Impact of the homozygous mutation in Nudix hydrolase 15 on myelosuppression with 6-mercaptopurine in a European girl with acute lymphoblastic leukemia: A case report / Impacto de la mutación homocigota en Nudix hidrolasa 15 sobre la mielosupresión con 6-mercaptopurina en una niña europea con leucemia linfoblástica aguda: A propósito de un caso

Una paciente pediátrica de 6 años, diagnosticada de leucemia linfoblástica aguda (LLA) de riesgo intermedio, presenta milotoxicidad grave y múltiples infecciones durante la fase de inducción IB del tratamiento con 6-mercaptopurina (6-MP). En las siguientes fases del protocolo de tratamiento, que incluía también 6-MP, la paciente continúa mostrando aplasia de médula ósea y neutropenia, requiriendo numerosos ajustes de dosis e interrupciones. La dosis recomendada de 6-MP se reduce entonces al 5 %. El análisis farmacogenético, realizado en la fase de inducción IB, detectó tres polimorfismos de nucleótido único (SNPs) en el gen que codifica para la enzima tiopurina S-metiltransferasa (TPMT), observándose un fenotipo de metabolizador normal para esta enzima. Como consecuencia, se requirió de un segundo análisis farmacogenético más completo, que reveló polimorfismos patológicos en el gen de la hidrolasa Nudix 15 (NUDT15), explicaría la mielotoxicidad observada en esta paciente. Por ello, un análisis farmacogenético completo debería llevarse a cabo con anterioridad al inicio de 6-MP y de manera rutinaria en la práctica clínica, para conseguir prevenir los efectos adversos graves y/o el fracaso terapéutico. (AU)

A 6-year-old girl diagnosed with intermediate-risk acute lymphoblastic leukemia (ALL) presented with severe my-elotoxicity and multiple infections during phase IB induction treatment with 6-mercaptopurine (6-MP). In the sub-sequent treatment phases, which included 6-MP, the patient continued to show bone marrow aplasia and neu-tropenia, necessitating numerous dose adjustments and interruptions. The recommended dose was eventually reduced to 5 %. A pharmacogenetic analysis, conducted in induction phase IB, detected three single-nucleotide polymorphisms (SNPs) of the thiopurine S-methyltransferase (TPMT) gene, and the phenotype of a normal metab-olizer was observed. As a result of a second pharmacogenetic analysis, pathological polymorphisms were revealed in Nudix hydrolase 15 (NUDT15), which may explain the patient’s myelotoxicity. Hence, a pharmacogenetic analysis performed in advance would have been able to prevent her from suffering severe toxicity and/or treatment failure. (AU)

Clinical Outcomes of First-line Therapies for Advanced Non-Small Cell Lung Cancer: A Systematic Review of Trials Published Between 2010 and 2020.

OBJECTIVES: To analyze the evolution of clinical outcomes derived from clinical trials on first-line therapies for advanced or metastatic non-small cell lung cancer (NSCLC) published between 2010 and 2020, focusing on how these outcomes impact survival rates and management of patients. METHODS: A systematic review of phase III and pivotal phase II clinical trials was conducted by a structured search on Medline and Embase. A comprehensive set of variables was collected to assess their influence on survival rates. We also estimated the clinical benefit by applying the ESMO-MCBS v1.1 and extracted the authors' conclusions. RESULTS: Sixty-six studies involving 34,951 patients were included. Best survival outcomes were found for nonsquamous non-small cell lung cancer (OS and progression-free survival medians: 19.4 and 10.2 mo) and for those expressing molecular targets (OS and progression-free survival medians: 23.8 and 11.0 mo). No significant influence on survival rates was observed for industry funding and disease stage (IIIB/IV vs. IV). ESMO-MCBS v1.1 was applied in 45 positive studies and resulted in a meaningful clinical benefit score in 37.8%. Quality of life (QoL) was reported in 57.6% of the original publications and showed statistical significance favoring the experimental arm in 33.3%. Positive authors' conclusions (75.7% of trials) were based on OS and/or QoL in 34% and on surrogate endpoints in 66%. CONCLUSIONS: Extended survival times and a steady improvement in QoL have been observed. However, there were more than twice as many studies reporting positive authors' conclusions as studies meeting the ESMO threshold for meaningful clinical benefit.

Incidence of nephrotoxicity associated with intravenous colistimethate sodium administration for the treatment of multidrug-resistant gram-negative bacterial infections.

