Patient-specific computational models predict prognosis in B cell lymphoma by quantifying pro-proliferative and anti-apoptotic signatures from genetic sequencing data.

Genetic heterogeneity and co-occurring driver mutations impact clinical outcomes in blood cancers, but predicting the emergent effect of co-occurring mutations that impact multiple complex and interacting signalling networks is challenging. Here, we used mathematical models to predict the impact of co-occurring mutations on cellular signalling and cell fates in diffuse large B cell lymphoma and multiple myeloma. Simulations predicted adverse impact on clinical prognosis when combinations of mutations induced both anti-apoptotic (AA) and pro-proliferative (PP) signalling. We integrated patient-specific mutational profiles into personalised lymphoma models, and identified patients characterised by simultaneous upregulation of anti-apoptotic and pro-proliferative (AAPP) signalling in all genomic and cell-of-origin classifications (8-25% of patients). In a discovery cohort and two validation cohorts, patients with upregulation of neither, one (AA or PP), or both (AAPP) signalling states had good, intermediate and poor prognosis respectively. Combining AAPP signalling with genetic or clinical prognostic predictors reliably stratified patients into striking prognostic categories. AAPP patients in poor prognosis genetic clusters had 7.8 months median overall survival, while patients lacking both features had 90% overall survival at 120 months in a validation cohort. Personalised computational models enable identification of novel risk-stratified patient subgroups, providing a valuable tool for future risk-adapted clinical trials.

A Single-Centre Experience of Post-COVID-19 Vaccine-Related Immune-Mediated Complications.

The significant impact of the COVID-19 pandemic has resulted in a worldwide effort to develop effective vaccines. In the United Kingdom, the COVID-19 vaccine development and roll-out has been overwhelmingly successful in reducing infections and deaths. However, case reports have emerged of a rare syndrome of vaccine-induced immune thrombocytopenia and thrombosis (VITT), as well as cases of immune thrombocytopenia (ITP). This has necessitated a better understanding of these conditions. However, as both VITT and "vaccine-associated ITP" are emerging conditions, evidence on the clinical features, epidemiology, and management is still evolving. Subsequently, with the initiation of the COVID-19 vaccine booster program, it has become increasingly important to continue to collect accurate data on post-COVID-19 vaccine complications to aid with their prompt recognition and management. In this case series, we report on the presentations and management of seven cases of post-COVID-19 vaccine-related immune-mediated complications which occurred at our center between the months of March and July 2021.

Thrombocytopenia: the good, the bad and the ugly.

New thrombocytopenia may be associated with a variety of conditions and diagnosis can be challenging. Presentation can vary from life-threatening bleeding or thrombosis to an incidental finding in an asymptomatic patient. New thrombocytopenia requires urgent investigation. Investigations are mainly guided by findings from the clinical history, physical examination, full blood count and blood film analysis. Aside from the actively bleeding patient, rare but life-threatening causes of thrombocytopenia must be identified early as they require urgent treatment. These include thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, suspicion of new acute promyelocytic leukaemia, and vaccine-induced prothrombotic immune thrombocytopenia. Here, we discuss how to approach a patient with new thrombocytopenia, along with key differentials not to be missed.

Lymphocytosis and chronic lymphocytic leukaemia: investigation and management.

Lymphocytosis is a common blood-test finding. Establishing whether the cause of lymphocytosis is benign or malignant is key to managing patients appropriately. A lymphocytosis should always prompt clinical review including a thorough history, examination and appropriate preliminary investigations (blood tests, blood film). The majority of patients with chronic lymphocytic leukaemia (CLL) present incidentally due to a lymphocytosis found on routine blood tests. Patient outcomes vary considerably based on genetic pre-disposition and various prognostic markers (age, Binet or Rai staging, and B2-microglobulin). Although not curative, chemo-immunotherapy is an effective treatment strategy for the majority of CLL patients with progressive disease. More recently, novel oral therapies have been developed that target key signalling and apoptosis pathways and that are being used in relapse settings and as first-line treatments for certain patients.

Sickle cell disease: an update.

Sickle cell disease is a common inherited disorder that is characterised by chronic haemolysis and vaso-occlusive episodes, resulting in severe pain and end-organ damage. The most frequent acute manifestation of sickle cell disease is a painful vaso-occlusive crisis, which can, in some cases, develop into a sickle chest crisis: a life-threatening complication of sickle cell disease that requires early recognition and prompt intervention to prevent progressive respiratory failure. In addition to the acute complications, patients with sickle cell disease are also at risk of a number of chronic complications that require multidisciplinary specialist input.

