Asciminib in Newly Diagnosed Chronic Myeloid Leukemia.

BACKGROUND: Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs). METHODS: In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum. RESULTS: A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%). CONCLUSIONS: In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

Geometric approaches to assessing the numerical feasibility for conducting matching-adjusted indirect comparisons.

We discuss how to handle matching-adjusted indirect comparison (MAIC) from a data analyst's perspective. We introduce several multivariate data analysis methods to assess the appropriateness of MAIC for a given set of baseline characteristics. These methods focus on comparing the baseline variables used in the matching of a study that provides the summary statistics or aggregated data (AD) and a study that provides individual patient level data (IPD). The methods identify situations when no numerical solutions are possible with the MAIC method. This helps to avoid misleading results being produced. Moreover, it has been observed that sometimes contradicting results are reported by two sets of MAIC analyses produced by two teams, each having their own IPD and applying MAIC using the AD published by the other team. We show that an intrinsic property of the MAIC estimated weights can be a contributing factor for this phenomenon.

A rare fraction of drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumourigenic potential.

Follicular lymphoma (FL) comprises nearly 25% of non-Hodgkin lymphoma cases and is clinically characterized by initial sensitivity to chemotherapy followed by relapse. FL stroma contains a special type of stromal cell found in the germinal centre of lymph nodes-the follicular dendritic cell (FDC). We first isolated tumourigenic cells from the FL cell line FLK-1 by side population (SP) technique, and found that SP cells, which express ABCG2, were enriched by chemotherapy and radiation treatments. In vitro, SP cells were attracted by and adhered to FDCs through chemokine (C-X-C motif) ligand 12/chemokine (C-X-C motif) receptor 4 (CXCL12/CXCR4) signalling. In vivo, limiting dilution assays showed SP cells were highly enriched in cancer stem cells (CSC), but required FDC for tumour formation in non-obese diabetic/severe combined immunodeficiency mice. Treatment with AMD3100, a specific CXCL12/CXCR4 inhibitor, eliminated tumour growth. These findings were then verified with FL cells isolated from an FL patient's ascitic fluid (FLA-1). Finally, we detected the ABCG2 expressing lymphoma cells in FL clinical specimens. Thus, we found that the highly tumourigenic FL cells having CSC-like activities (FL-SC) interact with FDCs in a CXCL12/CXCR4 dependent manner to resist chemotherapy. Our results indicate the importance of FL-SC and niche cell signalling in maintaining tumourigenicity. These signals represent novel targets for CSC eradication.

Can ultrasound be used as the primary screening modality for the localization of parathyroid disease prior to surgery for primary hyperparathyroidism? A review of 440 cases.

BACKGROUND/AIMS: Sestamibi scintigraphy and neck ultrasonography have both been proposed as screening modalities for the detection of abnormal parathyroid glands in patients with primary hyperparathyroidism. As a result, many surgeons use both techniques prior to surgery. The goal of this study was to independently evaluate both ultrasound and sestamibi as single-modality preoperative screening tools for primary hyperparathyroidism. METHODS: A retrospective review of consecutive patients who underwent surgery for primary hyperparathyroidism from January 1999 to December 2009. Imaging results were compared to surgical findings. RESULTS: 440 patients were found to meet inclusion criteria. Sensitivities for correct localization of a single parathyroid adenoma for sestamibi versus ultrasound were: 83% (95% CI 78-86) versus 72% (95% CI 67-76). Ultrasound operator had no influence on sensitivity, and ultrasound identified nodular thyroid disease in 31% of patients. CONCLUSION: Ultrasonography alone can be used as the primary screening modality in patients with primary hyperparathyroidism. Ultrasound sensitivity is conserved despite operator variability, and identifies concomitant thyroid pathology.

Mortality in the Baltimore union poultry cohort: non-malignant diseases.