Colistimethate sodium (CMS) is the inactive prodrug of colistin, CMS has a narrow antibacterial spectrum with concentration-dependent bactericidal activity against multidrug-resistant gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii. This study aimed to analyze potential correlations between clinical features and the development of CMS-induced nephrotoxicity. This retrospective cohort study was conducted in a tertiary-care university hospital between 1 January 2015 and 31 December 2019. A total of 163 patients received CMS therapy. 75 patients (46%) developed nephrotoxicity attributable to colistin treatment, although only 14 patients (8.6%) discontinued treatment for this reason. 95.7% of CMS were prescribed as target therapy. Acinetobacter baumannii spp. was the most commonly identified pathogen (72.4%) followed by P. aeruginosa (19.6%). Several risk factors associated with nephrotoxicity were identified, among these were age (HR 1.033, 95%CI 1.016-1.052, p < 0.001), Charlson Index (HR 1.158, 95%CI 1.0462-1.283; p = 0.005) and baseline creatinine level (HR 1.273, 95%CI 1.071-1.514, p = 0.006). In terms of in-hospital mortality, risk factors were age (HR 2.43, 95%CI 1.021-1.065, p < 0.001); Charlson Index (HR 1.274, 95%CI 1.116-1.454, p = 0.043), higher baseline creatinine levels (HR 1.391, 95%CI 1.084-1.785, p = 0.010) and nephrotoxicity due to CMS treatment (HR 5.383, 95%CI 3.126-9.276, p < 0.001). In-hospital mortality rate were higher in patients with nephrotoxicity (log rank test p < 0.001). In conclusion, the nephrotoxicity was reported in almost half of the patients. Its complex management, continuous renal dose adjustment and monitoring creatinine levels at least every 48 h leads to a high percentage of inappropriate use and treatment failure.

Analyzing the clinical benefit of newer therapies for advanced or metastatic non-small-cell lung cancer: application of the ESMO-magnitude of clinical benefit scale v1.1.

BACKGROUND: Despite newer therapies, advanced or metastatic non-small-cell lung cancer (NSCLC) continues to be the leading cause of cancer-related deaths worldwide. Deficits in the design and methods of randomized controlled trials (RCTs) may contribute to reducing the clinical benefit of therapies in oncology. To prioritize treatments based on efficacy results and toxicity data, the European Society for Medical Oncology (ESMO) has developed the Magnitude of Clinical Benefit Scale (MCBS). The objective of this study was to apply the ESMO-MCBS v1.1 to a cohort of RCTs on therapies for advanced or metastatic NSCLC. MATERIAL AND METHODS: Phase III and pivotal phase II trials, published between 2013 and 2018, investigating drug therapies for advanced NSCLC were included. PubMed was specifically searched for efficacy/toxicity updates. Treatments were graded 5 to 1 on the ESMO-MCBS v1.1, using the lower limit of the 95% confidence interval of the hazard ratio (HR), where scores 5 and 4 represent a substantial clinical benefit. Additionally, scores using the point estimate HR were generated, for comparison. Discrepancies between our grade estimations and the ones published on the ESMO website, as scorecards, were identified. RESULTS: ESMO-MCBS scores were calculated for 42 positive clinical trials. 54.8% met the ESMO-MCBS thresholds for clinically meaningful benefit (final grade of 4 or 5). That percentage decreased to 40.5% when considering the point estimate of the HR. 50.0% of the trials had no published scorecard on the ESMO website and discrepancies affected 11 (26.2%) studies. CONCLUSION: Almost half of the RCTs showing a statistically significant result favoring the experimental arm, failed to demonstrate a substantial clinical benefit according to the ESMO framework.

Dalbavancin is a novel antimicrobial against Gram-positive pathogens: clinical experience beyond labelled indications.

Very limited labelled indications have been approved for the newer antimicrobials. Data on the clinical uses, efficacy and safety of dalbavancin are scarce, thus here we sought to describe our clinical experience. 16-month observational prospective study was performed. 19 (86%) were used under off-label indications. 10 (46%) for osteoarticular infections, 5 (23%) bloodstream infections and 3 (14%) endocarditis. To highlight, one patient received dalbavancin as long-term suppressive therapy. Most frequent use reasons were promptly hospital discharge, 11 (65%), and the presence of resistant organisms involving limited treatment options, 5 (23%). Successful outcome was observed in >95% of the patients and only 1 (4.5%) adverse event was reported. Further evidence beyond labelled indications is urgently needed. Despite the limitations, dalbavancin appears to be a safe and efficient option for adult patients who have tried and/or failed other therapies due to multidrug-resistant Gram-positive organisms.