Acute leukaemia: no reason to panic.

Acute leukaemia is characterised by uncontrolled expansion of immature leukocytes, either myeloid or lymphoid progenitors, leading to acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL), respectively. If left untreated, it is life-threatening and can lead to death within weeks. When acute leukaemia is suspected, urgent haematology input should be sought. Appropriate investigations are needed promptly to confirm diagnosis and start treatment. A multidisciplinary approach is vital to ensure appropriate management.

Dissecting the impact of bromodomain inhibitors on the Interferon Regulatory Factor 4-MYC oncogenic axis in multiple myeloma.

B-cell progenitor fate determinant interferon regulatory factor 4 (IRF4) exerts key roles in the pathogenesis and progression of multiple myeloma (MM), a currently incurable plasma cell malignancy. Aberrant expression of IRF4 and the establishment of a positive auto-regulatory loop with oncogene MYC, drives a MM specific gene-expression program leading to the abnormal expansion of malignant immature plasma cells. Targeting the IRF4-MYC oncogenic loop has the potential to provide a selective and effective therapy for MM. Here we evaluate the use of bromodomain inhibitors to target the IRF4-MYC axis through combined inhibition of their known epigenetic regulators, BRD4 and CBP/EP300. Although all inhibitors induced cell death, we found no synergistic effect of targeting both of these regulators on the viability of MM cell-lines. Importantly, for all inhibitors over a time period up to 72 h, we detected reduced IRF4 mRNA, but a limited decrease in IRF4 protein expression or mRNA levels of downstream target genes. This indicates that inhibitor-induced loss of cell viability is not mediated through reduced IRF4 protein expression, as previously proposed. Further analysis revealed a long half-life of IRF4 protein in MM cells. In support of our experimental observations, gene network modeling of MM suggests that bromodomain inhibition is exerted primarily through MYC and not IRF4. These findings suggest that despite the autofeedback positive regulatory loop between IRF4 and MYC, bromodomain inhibitors are not effective at targeting IRF4 in MM and that novel therapeutic strategies should focus on the direct inhibition or degradation of IRF4.

Randomised open-label trial comparing intravenous iron and an erythropoiesis-stimulating agent versus oral iron to treat preoperative anaemia in cardiac surgery (INITIATE trial).

BACKGROUND: Preoperative anaemia is a risk factor for adverse postoperative outcomes after cardiac surgery. Iron deficiency is a frequent cause of low preoperative haemoglobin. An effective treatment for preoperative anaemia associated with iron deficiency has not been determined. METHODS: We conducted a single-centre, open-label, pragmatic randomised trial, enrolling 156 elective cardiac surgery patients who had low preoperative haemoglobin (100-130 g L-1) with iron deficiency (serum ferritin <100 µg L-1 or transferrin saturation <30%) to compare intravenous ferric derisomaltose 1000 mg and darbepoetin 200 µg subcutaneously (intervention group) with oral ferrous sulphate 600 mg daily (control group). The primary outcome was transfusion of at least one unit of allogeneic red cells during surgery and within the following 5 days. Secondary outcomes included the change in haemoglobin concentration between randomisation and surgery, red cell transfusion volume, postoperative blood loss, pre-specified postoperative complications, length of hospital stay, and in-hospital death. RESULTS: The odds of red cell transfusion were lower in the intervention group compared with the control group (adjusted odds ratio=0.33; 95% confidence interval [CI], 0.15-0.75; P=0.008). Of the secondary outcomes, the only significant difference was the increase in haemoglobin between randomisation and surgery, intervention vs control 9.5 g L-1 (95% CI, 6.8-12.2; P<0.001). CONCLUSIONS: In patients with a low preoperative haemoglobin and iron deficiency, preoperative treatment with a single dose of ferric derisomaltose and darbepoetin decreased the proportion of participants who received a perioperative blood transfusion as a consequence of a greater increase in haemoglobin compared with treatment with oral ferrous sulphate. CLINICAL TRIAL REGISTRATION: ISRCTN Number: 41421863; EUDRACT number: 2011-003695-36.

Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial.

BACKGROUND: Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors' clinical experience treating patients in the trial. METHODS: QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS: A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1-80) oral azacitidine treatment cycles or 6 (1-73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3-4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. CONCLUSION: Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012.