BACKGROUND: Workers in poultry plants have high exposure to a variety of transmissible agents present in poultry and their products. Subjects in the general population are also exposed. It is not known whether many of these agents cause disease in humans. If they do, we reason this would be readily evident in a highly exposed group such as poultry workers. We report here on mortality from non-malignant diseases in a cohort of poultry workers. METHODS: Mortality was compared with that of the US general population, and with that of a comparison group from the same union. Risk was estimated by standardized mortality ratio, proportional mortality ratio, and directly standardized risk ratio. RESULTS: Poultry workers as a group had an overall excess of deaths from diabetes, anterior horn disease, and hypertensive disease, and a deficit of deaths from intracerebral hemorrhage. Deaths from zoonotic bacterial diseases, helminthiasis, myasthenia gravis, schizophrenia, other diseases of the spinal cord, diseases of the esophagus and peritonitis were non-significantly elevated overall by all analyses, and significantly so in particular race/sex subgroups. CONCLUSIONS: Poultry workers may have excess occurrence of disease affecting several organs and systems, probably originating from widespread infection with a variety of microorganisms. The results for neurologic diseases could well represent important clues to the etiology of these diseases in humans. The small numbers of deaths involved in some cases limit interpretation.

Impact of thiazolidinedione safety warnings on medication use patterns and glycemic control among veterans with diabetes mellitus.

AIMS: In 2007, safety warnings were publicized regarding the association between thiazolidinediones (TZDs) and cardiovascular risks. This study investigated the impact of the publicized safety warnings on glycemic outcomes in patients with diabetes mellitus (DM). MATERIALS AND METHODS: The Veterans Integrated Services Network 16 database included 13,293 DM patients using TZDs (n=13,037 rosiglitazone, n=246 pioglitazone, n=10 both) during a baseline period of 03/01/07 to 05/31/07. Three medication use patterns groups (09/01/07 to 11/30/07) were defined as follows: (1) continuation on TZD treatment, (2) switching to other non-TZD treatment, (3) discontinuation of TZD treatment without any antidiabetic treatment. Primary outcome (09/01/07 to 02/29/08) was change from baseline in A1c. The analysis of variance was used to test the association between use patterns and A1c change. A logistic regression model was used to identify the predictors for use patterns. RESULTS: Patients (45.1%, n=5999) discontinued their TZD use. Both Groups 2 and 3 had significant A1c increases (both P values <.0001). Significant predictors for TZD discontinuation included black race, baseline heart disease, and diabetic complication [odds ratio (OR), 1.43; OR, 1.54; OR, 1.30, respectively]. Of the patients remaining on TZD therapy, 11.8% experienced improved A1c levels, and a lower percentage of patients (9.53%) experienced a deterioration in A1c levels (P<.0001). Patients who switched or discontinued an antidiabetic medication experienced improvements in body mass index (P<.0001) and triglycerides (P<.0036). The three use pattern groups had similar changes with regard to blood pressure and low-density lipoprotein. CONCLUSION: Thiazolidinedione safety warnings may have negatively impacted the glycemic control in DM patients.

Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study.

Uric acid has been proposed as an important risk factor in the development of primary hypertension in humans. However, limited information is available linking childhood uric acid levels and blood pressure levels in adulthood. This study examined 334 whites and 243 blacks enrolled in the Bogalusa Heart Study as children aged 5 to 17 years and as adults aged 18 to 35 years. The average follow-up period was 12 years. Childhood uric acid was significantly correlated with childhood and adult blood pressure, both systolic and diastolic. In a multivariate regression analysis, adjusting for age, sex, race, childhood body mass index, childhood uric acid levels, and change in levels of uric acid were significant predictors of adult diastolic blood pressure, whereas change in uric acid was a significant predictor of adult systolic blood pressures. In conclusion, elevated childhood serum uric acid levels are associated with increased blood pressure beginning in childhood and higher blood pressure levels that persist into adulthood, in males and females, whites and blacks, suggesting that early elevations in serum uric acid levels may play a key role in the development of human hypertension.