Factor eight inhibitor bypass activity (FEIBA) in the management of bleeds in hemophilia patients with high-titer inhibitors

The development of high-titer inhibitors to FVIII and less often to other coagulation factors are the most serious complication of hemophilia therapy and makes treatment of bleeds very challenging. At present, bypassing agents, such as factor eight inhibitor bypass activity (FEIBA) and activated recombinant factor VII (rFVIIa) are the only coagulation factor concentrates available for the treatment of bleeds in inhibitor patients. Both products are effective and safe, and their efficacy has been found to be comparable (approximately 80%) in a recent prospective study. A significant number of patients report a better effect of one or the other of the products, and in a minority of the patients none of the products are particularly effective. The hemostatic efficacy of bypassing agents is not considered equal to that of coagulation factor replacement in patients without inhibitors by most physicians. An improvement in hemostatic efficacy may be achieved by optimizing the dosing of by passing agents. However, the lack of standardized and validated laboratory assays reflecting the hemostatic efficacy of the bypassing agents is an obstacle to this achievement

Identification of copy number variants from exome sequence data

Background With advances in next generation sequencing technologies and genomic capture techniques, exome sequencing has become a cost-effective approach for mutation detection in genetic diseases. However, computational prediction of copy number variants (CNVs) from exome sequence data is a challenging task. Whilst numerous programs are available, they have different sensitivities, and have low sensitivity to detect smaller CNVs (1–4 exons). Additionally, exonic CNV discovery using standard aCGH has limitations due to the low probe density over exonic regions. The goal of our study was to develop a protocol to detect exonic CNVs (including shorter CNVs that cover 1–4 exons), combining computational prediction algorithms and a high-resolution custom CGH array. Results We used six published CNV prediction programs (ExomeCNV, CONTRA, ExomeCopy, ExomeDepth, CoNIFER, XHMM) and an in-house modification to ExomeCopy and ExomeDepth (ExCopyDepth) for computational CNV prediction on 30 exomes from the 1000 genomes project and 9 exomes from primary immunodeficiency patients. CNV predictions were tested using a custom CGH array designed to capture all exons (exaCGH). After this validation, we next evaluated the computational prediction of shorter CNVs. ExomeCopy and the in-house modified algorithm, ExCopyDepth, showed the highest capability in detecting shorter CNVs. Finally, the performance of each computational program was assessed by calculating the sensitivity and false positive rate. Conclusions In this paper, we assessed the ability of 6 computational programs to predict CNVs, focussing on short (1–4 exon) CNVs. We also tested these predictions using a custom array targeting exons. Based on these results, we propose a protocol to identify and confirm shorter exonic CNVs combining computational prediction algorithms and custom aCGH experiments

Successful Control of Hepatitis B Virus Reactivation following Restart of Ibrutinib in Chronic Lymphocytic Leukaemia

Ibrutinib is a targeted therapy drug that blocks the activity of Bruton’s tyrosine kinase, and it is an approved treatment for several mature B-cell malignancies including chronic lymphocytic leukaemia (CLL). Side effects include infections, cytopenia, nausea, and diarrhoea. In this report, we describe a case of hepatitis B reactivation in a female CLL patient undergoing treatment with ibrutinib. Diagnosis was confirmed with highly elevated hepatitis B virus DNA and a prior blood sample confirmed previous exposure. Ibrutinib was paused, and antiviral therapy was initiated with prompt clinical improvement. Ibrutinib was reinitiated shortly after clinical improvement. Thus, our case report demonstrates that systematic HBV screening is essential before starting treatment with ibrutinib. We suggest that antiviral prophylaxis is considered for patients at risk of reactivation, and ibrutinib may be continued following HBV reactivation with proper antiviral treatment

Continuous infusion of simoctocog alfa in haemophilia A patients undergoing surgeries

