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Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.
Yu, S, Zhang, Y, Yu, G, Wang, Y, Shao, R, Du, X, Xu, N, Lin, D, Zhao, W, Zhang, X, et al
Journal of internal medicine. 2024;(2):216-228
Abstract
BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION Clinical Trials Registry: NCT04424147.
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Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.
Quintanilha, JCF, Wang, J, Sibley, AB, Jiang, C, Etheridge, AS, Shen, F, Jiang, G, Mulkey, F, Patel, JN, Hertz, DL, et al
British journal of cancer. 2022;(2):265-274
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Abstract
BACKGROUND Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. METHODS A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. RESULTS The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). CONCLUSIONS The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).
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Predicting Gastrostomy Tube Placement After Intracerebral Hemorrhage: External Validation of the GRAVo Score.
Lin, D, Minyetty, M, Selim, M, Marchina, S, Carvalho, F, Heistand, E, Bhanu, G, Hasan, S, Kumar, S
Neurocritical care. 2022;(2):506-513
Abstract
BACKGROUND Dysphagia is a common consequence of intracerebral hemorrhages (ICH). It can lead to enduring impairments of dietary intake and the requirement for feeding via percutaneous gastrostomy (PEG) tubes. However, variabilities in the course of swallowing recovery after ICH make it difficult to anticipate the need for PEG placement in an individual patient. A new tool called the GRAVo score was recently developed to predict PEG tube placement after an ICH but has not been externally validated. Our study aims were to externally validate the GRAVo score in a multicenter cohort and reexamine the role of race in predicting PEG placement, given the uncertain biological plausibility for this relationship observed in the derivation cohort. METHODS Patients for this analysis were selected from a previously completed multicenter, randomized, double-blind futility design clinical trial, the Intracerebral Hemorrhage Deferoxamine trial, and underwent a retrospective review of prospectively collected data. The GRAVo scores were computed by using previously established methods using the following variables: Glasgow Coma Scale ≤ 12 (2 points), race (1 point for Black), age > 50 years (2 points), and ICH volume > 30 mL (1 point). Association of GRAVo scores with PEG placement were examined by using logistic regression analysis after adjustment for exposure to deferoxamine. Model performance was estimated by using area under the receiving operating characteristic curve (AUROC). Subsequently, a second model was created by excluding scores for race, and the AUROC of both models were compared. RESULTS A total of 291 patients with complete data points served as the study cohort; 38 (13%) underwent PEG placement. The median GRAVo score for patients in the PEG and non-PEG groups were 4 (interquartile range 3-4) versus 2 (interquartile range 2-3), respectively (p < 0.0001). External validation of the GRAVo score yielded an AUROC of 0.7008 (95% confidence interval 0.6036-0.78); the model obtained without assignment of scores for the variable race yielded an AUROC of 0.6958 (95% confidence interval 0.6124-0.7891). The receiver operating characteristic curves from both models demonstrated close overlap. CONCLUSIONS The results of our external validation demonstrate the validity of GRAVo scores for predicting PEG tube placement after an ICH. However, its performance was more modest compared with that of the derivation cohort. Inclusion of the race variable had no measurable effect on model performance. Differences in patient characteristics between these cohorts may have influenced our results. These findings should be taken into consideration when using the GRAVo score to assist clinical decision making on PEG placement after an ICH.