In this issue of Blood, Woessmann et al report on outcomes of 157 children with refractory or relapsed Burkitt lymphoma (BL) or Burkitt leukemia (B-AL) who were included in non-Hodgkin lymphoma-Berlin-Frankfurt-Münster (NHL-BFM) studies over a 30-year period.1 Despite various aggressive strategies, survival in the group that did not achieve remission with primary therapy remains distressingly low.
BL is a highly aggressive disease and the most common type of NHL in children. It is characterized by a very high proliferation rate and deregulation of the MYC gene. It consists of endemic, sporadic, and immunodeficiency-associated variants. Although it represents less than 5% of NHL cases in adults overall, it has a much higher incidence in the adolescent and young adult (AYA) population.2,3 The outcome for pediatric and AYA patients with the disease is excellent. With current standard treatment approaches that were modeled on 2 large cooperative group trials,4,5 pediatric and AYA patients have an event-free survival (EFS) and overall survival (OS) rate above 90% for patients with early-stage disease and an OS rate above 80% for those with advanced-stage disease. Recently, an international randomized phase 3 study investigated whether adding rituximab to standard therapy was beneficial for patients with high-risk disease; an interim analysis showed a 1-year EFS advantage was 94% in the group that received rituximab, and 81% in the group that received standard therapy alone.6 This led to early cessation of the randomization and to the conclusion that all pediatric patients with BL should receive rituximab. Given the very good outcomes in pediatric patients, attempts are currently underway to develop less toxic approaches with excellent outcomes equivalent to those in current standard approaches.7 However, patients with relapsed or refractory disease still have dismal outcomes, and there is no standard treatment approach for managing their disease.
The Woessmann et al study assesses characteristics, treatment paradigms, and outcomes of patients with BL or B-AL who had refractory or relapsed disease in a large cohort of 1979 patients treated on NHL-BFM studies over a 30-year period. In all, 157 patients (7.9%) had refractory or relapsed disease after first-line therapy and at a follow-up of 5 years; the probability of survival was disappointingly just 18.5%. More than one third of patients progressed during initial therapy, and overall, progressions and relapses occurred early at a median of 0.4 years after the start of treatment. In assessing the risk factors for survival in this relapsed or refractory group, progression during initial therapy was associated with a particularly poor outcome (11% survival). Because the study spanned 3 decades, many of the more recently accrued patients received rituximab, and of those who relapsed, just 10% survived, which demonstrates that relapses after improved first-line therapy are much more challenging to treat (see figure). Initial high-risk disease was also a poor prognostic factor and, as expected, outcomes were best for patients who had a complete response to reinduction therapy and went on to have a stem cell transplantation (with 63% survival).
Undoubtedly, treating patients who have refractory or relapsed disease after initial therapy for BL or B-AL is a substantial challenge in need of attention, as evidenced by the low survival rate in the Woessmann et al study and others. The difficulties in treating this group of patients is the aggressiveness of the disease when it relapses and how rapidly it progresses. Relapsed or refractory BL/B-AL is also rare, which makes it challenging to conduct clinical trials. Future research needs to better elucidate the biology of the disease and continue to identify molecular aberrations other than MYC that are key in BL pathogenesis.8 Ideally, this will pave the way for testing novel agents in relapsed or refractory patients as well as at diagnosis in those with high-risk features.9 From our understanding of BL biology, inhibition of targets such as PI3 kinase, cyclin-dependent kinases, and MYC is a rational strategy that should be considered for future development.10 Approaches such as chimeric antigen receptor T-cell therapy and bispecific antibodies, which are effective in acute lymphoblastic leukemia and diffuse large B-cell lymphoma, should also be considered. Given the survival rate of only 18.5% in this relapsed or refractory BL/B-AL pediatric population, there is an urgent need to develop successful novel strategies that use international collaborations between pediatric and adult groups.
Conflict-of-interest disclosure: The authors declare no competing financial interests.