Introduction There are two major principles for coagulation factor replacement in the clinical management of surgical procedures in patients with haemophilia, repetitive bolus injections every 6‐12 hours or administration of coagulation factor concentrates by continuous infusion. Aim The aim was to investigate the efficacy of simoctocog alfa (human‐cl rhFVIII) delivered by continuous infusion for bleeding prophylaxis during surgery in patients with haemophilia A. Methods We investigated the use of continuous infusion with simoctocog alfa in haemophilia A patients undergoing major surgical procedures at Oslo University Hospital from September 2015 to March 2018. The objectives were haemostatic outcome, in vivo recovery, stability over time at room temperature (3 days) and inhibitor development. Results Simoctocog alfa demonstrated treatment success in terms of haemostatic efficacy in 100% of major surgeries used as CI: 87% (n=21) excellent; 13% (n=3) good. No erythrocyte transfusions were required in any patient, no adverse events occurred and no inhibitors developed. The product was stable for 3 days at room temperature without loss of activity. Mean in vivo recovery was 1.8 (0.3) (IU/mL/IU/kg). Conclusion Continuous infusion with simoctocog alfa was found to achieve good/excellent haemostatic efficacy in all procedures. No adverse events occurred and no inhibitors developed

Chronic lymphocytic leukemia and secondary hematological malignancies: A nation-wide cancer registry study

Objective Chronic lymphocytic leukemia (CLL) treatment has changed dramatically, and landscape of second hematologic malignancies (SHM) evolves in the new era of targeted therapy. No data were available about the real‐world burden of SHM. Methods All 2631 patients with CLL in the Cancer registry of Norway registered 2003‐2012 were included. Results After median follow‐up of 6.6 years, 103 patients (4%) developed SHM. Diffuse large B‐cell lymphoma (DLBCL) was most common (n = 65; 63%). Median survival was 9.3 years (95% CI; 8.9‐9.8) in non‐SHM patients and 1.7 years in DLBCL, 0.8 years in Hodgkin lymphoma (n = 12), and 2.8 years in myeloid neoplasia (n = 15; 95% CI: 0.3‐2.6, 0.6‐2.9, and 0.4‐5.3, respectively; P < .001). Outcomes were poorest for SHM patients treated for CLL (HR 2.76, 95% CI 1.4‐5.5, P = 0.003). A higher proportion of men and younger age were found in SHM patients (median age 66 vs 72 years in non‐SHM; P < .001; men 68% vs 57%, P = .03). Myeloid neoplasia was rare (incidence rate 1/1000 person‐years; 95% CI: 0.6‐1.5) and tended to occur later than DLBCL in patients treated for CLL (median time from CLL to SHM 62 vs 45 months; P = .09). Conclusions SHM and especially myeloid malignancies were rare in chemoimmunotherapy era

National trends in incidence and survival of chronic lymphocytic leukemia in Norway for 1953–2012: a systematic analysis of population-based data

Chronic lymphocytic leukemia is a disease of the elderly, and despite major advances in treatment, remains incurable. The Cancer Registry of Norway has registered data on patients with chronic lymphocytic leukemia since 1953. We aimed to analyze trends in incidence and survival of chronic lymphocytic leukemia in Norway. We identified 7664 patients reported with chronic lymphocytic leukemia to the registry between 1953 and 2012. We gathered information on sex, age at diagnosis, date of death and basis for diagnosis. The age-standardized incidence increased from 0.6/100.000 person-years in 1953 to 3.1/100,000 person-years in 2012. We found a significant decrease in median age between 1993–2002 and 2003–2012 (75 vs. 72 years, 95%CI: 2.52–3.98, P < 0.001). Men were diagnosed at a significantly younger age than women. Immunophenotyping has become the most important diagnostic method after 2002. Median observed survival increased from 3 years in 1952–1963 to 8.5 years in 2003–2012. Five- and 10-year age-standardized net survival increased throughout the whole period across age groups and reached 79% and 57%, respectively. Median observed survival was significantly shorter in men than in women in 1993–2002 (4.9 vs. 6.1 years, P < 0.001). The gap between survival rates for men and women was diminishing in 2003–2012 in patients younger than 60 years while it remained considerable in older patients. Despite an aging Norwegian population, chronic lymphocytic leukemia (CLL) patients become younger at diagnosis. A fourfold increase in incidence, a prolonged survival, and major changes in diagnostic methods in Norway were observed