Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.Peer reviewe

Digitalisation of the drug prescribing process in Swiss hospitals - results of a survey.

The state of digitalisation in the healthcare sector in Switzerland is lagging, even as the national electronic health record (EHR) is being gradually implemented. Little is known about the implementation of electronic prescribing systems, their auxiliary features or drug datasets in Swiss hospitals.The aim of this study was to understand which electronic systems are implemented to support doctors in Swiss hospitals during the medication prescribing process. The survey was sent in spring 2021 to the chief pharmacists of the main Swiss hospitals. The survey focused on the introduction of the EHR, the clinical information system (CIS) and its prescribing module, as well as drug information data and clinical decision support systems (CDSS). The response rate was 98% (58/59 hospitals). Almost half of the hospitals (47%) were connected to the national EHR, almost all hospitals (86%) used a CIS and a vast majority of the hospitals (84%) had implemented electronic prescribing systems in their CIS. 10 years ago, around 63% of hospitals used a CIS and 40% were equipped with an electronic prescribing system. Today, CDSS of any kind were implemented in 50% of the hospitals, predominantly for drug-drug interactions. Drug master data were maintained in most hospitals (76%) via an automated interface, but mostly supplemented manually. Clinical drug information data were maintained in 74% of hospitals. In 67% of hospitals, datasets were imported via an automated interface. The digitalisation of the medical prescribing process in Swiss hospitals has progressed over the last decade. Drug prescriptions via electronic prescribing systems were introduced in most hospitals. However, this survey suggests that the current use of CDSS is far from exhausted, and that clinical drug information data could be maintained more efficiently. Optimising electronic support for healthcare professionals during the prescribing process still has considerable potential