Context: Tirzepatide is a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved by the US Food and Drug Administration in May 2022 for patients with type 2 diabetes mellitus (T2DM).Objective: We aimed to determine the rates of individual adverse events (AEs) related to 3 studied doses of tirzepatide.Methods: We performed a systematic review with meta-analysis including 5 databases (PubMed, Embase, CINAHL, Scopus, and Web of Science) for all clinical trials reporting AEs related to tirzepatide. The safety data from individual studies were extracted and analyzed through meta-regression to assess rates of individual AEs. Study quality assessment was performed using the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.Results: Ten trials (6836 participants) were included. Gastrointestinal (GI) AEs were the most commonly reported AEs and were dose dependent 39% (95% CI, 35%-43%), 46% (95% CI, 42%-49%), and 49% (95% CI, 38%-60%) for the 5, 10, and 15 mg dose, respectively. Among all GI AEs, nausea and diarrhea were most frequent at any dose of tirzepatide. Drug discontinuation due to AEs was highest with the 15 mg dose of tirzepatide (10%). Incidence of mild hypoglycemia (blood glucose < 70 mg/dL) was highest with tirzepatide 10 mg dose 22.6% (9.2%-39.8%). Rates of fatal AEs, severe hypoglycemia, acute pancreatitis, cholelithiasis, and cholecystitis were extremely low (≤ 1%) across all doses of tirzepatide.Conclusion: Tirzepatide is associated with a dose-dependent increase in incidence of GI AEs and AEs leading to drug discontinuation. Severe hypoglycemia, fatal AEs, acute pancreatitis, cholelithiasis, and cholecystitis are rare with this medication.

There has been a widespread adoption of hypomethylating agents (HMA: 5-Azacytidine (5-Aza)/decitabine) and venetoclax (Ven) for the treatment of acute myeloid leukemia (AML); however, the mechanisms behind the combination’s synergy are poorly understood. Monotherapy often encounters resistance, leading to suboptimal outcomes; however, the combination of HMA and Ven has demonstrated substantial improvements in treatment responses. This study elucidates multiple synergistic pathways contributing to this enhanced therapeutic effect. Key mechanisms include HMA-mediated downregulation of anti-apoptotic proteins, notably MCL-1, and the priming of cells for Ven through the induction of genes encoding pro-apoptotic proteins such as Noxa. Moreover, Ven induces sensitization to HMA, induces overcoming resistance by inhibiting the DHODH enzyme, and disrupts antioxidant pathways (Nrf2) induced by HMA. The combination further disrupts oxidative phosphorylation in leukemia stem cells, amplifying the therapeutic impact. Remarkably, clinical studies have revealed a favorable response, particularly in patients harboring specific mutations, such as IDH1/2, NPM1, CEBPA, or ASXL1. This prompts future studies to explore the nuanced underpinnings of these synergistic mechanisms in AML patients with these molecular signatures.

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).

With improvement in survival after chronic lymphocytic leukemia (CLL) diagnosis, the real-world burden of second hematological malignancies (SHM) has not been comprehensively assessed in recent era. We analyzed risk, incidence, and outcomes of SHM in CLL patients between 2000 and 2019 using SEER database. CLL patients had greater risk for hematological malignancies than general population [SIR, standardized incidence ratio (95% CI):2.58 (2.46-2.70); p < 0.05]. The risk for subsequent lymphoma increased by 1.75 folds in 2015-2019 compared to 2000-2004. The duration, after CLL diagnosis, of maximum risk for SHM decreased as 60-119 months for time-period 2000-2004, 6-11 months for 2005-2009 to 2-5 months for 2010-2014 and 2015-2019. Incidence of SHM was 2.5% in CLL survivors (1736/70,346) with lymphoid SHM being more common than myeloid SHM, and DLBCL being the most common pathology (n = 610, 35% of all SHM). Male sex, age <= 65 years at CLL diagnosis, and chemotherapy treatment were associated with higher risk for SHM. The median gap between CLL and SHM diagnoses was 46 months. The median survival for de-novo-AML, t-MN, CML, and aggressive NHL was 63, 86, 95, and 96 months respectively. Although SHM remains rare, there is increased risk in recent era, likely due to improved survival in CLL patients, necessitating active surveillance strategies.

PURPOSE: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), have an increased incidence of second malignancies. This study describes the patterns, risk factors, and outcomes of second malignancies in MPN with the aim of refining our knowledge. METHODS: Using SEER database (2000-2021), we identified patients diagnosed with MPNs. The incidence, patterns, and risk factors of second malignancies including synchronous neoplasms (SYNs, within 6 months of MPN diagnosis), second primary malignancies (SPMs, after 6 months), and secondary AML (s-AML) were assessed separately. Standardized incidence ratios (SIRs) assessed the risk of SPM and s-AML in the MPN cohort compared with the general population. RESULTS: Among 43,930 patients with MPN, 1.6% developed SYN, 9.1% SPM, and 1.5% s-AML. Lung, prostate, breast, and colorectal cancers were most frequent solid SPMs, with lung cancer risk particularly higher in PV (SIR, 1.47) and ET (SIR, 1.23). Older age at MPN diagnosis (age 40-59 years, odds ratio [OR; 95% CI], 3.82 [3.09 to 4.78]; age 60-84 years, OR [95% CI], 6.19 [5.02 to 7.7]; ref: 18-39 years) and male sex ( v female, OR [95% CI], 1.37 [1.28 to 1.46]) were associated with a higher risk of SPM. The overall SPM risk was higher than that of the general population (SIR [95% CI], 1.14 [1.11 to 1.18]; P < .05), with a particularly higher risk of hematologic SPMs (SIR [95% CI], 1.70 [1.55 to 1.85]; P < .05) and s-AML (SIR [95% CI], 19.36 [17.92 to 20.88]; P < .05). SPM development was associated with reduced median survival (125 v 184 months, P < .0001) after MPN diagnosis. s-AML progression reduced the median survival to 80, 82, and 43 months for patients with PV, ET, and PMF, respectively. CONCLUSION: Patients with MPN have a higher risk of second malignancies, compared with the general population, which is associated with reduced survival. This necessitates age-appropriate cancer screening, dermatologic examinations, and long-term surveillance. Further studies are warranted to delineate the underlying factors contributing to this risk.

Characteristics of patients with and without sMNs after index diagnosis of DLBCL, FL, or multiple myeloma diagnosed 2000–2011 using SEER-Medicare, expressed in numbers.