Role of Underlying Liver Pathology in the Development of Immune-Related Hepatitis: A Case-Control Study.

BACKGROUND: Immune-related hepatitis (irH) is a serious immune-related adverse event (IRAE) that may result in morbidity, immune checkpoint inhibitor (ICI) therapy interruption and, rarely, mortality. The impact of underlying liver pathology, including liver metastasis, on the incidence of irH remains poorly understood. OBJECTIVES: We hypothesized that the presence of underlying liver pathology increased the risk of irH in patients with cancer treated with ICI. PATIENTS AND METHODS: We conducted a retrospective case-control study of irH in patients with cancer receiving first ICI treatment from 2016-2020. Provider documented cases of ≥ grade 2 irH were identified and control matched in a 2:1 ratio based on age, sex, time of ICI initiation, and follow-up time. Conditional logistic regression was used to estimate the relationship between irH and liver metastasis at ICI initiation. RESULTS: Ninety-seven cases of irH were identified, 29% of which had liver metastases at time of ICI initiation. Thirty-eight percent of patients developed grade 2, 47% grade 3, and 14% grade 4 irH. When adjusted for covariates/confounders, the presence of liver metastasis was associated with increased odds of irH (aOR 2.79 95% CI 1.37-5.66, p = 0.005). The presence of liver metastases did not correlate with irH grade or rate of irH recurrence after ICI rechallenge. CONCLUSIONS: Presence of liver metastases increased the odds of irH in patients with first-time ICI therapy. Limitations include the retrospective nature, moderate sample size, possible selection bias and confounding. Our findings are hypothesis-generating and warrant external validation as well as tissue and circulating biomarker exploration.

Impact of Plerixafor Use at Different Peripheral Blood CD34+ Thresholds on Autologous Stem Cell Collection in Patients with Multiple Myeloma.

Patients with multiple myeloma (MM) scheduled for autologous stem cell transplantation must undergo autologous stem cell mobilization; unfortunately, however, many do not obtain an adequate collection yield. Despite the availability of plerixafor, its widespread and uniform use is limited by its cost, and consequently, many institutions have adopted various risk-adapted algorithms. We report our mobilization experience as we have modified our plerixafor algorithm to a more liberal one, with the expectation of greater collection efficiency and mobilization success with higher plerixafor use. A total of 344 mobilization attempts were analyzed over 3 time periods and using 3 different peripheral blood CD34+ cell counts to guide plerixafor use: <15/µL (n = 66), <20/µL (n = 130), and <40/µL (n = 148). The primary endpoints were evaluation of changes in mean plerixafor utilization and apheresis days and assessment of the impact on overall mobilization costs. Secondary endpoints were a description of the impact of lenalidomide use on mobilization and evaluation of the rate of mobilization failure. We found that mean plerixafor use increased from 1.32 to 1.65 to 1.74 doses per mobilization (P = .026) and the mean days of apheresis decreased from 2.15 to 2.17 to 1.89 days per mobilization for the <15/µL, <20/µL, and <40/µL cohorts, respectively (P = .011). The combined cost of plerixafor and apheresis procedures at a threshold of 40/µL is close to that at a threshold of 15/µL, while saving 26 apheresis days per 100 patients. In general, there were low rates of mobilization failure across all thresholds. Patients who received more than 6 cycles of lenalidomide demonstrated impaired mobilization and required more apheresis sessions (P < .013) and greater plerixafor use (P < .001) to achieve target stem cell yields. Overall, using plerixafor in patients with MM, with a day 4 pCD34 count of <40/µL is a reasonable and cost-effective strategy to optimize apheresis utilization.

SH2 domains recognize contextual peptide sequence information to determine selectivity.

Selective ligand recognition by modular protein interaction domains is a primary determinant of specificity in signaling pathways. Src homology 2 (SH2) domains fulfill this capacity immediately downstream of tyrosine kinases, acting to recruit their host polypeptides to ligand proteins harboring phosphorylated tyrosine residues. The degree to which SH2 domains are selective and the mechanisms underlying selectivity are fundamental to understanding phosphotyrosine signaling networks. An examination of interactions between 50 SH2 domains and a set of 192 phosphotyrosine peptides corresponding to physiological motifs within FGF, insulin, and IGF-1 receptor pathways indicates that individual SH2 domains have distinct recognition properties and exhibit a remarkable degree of selectivity beyond that predicted by previously described binding motifs. The underlying basis for such selectivity is the ability of SH2 domains to recognize both permissive amino acid residues that enhance binding and non-permissive amino acid residues that oppose binding in the vicinity of the essential phosphotyrosine. Neighboring positions affect one another so local sequence context matters to SH2 domains. This complex linguistics allows SH2 domains to distinguish subtle differences in peptide ligands. This newly appreciated contextual dependence substantially increases the accessible information content embedded in the peptide ligands that can be effectively integrated to determine binding. This concept may serve more broadly as a paradigm for subtle recognition of physiological ligands by protein interaction domains.