAR-T benefit would be significantly lower than that reported in the study.

These important yet sobering CAR-T results in relapsed BL are reflected in a small, prospective study of CAR-T with or without autograft, where 12-month survival was 33% for CAR-T alone.² These outcomes highlight clear gaps in both BL management and CAR-T development. Future BL research efforts should be focused on global community approaches to improve risk stratification, monitoring, and use of biologically and risk-based therapies at all key junctures in the disease course (see figure).

BL is a highly aggressive malignancy affecting both children and adults, with dysregulated oncogenic MYC activity most commonly driven by the hallmark t(8;14)(q24;q32) translocation.³ Historically divided into endemic, sporadic, and immunodeficiency-associated subtypes, these delineations are being challenged with the common nature of Epstein-Barr virus (EBV) positivity and clear differences in molecular features associated with EBV status. BL is cured in approximately 70% of adult patients from high-income countries, but clinical risk varies considerably. Two international studies of >600 BL cases assessed key clinical characteristics.^4,5 These large analyses showed that previously reported promising outcomes from landmark trials were poorly replicated in routine care. In addition, the authors were able to robustly identify common measures of disease burden to categorize risk. Low-risk disease (age <40 years, performance status <2, serum lactate dehydrogenase <3-fold upper normal limit, and no central nervous system involvement) confers a 3-year overall survival of 96% but comprises only 18% of cases, whereas patients with ≥2 factors (46%) can expect a long-term survival probability of only 59%. Central nervous system involvement, present in 30% to 50% of cases, creates additional challenges in disease control. Progress has been made in improving HIV-associated BL outcomes, with no survival difference reported⁶; however, older patients have significantly inferior outcomes, potentially due to the poor tolerance of intensive regimens used in BL and unfavorable biology. The treatment-related mortality from these large data sets was 10%, but 15% to 17% in those >40 years of age. Importantly, those treated in community settings had inferior outcomes and very few data inform practice in low- and middle-income countries with high endemic BL rates, and CAR-T particularly is inaccessible.

Molecular aberrations in BL have been well annotated and vary with BL type, EBV status, and patient age,^7-9 but these have not translated into rational studies of relevant therapies, enhanced stratifications, or new treatment paradigms. Accordingly, in relapsed BL, no new therapies have demonstrated success with near identical progression-free survival and overall survival in large series, indicating that relapse almost universally results in death. Increased use of molecular knowledge, virus status, and clinical features can potentially improve risk stratification and treatment.

Validation of standardized, refined response assessments with sophisticated positron emission tomography imaging modalities and measurable residual disease (MRD) must be prioritized with the goal of adaptive therapy to maximize cure potential and minimize treatment-related morbidity and mortality. Samples et al exemplified this in their report of relapse at 74 days postallograft in a patient who was MRD-negative and had achieved clinical CR; however, due to the lack of a standardized MRD for BL, the relative sensitivity of the assay would be difficult to assess.

Although subject to real-world data selection biases, outcomes from the Samples et al study reveal that CD19-directed CAR-T therapy does not offer solutions to all CD19-expressing lymphomas, but also significant toxicity variations with higher NRM than diffuse large B-cell lymphoma trials. That we needed to wait for real-world data to identify such shortfalls raises additional issues with commercial approvals for treatment of diseases that are largely untested and a strong need for formal postapproval analyses in subtypes with a lack of adequate representation in registration trials particularly for high-toxicity, resource-intensive treatments. Drug development is increasingly becoming a for-profit industry and this leaves behind patients with BL and other rare diseases. Acknowledging that drug safety is difficult to assess in diseases as aggressive as BL, early-phase studies more frequently limit recruitment to those diseases the industry sees as profitable in the longer term. A clinicaltrials.gov search for BL yields only 32 ongoing studies, most also recruiting other orphan aggressive lymphomas with no quotas for any given subtype. Regulatory changes to trial design and increased incentives to academia and industry are needed to ensure equitable access and development of rational therapies for orphan diseases.

Enhanced information technology capability has increased real-world data collaborations, as exemplified by Samples and colleagues. Further efforts aimed at improving knowledge in BL include global initiatives such as the International Burkitt Lymphoma Network (www.burkitt-lymphoma.org), which is developing a global registry, will facilitate trials, translational studies, and large-scale data analyses. Yet, these still require government and industry financial and drug support to improve outcomes worldwide.

In summary, many challenges in BL remain, and considering the poor sustained efficacy, coupled with the significant toxicity described by Samples et al, the high toxicity, resource, and financial implications do not warrant adding BL to the “CAR-T cart” any time soon. Exploration of better risk stratification, monitoring, tailored up-front treatment, and therapeutic options at relapse for BL patients are desperately needed but can be achieved with further collaborations.

Conflict-of-interest disclosure: E.A.H. received research funding (paid to institution) from Roche, Bristol-Myers Squibb, Merck KgA, AstraZeneca, and Merck; has held consultant or advisory roles for Roche (paid to institution), Merck Sharp & Dohme (paid to institution), AstraZeneca (paid to institution), Gilead, Antengene (paid to institution), Novartis (paid to institution), Regeneron, Janssen (paid to institution), Specialised Therapeutics (paid to institution), and Sobi (paid to institution); received travel expenses from AstraZeneca; and is a member of the International Burkitt Lymphoma Network. G.P.G. has received research funding from Merck KgA and BeiGene (paid to institution); has held consultant or advisory roles for Roche, Merck Sharp & Dohme, AstraZeneca, Gilead, Janssen, Clinigen, and Prelude Therapeutics; received travel expenses from Novartis; and is a member of the International Burkitt Lymphoma Network.