An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q): Gain of 16p13.3

Deletion 13q [del(13q)] is a favorable prognostic marker if it is detected as a sole abnormality in chronic lymphocytic leukemia (CLL). However the clinical courses of cases with isolated del(13q) are quite heterogeneous. In our study, we investigated copy number variations (CNVs), loss of heterozygosity (LOH), and the size of del(13q) in 30 CLL patients with isolated del(13q). We used CGH+SNP microarrays in order to understand the cause of this clinical heterogeneity. We detected del(13q) in 28/30 CLL cases. The size of the deletion varied from 0.34 to 28.81 Mb, and there was no clinical effect of the deletion size. We found new prognostic markers, especially the gain of 16p13.3. These markers have statistically significant associations with short time to first treatment and advanced disease stage. Detecting both CNVs and LOH at the same time is an advantageous feature of aCGH+SNP. However, it is very challenging for the array analysis to detect mosaic anomalies. Therefore, it is very important to confirm the results by FISH. In our study, we detected approximately 9% mosaic del(13q) by microarray. In addition, the gain of 16p13.3 may affect the disease prognosis in CLL. However, additional studies with more patients are needed to confirm these results.

Long-term safety and exploratory efficacy of fevipiprant in patients with inadequately controlled asthma: the SPIRIT randomised clinical trial

Background The prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites. Methods SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits. Results In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks’ treatment, while 163 received ≥ 104 weeks’ treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies. In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor. Conclusions In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile. Trial registration Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517.

116 Continuous vs. discontinuous arrhythmia monitoring in patients with myocarditis: insights from a single-centre experience

Aims Although potentially life-threatening, arrhythmias in myocarditis are under-reported. To assess diagnostic yield and clinical impact of continuous arrhythmia monitoring (CAM) in patients with arrhythmic myocarditis. Methods and results We enrolled consecutive adult patients (n = 104; 71% males, age 47 ± 11 years, mean LVEF 50 ± 13%) with biopsy-proven active myocarditis and de novo ventricular arrhythmias (VA). All patients underwent prospective monitoring by both sequential 24-h Holter ECGs (4/y in the first year; 2/y in years 2–5; 1/y later) and CAM, including either ICD (n = 62; 60%) or loop recorder (n = 42; 40%). By 3.7 ± 1.6 year follow-up, 45 patients (43%) had VT, 67 (64%) NSVT, and 102 (98%) premature ventricular complexes (PVCs). As compared to Holter ECG (average 9.5 exams per patient), CAM identified more patients with VA (VT: 45 vs. 4; NSVT: 64 vs. 45; both P < 0.001), more VA episodes (VT: 100 vs. 4%; NSVT: 91 vs. 12%), and earlier NSVT timing (median 6 vs. 24 months, P < 0.001). Conversely, Holter ECG allowed VA morphology characterization and daily PVC quantification. The time to first treatment modification was 12 ± 9 months by CAM vs. 33 ± 16 months by Holter ECG (P < 0.001), and drug withdrawal was always CAM-dependent. Guided by CAM findings, 8 patients (8%) started anticoagulants for newly diagnosed atrial arrhythmias. Differently from ICDs, loop recorders did not interfere with the interpretation of cardiac magnetic resonance. Conclusions In patients with arrhythmic myocarditis, CAM allowed accurate arrhythmia detection and showed a considerable clinical impact. As a complementary exam, VA characterization and PVC burden were better assessed by repeated Holter ECGs.

