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Measurable residual disease (MRD) is an established component of acute lymphoblastic leukemia (ALL) management in both children and adults. Society guidelines and expert consensus documents include assessment of MRD as the standard of care following induction therapy, consolidation therapy, and at additional time points, depending on the treatment regimen administered. Further, the approval of blinatumomab for MRD+ B-ALL has advanced the concept of MRD response as a clinical endpoint in ALL. Although the utility of MRD in ALL has been well defined over the last decades, several questions remain. In this review we focus on areas of ongoing controversy and exploration in ALL MRD, including the following: (1) Does increasing the depth of MRD assessment add prognostic value? (2) Is there a role for ongoing MRD monitoring once patients achieve MRD response? (3) Can MRD assessment of the peripheral blood be substituted for bone marrow? (4) Should MRD assays be applied to the analysis of the central nervous system (CNS)? Ongoing studies should answer the majority of these questions in the coming years.

Measurable residual disease (MRD) is an adverse prognostic factor in adult acute lymphoblastic leukemia (ALL) patients undergoing hematopoietic cell transplantation (HCT). Next-generation sequencing (NGS) can detect MRD with a sensitivity of 10-6, but the prognostic value of NGS-based MRD in adult ALL patients undergoing HCT remains minimally studied. To evaluate the prognostic value of NGS-based MRD in adult ALL patients undergoing HCT. Patients with ALL aged ≥18 years old who underwent allogeneic HCT at Stanford University or Oregon Health & Science University between January 2014-April 2021 and who were evaluated for MRD using the NGS-based clonoSEQ assay were included in this study. MRD was assessed pre-HCT (MRDpre) and for up to 1 year post-HCT (MRDpost). Patients were followed for leukemia relapse and survival for up to 2 years post-HCT. 158 patients had a trackable clonotype for MRD monitoring. The cumulative incidence of relapse was increased at all levels of MRDpre, including in patients who had low MRDpre of

The three types of interferon (IFN) have roles in antimicrobial immunity and inflammation that must be properly balanced to maintain tissue homeostasis. For example, IFNs are elevated in the context of inflammatory bowel disease and may synergize with inflammatory cytokines such as tumor necrosis factor alpha (TNFα) to promote tissue damage. Prior studies suggest that in mouse intestinal epithelial cells (IECs), type III IFNs are preferentially produced during viral infections and are less cytotoxic than type I IFN. Here, we generated human IEC organoid lines from biopsies of ileum, ascending colon, and sigmoid colon of three healthy subjects to establish the baseline responses of normal human IECs to types I, II, and III IFN. We found that all IFN types elicited responses that were qualitatively consistent across intestinal biopsy sites. However, IFN types differed in magnitude of STAT1 phosphorylation and identity of genes in their downstream transcriptional programs. Specifically, there was a core transcriptional module shared by IFN types, but types I and II IFN stimulated unique transcriptional modules beyond this core gene signature. The transcriptional modules of type I and II IFN included pro-apoptotic genes, and expression of these genes correlated with potentiation of TNFα cytotoxicity. These data define the response profiles of healthy human IEC organoids across IFN types, and suggest that cytotoxic effects mediated by TNFα in inflamed tissues may be amplified by a simultaneous high-magnitude IFN response.