Abstract
Simple SummaryIn general, the non-Hodgkin lymphoma (NHL), anaplastic large cell lymphoma (ALCL) diagnosed in childhood has a good survival outcome when treated with multi-agent chemotherapy. However, side effects of treatment are common, and outcomes are poorer after relapse, which occurs in up to 30% of cases. New drugs are required that are more effective and have fewer side effects. Targeted therapies are potential solutions to these problems, however, the development of resistance may limit their impact. This review summarises the potential resistance mechanisms to these targeted therapies.Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.
Highlights
Coordinated international efforts to study the treatment of paediatric anaplastic large cell lymphoma (ALCL), in addition to knowledge gained from investigating adult ALCL and other anaplastic lymphoma kinase (ALK)-positive diseases, has led to the suggestion that ALK tyrosine kinase inhibitors (ALK TKIs), armed antibodies to CD30 (such as brentuximab vedotin (BV)) and immune checkpoint inhibitors may be useful drugs to overcome the current challenges in the treatment of paediatric ALCL
We have shown that activation of signalling via the IL10R bypasses NPM-ALK to activate STAT3 in ALCL mediating resistance to crizotinib, alectinib, brigatinib and lorlatinib [142]
There is a trade-off between reducing side effects and the potential for resistance to develop when choosing targeted therapies for ALK-positive paediatric ALCL
Summary
Anaplastic large cell lymphoma (ALCL) is a peripheral T cell non-Hodgkin lymphoma (NHL) with an annual incidence of 1.2 per million children aged under 15 [1]. The majority of paediatric ALCL is ALK-positive, usually due to a t(2;5)(p23;q35) chromosomal translocation causing the expression of the oncogenic breakpoint product NPM1-ALK [1,3]. This translocation results in unregulated ligandindependent activation of ALK, a receptor tyrosine kinase [2,4], due to homodimerization and auto-phosphorylation of its kinase domain [5] (Figure 1). Gene expression profiles of ALCL share features with T helper 17 (Th17) cells [24], and with early thymic progenitors or haemopoietic stem cells [25] Whether this latter genetic signature is a consequence of the cell of origin or NPM1-ALK-induced activity is debatable. Its exact cell of origin and pathogenesis remains the subject of continued research
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