The Outcome of CLL Patients According to IGHV Mutational Status: An Israeli Perspective

Introduction: The prognostic significance of immunoglobulin heavy-chain variable region gene (IGHV) mutational status in chronic lymphocytic leukemia (CLL) is well established. Previous studies have shown that CLL patients with mutated IGHV (M-IGHV) have a better prognosis, manifested in a longer time-to first treatment (TTFT) and overall survival (OS). Here we present an analysis on the impact of IGHV mutational status in an Israeli cohort of patients with CLL. Methods: A total of 254 patients with CLL (diagnosed from 1991 to 2020), followed at the Tel-Aviv Sourasky Medical Center were included. The IGHV mutational status has been determined by next-generation sequencing (NGS) or cDNA Sanger. The sequences with a germline homology 98% or higher were considered unmutated, and those with a homology less than 98% as mutated CLL. IGHV subsets were analyzed using the ARResT/AssignSubsets website. All data were statistically analyzed by IBM SPSS Statistics 27 (IBM Corporation, Armonk, NY, USA), P-values were two-sided, and the significance level was determined at a<0.05 were considered significant. Results: Out of 254 patients, 132 (52.0%) had an unmutated IGHV gene (UM-IGHV), and 122 (48.0%) were mutated (M-IGHV). At diagnosis, most patients (Table 1) were ≤65 years of age (n=157, 61.8%), males (n=160, 63.0%) and had an absolute lymphocytic count equal to or less than (≤)15.0 x10 9/L (n=115, 52.5%). Advanced Binet stage was more commonly associated with UM-IGHV (n=44, 57.9%) (P=0.033). Among 240 patients (94.1%), the most frequently used VH gene segments (Figure 1) included; VH1-69 (n=35, 14.6%), VH4-34 (n=24, 10.0%), VH1-2 (n=17, 7.1%), and VH3-23 (n=16, 6.7%). Six major B-cell receptors (BCR) subsets (Figure 2) were identified in 21/180 of patients (11.7%), which most commonly included: CLL#1 (n=6, 28.6%), CLL#4 (n=5, 23.8%), and CLL#2(n=3, 14.3%). Patients with M-IGHV had a longer time to first treatment (TTFT) (P<0.001, hazard ratio (HR)=2.5, 95% confidence interval [1.8-3.5], Figure 3A) and a better overall survival (OS) (P=0.002, HR=2.7, [1.4-5.1]) compared to those with UM-IGHV gene (Figure 3B). In multivariate analyses of the entire cohort; for TTFT (Table 2A), males (P=0.002, HR=1.9, [1.3-2.9]), >65 years of age at diagnosis (P=0.008, HR=1.8, [1.2-2.7]), advanced Binet stage (P<0.001, HR=2.4, [1.5-3.8]) and UM-IGHV mutational status (P=<0.001, HR=2.0, [1.3-2.9]) were found to be significant predictors for shorter TTFT, while in a multivariate analysis for OS (Table 2B), only >65 years of age at diagnosis (P=0.010, HR=2.6, [1.3-5.5]) and UM-IGHV mutational status (P=0.004, HR=2.9, [1.4-5.9]) were found to be significant factors for shorter OS. In multivariate analyses performed separately for each IGHV mutational status group; males (P=0.021, HR=2.1, [1.1-4.0]), age >65 years (P=0.002, HR=3.2, [1.5-6.4]) and advanced Binet stage (P<0.001, HR=4.1, [1.9-8.7]) were found as independent predictors for a shorter TTFT in M-IGHV patients, while only males retained a statistically significance in UM-IGHV patients (P=0.017 HR=2.0, [1.1-3.5]). Furthermore, in a multivariate analysis for OS; age>65 years at diagnosis (P=0.039, HR=4.3, [1.1-17.0]) was the only independent predictor in M-IGHV patients, while no variable maintained its statistical significance in UM-IGHV cases. Conclusion: As previously studied, our cohort demonstrates that M-IGHV CLL patients have better TTFT and OS. However, the rate of BCR subsets in Israel appears to be lower than expected. A separated multivariate analysis for M-IGHV and UM-IGHV patients revealed different independent predictors for TTFT and OS to each of the IGHV mutational status groups. Further studies with larger cohorts are required to deeply study these differences and provide further clinical insight into the pathophysiology of CLL. Figure 1 Figure 1. Disclosures Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria.

