Multigene Profiling of Circulating Tumor Cells (CTCs) for Prognostic Assessment in Treatment-Naïve Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

The substantial biological heterogeneity of metastatic prostate cancer has hindered the development of personalized therapeutic approaches. Therefore, it is difficult to predict the course of metastatic hormone-sensitive prostate cancer (mHSPC), with some men remaining on first-line androgen deprivation therapy (ADT) for several years while others progress more rapidly. Improving our ability to risk-stratify patients would allow for the optimization of systemic therapies and support the development of stratified prospective clinical trials focused on patients likely to have the greatest potential benefit. Here, we applied a liquid biopsy approach to identify clinically relevant, blood-based prognostic biomarkers in patients with mHSPC. Gene expression indicating the presence of CTCs was greater in CHAARTED high-volume (HV) patients (52% CTChigh) than in low-volume (LV) patients (23% CTChigh; * p = 0.03). HV disease (p = 0.005, q = 0.033) and CTC presence at baseline prior to treatment initiation (p = 0.008, q = 0.033) were found to be independently associated with the risk of nonresponse at 7 months. The pooled gene expression from CTCs of pre-ADT samples found AR, DSG2, KLK3, MDK, and PCA3 as genes predictive of nonresponse. These observations support the utility of liquid biomarker approaches to identify patients with poor initial response. This approach could facilitate more precise treatment intensification in the highest risk patients.

Establishing clinical remission criteria and the framework of a treat-to-target algorithm for Takayasu arteritis: Results of a Delphi exercise carried out by an expert panel of the Japan Research Committee of the Ministry of Health, Labour and Welfare for intractable vasculitis

ABSTRACT Objectives To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK). Methods A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 paediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over four reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with three patients. Results Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0–5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including positron emission tomography–computed tomography, and two on treatment intensification. Conclusions We developed a T2T algorithm and proposals for standardised remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.

LDL-cholesterol trajectories and statin treatment in Finnish type 2 diabetes patients: a growth mixture model

We aimed to identify distinct longitudinal trends of LDL-cholesterol (LDL-C) levels and investigate these trajectories’ association with statin treatment. This retrospective cohort study used electronic health records from 8592 type 2 diabetes patients in North Karelia, Finland, comprising all primary and specialised care visits 2011‒2017. We compared LDL-C trajectory groups assessing LDL-C treatment target achievement and changes in statin treatment intensity. Using a growth mixture model, we identified four LDL-C trajectory groups. The majority (85.9%) had “moderate-stable” LDL-C levels around 2.3 mmol/L. The second-largest group (7.7%) consisted of predominantly untreated patients with alarmingly “high-stable” LDL-C levels around 3.9 mmol/L. The “decreasing” group (3.8%) was characterised by large improvements in initially very high LDL-C levels, along with the highest statin treatment intensification rates, while among patients with “increasing” LDL-C (2.5%), statin treatment declined drastically. In all the trajectory groups, women had significantly higher average LDL-C levels and received less frequent any statin treatment and high-intensity treatment than men. Overall, 41.9% of patients had no statin prescribed at the end of follow-up. Efforts to control LDL-C should be increased—especially in patients with continuously elevated levels—by initiating and intensifying statin treatment earlier and re-initiating the treatment after discontinuation if possible.

Bowel Ultrasound: a Non-invasive, Easy to Use Method to Predict the Need to Intensify Therapy in Inflammatory Bowel Disease Patients

Background and Aims: Bowel ultrasound (BU) is a non-invasive, inexpensive, widely available tool, valuable for inflammatory bowel disease (IBD) assessment. The aim of the present study was to investigate the clinical utility of BU to predict the need to intensify therapy in IBD patients. Methods: One hundred seventeen IBD patients (89 Crohn’s disease, and 28 ulcerative colitis) diagnosis established at least 6 months before enrolment, undergoing maintenance therapy were prospectively included in the study. Bowel ultrasound investigated the following parameters: the bowel wall thickness (BWT), loss of wall stratification, the presence of the bowel wall Doppler signal, the visible lymph nodes, the mucosal hyperechoic spots, and the irregular external bowel wall. The patients were followed-up for 6 months, registering the need to escalate the treatment regimen. Subgroup analyses were conducted for patients requiring immediate treatment intensification (37 subjects), due to active disease at baseline and patients with subsequent treatment intensification, in the 6 months follow-up period (21 cases) in comparison to patients that required no therapeutic optimization (59). Results: During the follow-up, 49.6% of patients needed treatment escalation. All the investigated BU variables were significantly associated with the main outcome. In the multivariate analysis, the mean BWT (p<0.0001), and the presence of the bowel wall Doppler signal (p=0.007) were independent predictors of the main outcome. For the subgroup analyses: mean BWT (p=0.0001) and the presence of the bowel wall Doppler signal (p=0.01) were independent predictors for immediate treatment intensification (active disease at baseline) and mean BWT (p=0.0003) and the lack of bowel wall stratification (p=0.05) were independent predictors for the need of subsequent therapeutic optimization. Logistic regression prediction models and prediction scores (BU score) had the best AUROC values (>0.91) when compared to traditional biomarkers of active inflammation, such as C reactive protein or fecal calprotectin. Conclusion: Bowel ultrasound could be used as a non-invasive, easy to use diagnostic tool to predict the need to intensify therapy in patients with IBD.

