Limited data are available on late immune-related adverse events (IRAEs) in patients with metastatic NSCLC receiving immunotherapy (ICI) beyond 2 years. A single-institution retrospective analysis including patients who received longer than 2 years of ICI therapy for metastatic NSCLC between 2012 and 2023 was performed. Late IRAEs were defined as those occurring longer than 2 years after initiation of ICI therapy. The association of late IRAE with OS and PFS was assessed using an extended Cox regression with late IRAE modeled as a time-varying covariate. In a cohort of 76 patients who received longer than 2 years of ICI, the median duration of treatment was 41.9 months, and 44 out of 76 (58%) experienced an early IRAE before 2 years. After 2 years on ICI, 38 out of 76 (50%) of patients experienced a late IRAE, many of whom (39%) had no previous early IRAE. Higher rates of late IRAEs were seen in females (p = 0.032), White patients (p = 0.041), and patients with previous grade 2 or higher IRAE (p = 0.020). Late IRAE occurrence was not associated with median progression-free survival or median overall survival. In patients receiving extended-duration ICI beyond 2 years, late IRAEs were common and often occurred in patients without previous history of IRAE. These findings support consideration of ICI discontinuation at 2 years.

Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020. We performed univariate and multivariate analyses to evaluate the impact of opioid use on duration of therapy (DOT) and overall survival (OS). Patients with no or low opioid use (n = 172) had a median DOT of 12.2 months (95% CI: 6.9–17.4) compared to 1.9 months (95% CI: 1.8–2.0) for those with high opioid use (n = 37, HR 0.26 95% CI: 0.17–0.40, p < 0.001). Patients with no or low opioid use had a median OS of 22.6 months (95% CI: 14.8–30.4) compared to 3.8 months (95% CI: 2.7–4.9) for those with high opioid use (HR 0.26 95% CI: 0.17–0.40 p < 0.001). High opioid use was associated with a shorter DOT and worse OS. This difference remained significant when accounting for possible confounding variables. These data warrant investigation of possible mechanistic interactions between opioids, tumor progression, and ICIs, as well as prospective evaluation of opioid-sparing pain management strategies, where possible.

With a prolonging duration of survivorship, patients with multiple myeloma (MM) who receive high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) have an increased risk of secondary malignancy, most concerning acute leukemia. We retrospectively reviewed the records of all patients with MM who underwent auto-HCT between January 1, 2010, and January 1, 2023, who later developed therapy-related acute leukemia (t-AL). Of 1770 patients with MM who underwent auto-HCT, 18 (1.01%) developed t-AL at a mean interval of 60.0 ± 41.3 months after auto-HCT. The patients with t-AL consisted of 9 (50%) with B-cell acute lymphoblastic leukemia (B-ALL), 8 (44.4%) with acute myeloid leukemia (AML), and 1 (5.6%) with acute promyelocytic leukemia (APML). All patients had received an alkylating agent as part of induction, and the majority received lenalidomide as maintenance therapy. Genetic abnormalities of t-AL were consistent with prior reports. Median overall survival from diagnosis of t-AL was 19.5 months. In patients with t-AL who entered CR, long term survival was common. Further research on predisposing conditions to developing t-AL in patients with MM undergoing auto-HCT is warranted.

Polycomb repressive complex 2 (PRC2) is known to regulate gene expression and chromatin structure as it methylates H3K27, resulting in gene silencing. Studies have shown that PRC2 has dual functions in oncogenesis that allow it to function as both an oncogene and a tumor suppressor. Because of this, nuanced strategies are necessary to promote or inhibit PRC2 activity therapeutically. Given the therapeutic vulnerabilities and associated risks in oncological applications, a structured literature review on PRC2 was conducted to showcase similar cofactor competitor inhibitors of PRC2. Key inhibitors such as Tazemetostat, GSK126, Valemetostat, and UNC1999 have shown promise for clinical use within various studies. Tazemetostat and GSK126 are both highly selective for wild-type and lymphoma-associated EZH2 mutants. Valemetostat and UNC1999 have shown promise as orally bioavailable and SAM-competitive inhibitors of both EZH1 and EZH2, giving them greater efficacy against potential drug resistance. The development of other PRC2 inhibitors, particularly inhibitors targeting the EED or SUZ12 subunit, is also being explored with the development of drugs like EED 226. This review aims to bridge gaps in the current literature and provide a unified perspective on promising PRC2 inhibitors as therapeutic agents in the treatment of lymphomas and solid tumors.