Circulating CXCL13 could be served as a biomarker for chronic lymphocytic leukemia severity

BACKGROUND: Recent reports indicated the importance of chemotractants CXCL-13 in solid tumors and lymphoid malignancies. However, the prognostic value of the mentioned cytokines as biomarkers in chronic lymphocytic leukemia patient’s remains to be identified. Therefore; this study was designed in order to address the relation between CXCL-13 concentrations levels and markers of severity in CLL patients. METHODS: Our study included 150 CLL patients and 20 controls. Serum CXCL-13 was determined by ELISA for CLL patients at diagnosis as well as controls. RESULTS: The serum CXCL-13 levels were significantly higher in CLL patients as compared to controls. The high CXCL-13 concentration levels was significantly associated with high number of smudge cells; high LDH; high grade of Rai stage, short time to first treatment (TTT). Cox regression analysis was conducted for prediction of TTT, using age, gender, WBCs, smudge cells, CXCL-13, LDH, ZAP70, CD38, β2-microglobulin, Rai staging as covariates. High LDH, CXCL-13 and CD38% were significantly independent predictor for shorter TTT. CONCLUSION: High CXCL-13 serum levels at CLL diagnosis is correlated with other markers of disease activity; and could be served as biomarkers that predict CLL patient’s outcome.

TP10.2.11The consequences of COVID-19 on the colorectal red-flag cancer pathway- A 3 month review 2019 to 2020

Aim The COVID-19 pandemic is an evolving healthcare challenge introducing greater burden on existing resources. With 1,100 people in Northern Ireland diagnosed with colorectal cancer (CRC) per annum, concerns over disruption of cancer services and secondary consequences have been highlighted. We aim to evaluate the impact of COVID-19 on the CRC red flag pathway in comparison to the pre-COVID era. Methods Two comparative data sets were compiled through retrospective analysis of red-flag colorectal referrals over a 3-month period for both April to June 2019 and 2020. A comprehensive review of each patient’s electronic care record and medical notes was completed. Patient demographics, co-morbidity, referral information, time to hospital appointment and investigation modality were documented. For patients identified with CRC the stage and time to first definitive treatment was documented. Results A total of 47 CRCs were identified from both red-flag referral groups; 25 CRCs 2019 compared to 22 in 2020. Median age at time of referral was 79 years in 2019 compared to 71 years in 2020. Time to outpatient review was significantly less during 2020 compared to 2019; 16 days and 31 days respectively (p < 0.05). Time to first treatment was 103 days 2019 compared to 75 days 2020 (p < 0.05). Advanced diagnostic stage or increased number of emergency hospital presentations in the COVID-19 period was not demonstrated. Conclusion Despite disruption of established colorectal cancer services during the COVID-19 pandemic, we demonstrated patients waited less time to outpatient review and intervention. With comparative cases of CRC to the pre-COVID era diagnosed.

Clinical impact of continuous electrical monitoring in patients with arrhythmic myocarditis: a prospective cohort study

