Response-adapted, time-limited venetoclax, umbralisib, and ublituximab for relapsed/refractory chronic lymphocytic leukemia.

ABSTRACT: Many patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Owing to the synergistic antitumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment. We conducted a phase 1/2 clinical trial to determine the safety and efficacy of venetoclax in combination with umbralisib and the anti-CD20 monoclonal antibody, ublituximab, (U2-VeN) in patients with relapsed/refractory CLL (N = 46) and Richter transformation (N = 5). After 12 cycles, treatment was stopped for patients with CLL who achieved undetectable minimal residual disease (uMRD). Adverse events of special interest included diarrhea in 50% of patients (11% grade 3/4), and aspartate aminotransferase and/or alanine aminotransferase elevation in 15 patients (33%), with 3 (7%) grade 3/4. There were no cases of tumor lysis syndrome related to venetoclax, with outpatient initiation in 96% of patients. The intent-to-treat overall response rate for CLL was 98% with best response of 100% in evaluable patients (42% complete responses). The end-of-treatment rate of uMRD at 10-4 in bone marrow was 77% (30/39), including a 71% uMRD rate among 14 patients refractory to prior BTK inhibitor. Time-limited venetoclax and U2 is safe and highly effective combination therapy for patients with relapsed/refractory CLL including those who have been previously treated with covalent BTK inhibitors. This trial was registered on www.clinicaltrials.gov as #NCT03379051.

Development of a Dundee Ground Truth imaging protocol for recording indoor crime scenes to facilitate virtual reality reconstruction.

Early and accurate visualisation of a crime scene is highly desirable such that a rapid, agile, and informed decision-making process can be undertaken by an investigative team. We present a new standard operating procedure for imaging an indoor scene using DSLR cameras conventionally used by crime scene investigators and examiners. The standard operating procedure (SOP) enables the systematic photography of indoor spaces in such a way that the Structure from Motion (SfM) photogrammetry technique can be implemented, allowing the scene to be recreated in Virtual Reality (VR). To demonstrate the method's validity, we compare two VR-rendered representations of an example scene using (a) photographs taken by an experienced crime scene examiner using a conventional photographic method and (b) photographs taken by a novice photographer following the developed SOP.

Comparison of mandibular cortical thickness and QCT-derived bone mineral density (BMD) in survivors of childhood acute lymphoblastic leukemia: a retrospective study.

OBJECTIVE: To examine whether panoramic radiograph-determined mandibular cortical thickness correlated with quantitative computed tomography-derived bone mineral density (BMD) in survivors of childhood acute lymphoblastic leukemia (ALL). METHODS: We identified patients treated for ALL at St. Jude Children's Research Hospital, seen in the After Completion of Therapy (ACT) Clinic between January of 2006 and January of 2014 who had QCT-derived BMD and panoramic radiographs obtained within 1 month of each other. Panoramic radiographs were independently scored by a pediatric radiologist, two pediatric dentists, and a general dentist using the Klemetti technique. We used the Spearman's rank correlation test and the multivariate regression model to investigate the effect of evaluator experience on results. RESULTS: The study cohort comprised 181 patients with 320 paired studies: 112 (62%) male, 112 (71%) were white. Median age at ALL diagnosis was 6.4 (range, 0-18.8) years. Median age at study was 11.9 (range, 3.3 to 29.4) years. The median average BMD was 154.6 (range, 0.73-256) mg/cc; median QCT Z-score (age and gender adjusted) was -0.875 (range, -5.04 to 3.2). We found very weak association between panoramic radiograph score and both QCT-BMD average (P = 0.53) and QCT Z-score (P = 0.39). Results were not influenced by level of reader experience. CONCLUSIONS: The Klemetti technique of estimating BMD does not predict BMD deficits in children and young adult survivors of ALL, regardless of reviewer expertise. Alternative methods are needed whereby dental healthcare providers can identify and refer patients at risk for BMD deficits for detailed assessment and intervention.

Interrupted development of dentition in children receiving bone marrow transplantation for acute lymphocytic Leukemia: a case series.

This case series depicts dental anomalies that may develop in children who have undergone bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL). The most common finding in these patients was root stunting; other abnormalities included microdontia, hypodontia, taurodontia, caries, enamel pearls, and pulpal calcification. Recognition of these adverse effects of BMT on odontogenesis, as demonstrated on panoramic radiograph images, will allow healthcare providers to explain to parents and patients the possible dental outcomes associated with BMT and to optimize their dental health regimen.