Adverse Impact of DNA Methylation Regulatory Gene Mutations on the Prognosis of AML Patients in the 2017 ELN Favorable Risk Group, Particularly Those Defined by NPM1 Mutation

The 2017 ELN risk stratification has been widely adopted, but some studies have suggested the outcomes are heterogenous within the ELN risk groups and may be affected by other co-existing genetic mutations. This study evaluated the impact of DNA methylation regulatory gene (TET2, IDH1/2, DNMT3A, SETBP1) mutations (DMRGM) evaluated by NGS in the outcome of AML patients in each ELN risk group. A total of 114 patients were analyzed with a median follow-up of 12 months. Overall, 30.7% (35/114) of patients had DMRGM. DMRGM status had no impact on CR rate in each ELN risk group. The OS, however, was significantly shorter in patients with DMRGM compared to those without DMRGM (median OS: 12 vs. 33 months, p = 0.0053). Multivariate analysis showed DMRGM status was an independent unfavorable factor for OS (HR: 2.704, 95% CI: 1.451–5.041, p = 0.0017). The adverse OS impact of DMRGM was only observed in the ELN favorable group (7 months vs. not reached, p = 0.0001), but not in the intermediate or adverse group. Among the favorable group with DMRGM (n = 16), DMRGM occurred predominantly in cases with mutated NPM1 (15/16, or 93.8%). Our results suggest that DMRGM adversely impact the outcomes of ELN favorable group patients, particularly those with mutated NPM1. Further studies are warranted to confirm our observations

Thrombotic Microangiopathy and Acute Kidney Injury Induced After Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors VEGF Blockade-Related TMA After Intravitreal Use.

Vascular endothelial growth factor (VEGF) inhibition can cause worsening hypertension, proteinuria, chronic kidney injury, and glomerular disease. Thrombotic microangiopathy (TMA) and other nephrotic disorders have been reported with systemic VEGF blockade. These same agents are given intravitreally for age-related macular degeneration (AMD) and diabetic retinopathy (DR), albeit at lower doses than those given for systemic indications. Systemic absorption of anti-VEGF agents when given intravitreally has been shown consistently along with evidence of significant intravascular VEGF suppression. While worsening hypertension has only been seen in some large-scale studies, case reports show worsening proteinuria and diverse glomerular diseases. These include TMA-associated lesions like focal and segmental glomerulosclerosis with collapsing features (cFSGS). In this paper, we report three cases of TMA likely associated with the use of intravitreal anti-VEGF therapy. These patients developed the signature lesion of VEGF blockade in a 6 to 11 month time frame after starting intravitreal VEGF inhibitors. The literature is reviewed showing similar cases. Intravitreal VEGF blockade may cause these adverse events in a hitherto unidentified subgroup of patients. Well-controlled prospective observational trials are needed to determine the event rate and identify which subgroups of patients are at increased risk. A registry for patients who develop worsening hypertension, proteinuria exacerbation, and glomerular diseases from intravitreal VEGF blockade is proposed