Cancer cohorts are now known to be associated with increased rates of clonal hematopoiesis (CH). We sort to characterize the hematopoietic compartment of patients with melanoma and non-small cell lung cancer (NSCLC) given our recent population level analysis reporting evolving rates of secondary leukemias. The advent of immune checkpoint blockade (ICB) has dramatically changed our understanding of cancer biology and has altered the standards of care for patients. However, the impact of ICB on hematopoietic myeloid clonal expansion remains to be determined. We studied if exposure to ICB therapy affects hematopoietic clonal architecture and if their evolution contributed to altered hematopoiesis. Blood samples from patients with melanoma and NSCLC (n = 142) demonstrated a high prevalence of CH. Serial samples (or post ICB exposure samples; n = 25) were evaluated in melanoma and NSCLC patients. Error-corrected sequencing of a targeted panel of genes recurrently mutated in CH was performed on peripheral blood genomic DNA. In serial sample analysis, we observed that mutations in DNMT3A and TET2 increased in size with longer ICB exposures in the melanoma cohort. We also noted that patients with larger size DNMT3A mutations with further post ICB clone size expansion had longer durations of ICB exposure. All serial samples in this cohort showed a statistically significant change in VAF from baseline. In the serial sample analysis of NSCLC patients, we observed similar epigenetic expansion, although not statistically significant. Our study generates a hypothesis for two important questions: (a) Can DNMT3A or TET2 CH serve as predictors of a response to ICB therapy and serve as a novel biomarker of response to ICB therapy? (b) As ICB-exposed patients continue to live longer, the myeloid clonal expansion may portend an increased risk for subsequent myeloid malignancy development. Until now, the selective pressure of ICB/T-cell activating therapies on hematopoietic stem cells were less known and we report preliminary evidence of clonal expansion in epigenetic modifier genes (also referred to as inflammatory CH genes).

Colorectal cancer (CRC) kills approximately 850,000 people annually and is the second leading cause of cancer mortality worldwide. After curative-intent surgical resection, recurrence rates of 15–20% in stage II and 30–40% in stage III diseases highlight the fundamental limitations of pathological staging as the sole basis for adjuvant treatment decision-making. Circulating tumor DNA (ctDNA), which comprises tumor-derived cell-free DNA fragments shed into the bloodstream by dying cancer cells, offers a direct and dynamic readout of molecular residual disease (MRD) in the postoperative period. Because ctDNA clears within hours of macroscopically complete surgery, any persistently detectable postoperative signal reflects viable microscopic disease rather than surgical contamination. Over the past decade, evidence has matured rapidly from proof-of-concept observational studies to completed randomized clinical trials, culminating in the recent publication of DYNAMIC-III and ALTAIR in 2025–2026. The DYNAMIC trial established that ctDNA-guided management reduced adjuvant chemotherapy use from 27.9% to 15.3% in stage II colon cancer while maintaining an equivalent five-year recurrence-free survival (88% vs. 87%; difference 1.1%, 95% CI 5.8% to 8.0%). The GALAXY study confirmed ctDNA as the most powerful prognostic biomarker in resected CRC, with a disease-free survival hazard ratio of 11.99. Critically, DYNAMIC-III demonstrated that escalating chemotherapy intensity in ctDNA-positive stage III patients did not improve recurrence-free survival (HR 1.11, p = 0.6), and the phase III ALTAIR trial showed that trifluridine/tipiracil failed to significantly improve disease-free survival at the point of molecular recurrence (HR 0.79, p = 0.107). This review critically synthesizes the current evidence for ctDNA-guided treatment decisions in resected CRC across three therapeutic strategies: de-escalation in ctDNA-negative patients, escalation in ctDNA-positive patients, and post-adjuvant therapy at the point of molecular recurrence. Future progress requires biomarker-matched escalation strategies, adaptive trial designs, and formal validation of ctDNA clearance as a surrogate endpoint for predicting patient outcomes.

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by a heterogeneous risk of progression to overt multiple myeloma (MM). Historically managed with active surveillance, advances in risk stratification and the development of novel therapeutics have renewed debate regarding early intervention, particularly in patients with high-risk disease. We conducted a narrative review of clinical trials and observational studies evaluating early treatment versus observation in SMM. Outcomes assessed included progression-free survival (PFS), time to progression (TTP), overall survival (OS), treatment-related toxicity, and quality-of-life measures, alongside evolving diagnostic criteria and risk-stratification models that influence therapeutic decision-making. Early randomized trials using conventional cytotoxic therapy did not demonstrate a survival advantage and supported observation as the standard management approach. However, contemporary studies using novel agents have demonstrated improved disease control in selected high-risk populations. The QuiRedex and ECOG-E3A06 trials showed significant reductions in progression risk with lenalidomide-based therapy, and long-term follow-up suggests a potential overall survival benefit in Qui-Redex. The phase III AQUILA trial further demonstrated delayed progression with daratumumab in high-risk SMM using updated diagnostic criteria. Phase II studies evaluating combination regimens, including KRd-based and daratumumab-containing approaches, have reported high response rates and MRD negativity, although survival data remain immature. Importantly, many benefits reflect delayed biochemical or imaging-defined progression rather than prevention of symptomatic end-organ damage. Current evidence supports selective early intervention in carefully defined high-risk SMM populations; however, uncertainties remain regarding long-term survival benefit, optimal treatment duration, quality-of-life impact, and clonal evolution. Active surveillance with modern monitoring remains appropriate for many patients.

Purposeof Review: Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the age-associated expansion of hematopoietic stem and progenitor cells (HSPCs) bearing somatic mutations in genes such as DNMT3A, TET2, ASXL1, and JAK2, without overt cytopenias or hematologic malignancy. CHIP is increasingly understood as a systemic inflammatory condition that influences extra-hematopoietic organs. Recent findings highlight its role in gastrointestinal (GI) pathology through immune dysregulation, chronic inflammation, and fibrogenic remodeling. Recent Findings: In the liver, CHIP, particularly TET2 and DNMT3A mutations, enhances IL-6 and NLRP3 inflammasome signaling in Kupffer cells, promoting hepatic inflammation, fibrosis, and heightened risk for cirrhosis and hepatocellular carcinoma. In inflammatory bowel disease (IBD), persistent cytokine exposure may select for pro-inflammatory clones, with TET2-mutant CHIP linked to severe disease phenotypes. In colorectal cancer, mutant macrophage and monocyte populations derived from CHIP alter tumor immune microenvironments, affecting tumor progression and therapeutic responsiveness, including checkpoint blockade efficacy. Summary: Together, these findings suggest that hematopoietic clones harboring specific mutations may act as upstream regulators of chronic inflammation and carcinogenesis within the GI tract. This review consolidates gene-specific mechanisms, interactions with the gut-liver immune axis, and implications for targeted interventions linking CHIP with gastrointestinal inflammation, fibrosis, and malignancy.