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

Monoklonal gammopati av klinisk betydning

Monoklonal gammopati er hyppig og kan være assosiert med alvorlig sykdom, men målrettet behandling kan gi betydelig helsegevinst. Det er godt kjent at funn av monoklonal gammopati bør føre til en vurdering om pasienten kan ha myelomatose eller annen B-lymfoproliferativ sykdom, men at det monoklonale immunglobulinet direkte kan føre til sykdom, er langt mindre kjent

Cold agglutinin disease: Current challenges and future prospects

Abstract: Cold agglutinin disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic disease, accounting for 15–25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials

Cryopreservation of primary B cells minimally influences their signaling responses

Phospho flow is a powerful approach to detect cell signaling aberrations, identify biomarkers and assess pharmacodynamics, and can be performed using cryopreserved samples. The effects of cryopreservation on signaling responses and the reproducibility of phospho flow measurements are however unknown in many cell systems. Here, B lymphocytes were isolated from healthy donors and patients with the B cell malignancy chronic lymphocytic leukemia and analyzed by phospho flow using phospho-specific antibodies targeting 20 different protein epitopes. Cells were analyzed both at basal conditions and after activation of cluster of differentiation 40 (CD40) or the B cell receptor. Pharmacodynamics of the novel pathway inhibitor ibrutinib was also assessed. At all conditions, fresh cells were compared to cryopreserved cells. Minimal variation between fresh and frozen samples was detected. Reproducibility was tested by running samples from the same donors in different experiments. The results demonstrate reproducibility across different phospho flow runs and support the use of cryopreserved samples in future phospho flow studies of B lymphocytes

A case of post-transfusion purpura with severe refractory thrombocytopenia but no cutaneous manifestations

Posttransfusion purpura is a serious adverse effect of transfusion due to HPA-antibodies. A young female was diagnosed with acute leukaemia, and treatment commenced. Severe thrombocytopenia ensued. No platelet increment was achieved despite transfusions with buffy coat, HLA-compatible, and HPA-1a negative platelets. The workup indicated the presence of anti-HPA-1a. When the diagnosis of posttransfusion purpura was sufficiently substantiated, she had experienced a fatal intracerebral haemorrhage

A Case of Posttransfusion Purpura with Severe Refractory Thrombocytopenia but No Cutaneous Manifestations

Posttransfusion purpura is a serious adverse effect of transfusion due to HPA-antibodies. A young female was diagnosed with acute leukaemia, and treatment commenced. Severe thrombocytopenia ensued. No platelet increment was achieved despite transfusions with buffy coat, HLA-compatible, and HPA-1a negative platelets. The workup indicated the presence of anti-HPA-1a. When the diagnosis of posttransfusion purpura was sufficiently substantiated, she had experienced a fatal intracerebral haemorrhage

Cytokinesis arrest and multiple centrosomes in B cell chronic lymphocytic leukaemia

Cytokinesis failure leads to the emergence of tetraploid cells and multiple centrosomes. Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in adults and is characterized by clonal B cell expansion. Here, we show that a significant number of peripheral blood CLL cells are arrested in cytokinesis and that this event occurred after nuclear envelope reformation and before cytoplasmic abscission. mRNA expression data showed that several genes known to be crucial for cell cycle regulation, checkpoint and centromere function, such as ING4, ING5, CDKN1A and CDK4, were significantly dysregulated in CLL samples. Our results demonstrate that CLL cells exhibit difficulties in completing mitosis, which is different from but may, at least in part, explain the previously reported accumulation of CLL cells in G0/1