Isatuximab Rescue for Inadequate Response to Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: Interim Analysis of the Phase II Iril Study of the Australian Myeloma Research Consortium (AMaRC 18-02)

Background: Almost two thirds of transplant-ineligible, treatment naïve multiple myeloma (NDMM, TNE) patients (pts) do not proceed to second line anti-MM therapy. Given depth of response to initial therapy correlates to overall survival (OS), a deep remission should also be the target for this cohort of generally elderly and frail patients. However, this should not come at the expense of either treatment-related or fiscal toxicity. IRIL is a phase II, multicentre, response-adapted study examining treatment intensification with isatuximab (Isa; supported by Sanofi/Genzyme), an anti-CD38 monoclonal antibody, for pts not achieving pre-defined target responses to lenalidomide and dexamethasone (Rd). Method: TNE NDMM pts meeting IMWG criteria for treatment are eligible for enrolment. Pts commence treatment with lenalidomide [25mg D1-D21 of a 28-day cycle (C)] and dexamethasone [40mg (20mg for those aged ³75 years) PO weekly]. Failure to achieve pre-defined target response [&lt;PR after 4 cycles, &lt;VGPR after 6, or &lt;CR after 9 cycles of Rd] or progressive disease (PD) within the first 9 cycles of Rd leads to addition of Isa (10mg/kg IV weekly for cycle 1, then fortnightly) until PD or adverse events (AEs) that warrant treatment cessation. The primary endpoint is to evaluate the rate of achievement of ³PR following completion of 6 cycles Isa-Rd in those who failed to achieve &lt;PR after C4 Rd. The secondary endpoints are to evaluate overall improvement in depth of response to Isa-Rd, progression free survival (PFS), OS, and safety. Results: From June 2019 to June 2021, 42 pts [52.3% male, median age 77.7 yrs (range 68.5-86.0), R-ISS Stage I (n=8), Stage II (n=23) and Stage III (n=7)] were accrued. 30 pts have completed at least C4 Rd and were deemed evaluable (12 non-evaluable; 5 only recently recruited, 5 withdrew consent (WD) due to logistic reasons, 2 PD pre-C4 and were taken of study at investigator discretion). Of the 30 evaluable pts (see Figure 1), 25 remain on study with 2 further WD (logistic reasons) and 3 deaths. In total, 25pts have had treatment intensification with Isa [9pts (5&lt;PR and 4 PD) prior to C4 Rd, 11/13 eligible &lt; VGPR after C6 Rd (1 omission in error, 1 pt WD consent), 4/5 eligible pts &lt; CR after C9 Rd (1 omission in error) and 1 PD at C6]. 18/25 patients have had at least 6 months of Isa intensification with increased depth of response in 12 (66.7%) pts. Of the 9 pts rescued with Isa after not reaching target response post C4 Rd, 7 have completed 6 Isa-Rd cycles with 100% deepening of response (5 PR, 4 VGPR). The overall response rate in the cohort of evaluable patients is 100% (16 PR, 14 VGPR). The median (±SD) follow-up time of the evaluable cohort was 9.96 ± 6.24 months with med OS not reached. Thirty-one (73.8%) pts experienced any grade AE (median = 6; range 1-21). Grade 3 or 4 AEs were reported in 16 pts (34 events in total; median per pt = 2; range 1-5). Most common ³ Grade 3 events include infection (10), neutropenia (7) and insomnia and mood disorder (3 each). Neutropenia was the single grade 4 AE in a patient on Rd. Fewer of the reported grade 3 or 4 AEs occurred while on Isa-Rd (16) than while on Rd alone (n=18) with causality was less frequently attributed to Isa (n=4) than R (n=17) or d (n=14). Conclusion: A response-adapted approach for TNE NDMM pts with isatuximab intensification upon inadequate response to standard-of-care lenalidomide-dexamethasone is both safe and effective. Isa-Rd leads to universal deepening of response in patients failing to achieve a PR or better after 4 months of Rd, while the overall response rate in evaluable patients, irrespective of initial response to Rd, is 100%. Isa-Rd is well tolerated in this elderly patient cohort. The safety profile for the combination Isa-Rd is similar to previous reports. Patient accrual is ongoing. Figure 1: Swimmer's plot highlighting patient response after C4 Rd, timepoints of isatuximab intensification (*Isa) and subsequent depth and duration of response. Figure 1 Figure 1. Disclosures Janowski: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Quach: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees.