Sanctuary sites and extramedullary relapses in the chemo-free world: insights from immunotherapies in B-ALL

When acute lymphoblastic leukemia (ALL) involves extramedullary sites, the appropriate pathologic term for this is lymphoblastic lymphoma. The biological mechanisms underpinning this process are not clear, but they are presumed to involve a multifactorial interplay between tumor cells and the microenvironment of the tissue in which they develop (eg, lymph nodes, thymus, leptomeninges). Importantly for clinicians, these factors may impair the efficacy of systemic therapy given to treat ALL. This gives rise to "sanctuary sites," so named because of the relative protection they provide to malignant blasts that may possess these characteristics. This has become increasingly relevant in the era of "chemotherapy-free" approaches for B-cell ALL, where the potency of antigen-targeted immunotherapies (eg, blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor-modified T cells) has been leveraged to reduce or eliminate the reliance on cytotoxic chemotherapy. Such approaches are appealing for their high response rates and favorable toxicity profiles compared to chemotherapy. However, extramedullary relapses have been observed with increased frequency: an outcome historically seen in around 10% of such cases, this can represent over 50% of relapses in some series. This review provides an overview of this emerging issue and what clinicians and investigators can do to address it.