Background Although potentially life-threatening, arrhythmias in myocarditis are under-reported. Purpose To assess diagnostic yield and clinical impact of continuous arrhythmia monitoring (CAM) in patients with arrhythmic myocarditis. Methods We enrolled consecutive adult patients (n=104; 71% males, age 47±11y, mean LVEF 50±13%) with biopsy-proven active myocarditis and de novo ventricular arrhythmias (VA). All patients underwent prospective monitoring by both sequential 24-hour Holter ECGs (4/y in the first year; 2/y in years 2–5; 1/y later) and CAM, including either ICD (n=62; 60%) or loop recorder (n=42; 40%). Results By 3.7±1.6 y follow-up, 45 patients (43%) had VT, 67 (64%) NSVT, and 102 (98%) premature ventricular complexes (PVC). As compared to Holter ECG (average 9.5 exams per patient), CAM identified more patients with VA (VT: 45 vs. 4; NSVT: 64 vs. 45; both p<0.001), more VA episodes (VT: 100 vs. 4%; NSVT: 91 vs. 12%), and earlier NSVT timing (median 6 vs. 24 months, p<0.001). Conversely, Holter ECG allowed VA morphology characterization and daily PVC quantification. The time to first treatment modification was 12±9 months by CAM vs. 33±16 months by Holter ECG (p<0.001), and drug withdrawal was always CAM-dependent. Guided by CAM findings, 8 patients (8%) started anticoagulants for newly-diagnosed atrial arrhythmias. Differently from ICDs, loop recorders did not interfere with the interpretation of cardiac magnetic resonance. Conclusion In patients with arrhythmic myocarditis, CAM allowed accurate arrhythmia detection and showed a considerable clinical impact. As a complementary exam, VA characterization and PVC burden were better assed by repeated Holter ECGs. FUNDunding Acknowledgement Type of funding sources: None.

CD200 Baseline Serum Levels Predict Prognosis of Chronic Lymphocytic Leukemia

Membrane-bound CD200 is overexpressed in chronic lymphocytic leukemia (CLL), and there is some evidence that its soluble ectodomain (sCD200) could also be involved in the pathophysiology and the disease. However, very little is known about sCD200’s prognostic significance. sCD200 was tested at diagnosis in 272 patients with CLL and in 78 age- and sex-matched healthy subjects using a specific human CD200 (OX-2 membrane glycoprotein) ELISA kit. A significantly higher concentration of sCD200 was found in CLL patients compared to controls. In our cohort, sCD200 was significantly higher in patients who were older than 66 years, with Binet stage C, unmutated IgVH and unfavorable (del11q or del17p) FISH. Time-to-first treatment and overall survival were significantly shorter in patients with higher sCD200 concentration, using as a cut-off 1281 pg/mL, the median value for sCD200 concentration in the whole CLL cohort. However, the prognostic impact of sCD200 was not confirmed in multivariate analysis. Baseline sCD200 values appeared to have an impact on the response to chemotherapy or chemo-immunotherapy, but not to targeted agents. Collectively, our data show that sCD200 serum levels correlate with more aggressive clinical and biological features and are able to predict a worse prognosis. This work supports the relevant role of CD200 not only as a diagnostic tool but also as a prognostic indicator and a potential therapeutic target in CLL.

Antibacterial use by birth year and birth season in children 0-2 years in Norway

Introduction: Consumption of antibacterials in children follows seasonal cycles, and time to first treatment depends on birth season. The aim of this study was to describe dispensing rate, one-year periodic prevalence, and age at first prescription in children aged 0-2 years in Norway.Methods: We used data from the Norwegian prescription database and included all dispensed prescriptions on systemic antibacterials in 2008-2017 during the first three years of life to children born 2005-2014. We calculated age by subtracting birth month and birth year from date of collection of prescription. We used multiple linear regression to investigate the effect of birth season on age at first dispensed prescription.Results: We included 714 262 prescriptions to 281 888 individuals (53.1% boys). In 2016, one-year-old boys had the highest periodic prevalence (35.6%) and the highest dispense rate (545/1000 individuals), followed by one-year-old girls (32.6%, 478/1000 individuals). The lowest prevalence and dispense rate in all age groups was found towards the end of the period. Winter months had the highest proportion of dispensed prescriptions, and children born in autumn were significantly younger when collecting their first prescription. On average, boys collected their first prescription 26 days younger compared to girls.Conclusion: One-year-olds have the highest periodic prevalence and the highest dispense rate. This contrast with results from other studies on Norwegian data and is probably attributed to our use of birth month for calculation of age. Children born in autumn were younger when collecting their first prescription compared to other birth seasons. It is unknown whether this has any long-term clinical implications.

Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone’s biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell’C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT’s explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHVunmut and LDT>12months group showed a predominant prognostic role over IGHVmut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.