Real-world experience of SARS-CoV-2 antibody assays in UK healthcare workers.

BACKGROUND: The seroprevalence of antibodies to SARS-CoV-2 in healthcare workers is variable throughout the world. This study compares the use of two antibody assays among large cohorts of healthcare workers in southern England. METHODS: This cohort study includes data obtained from staff at Western Sussex Hospitals NHS Foundation Trust (WSHT) and Brighton and Sussex University Hospitals (BSUH) during voluntary antibody testing, using Abbott and Roche SARS-CoV-2 antibody assays at each Trust respectively. RESULTS: The observed seroprevalence level was 7.9% for the WSHT/Abbott cohort versus 13% for the BSUH/Roche cohort. Based on a previous positive PCR, we find that the false-negative rate of the Abbott and Roche assays were 60.2% and 19% respectively, implying sensitivity levels of 39.8% and 81%. Within these cohorts, seropositivity was most strongly associated with those of South Asian ethnicity, allied health professionals and male sex (p<0.0001). CONCLUSIONS: In this real-world study, neither antibody test performed to the specification level stated by the manufacturer. More rigorous testing of these and other assays in target populations is recommended prior to widespread usage if they are to provide data that might be useful to control the pandemic.

BRD4-mediated repression of p53 is a target for combination therapy in AML.

Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi's ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.

Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19?

BACKGROUND: COVID-19 infection is characterised, among other features, by a prothrombotic state with high rate of venous thromboembolism (VTE), D-dimer, and fibrinogen levels. Clinical observations have also highlighted that these patients have elevated von Willebrand factor (vWF) and factor VIIIc. METHODS: 24 consecutive COVID-19 positive patients were selected from the intensive care unit (ICU) or the high acuity ward of Brighton and Sussex University Hospitals NHS Trust. RESULTS: The rate of VTE was 25% and mortality rate was 16.7%. Fibrinogen and D-Dimers were elevated, 7.9 (1.6) g/L and 2.4 (2.02) ug/ml respectively. Factor VIIIc and von vWF antigen levels were both extremely elevated at 279 (148) u/dL and 350 (131) % respectively, which are comparable to levels seen in ICU patients with severe sepsis. vWF levels were significantly higher in patients that died (p=0.017) and showed a positive correlation with age. There was a statistically significant association between COVID-19 disease and non-O blood group (p=0.02); 80% (4/5) of COVID-19 patients with VTE were blood group A. CONCLUSION: Very high levels of vWF and factor VIIIc are common in COVID-19 patients, comparable to levels in severely septic non-COVID ICU patients. This could contribute to the hypercoagulable state and increased VTE rate in COVID-19. Further studies are needed to evaluate the use of vWF for stratifying thrombotic risk in COVID-19 and to determine if elevated vWF is contributing to disease pathogenesis.

Thrombotic risk in COVID-19: a case series and case-control study.

BACKGROUND: A possible association between COVID-19 infection and thrombosis, either as a direct consequence of the virus or as a complication of inflammation, is emerging in the literature. Data on the incidence of venous thromboembolism (VTE) are extremely limited. METHODS: We describe three cases of thromboembolism refractory to heparin treatment, the incidence of VTE in an inpatient cohort, and a case-control study to identify risk factors associated with VTE. RESULTS: We identified 274 confirmed (208) or probable (66) COVID-19 patients. 21 (7.7%) were diagnosed with VTE. D-dimer was elevated in both cases (confirmed VTE) and controls (no confirmed VTE) but higher levels were seen in confirmed VTE cases (4.1 vs 1.2 µg/mL, p<0.001). CONCLUSION: Incidence of VTE is high in patients hospitalised with COVID-19. Urgent clinical trials are needed to evaluate the role of anticoagulation in COVID-19. Monitoring of D-dimer and anti-factor Xa levels may be beneficial in guiding management.

The renin-angiotensin system - a therapeutic target in COVID-19?

COVID-19, caused by infection with SARS-CoV-2, is a disease characterised by cough, fever and fatigue, which progresses to life-threatening lung injury in approximately 5% of patients. The SARS-CoV-2 virus enters the cell via ACE2. ACE2 is a component of the renin-angiotensin system (RAS) which has an important counterregulatory effect on the classical ACE-dependent pathway. Several antihypertensives increase ACE2 expression or activity, leading to concern that this may facilitate SARS-CoV-2 entry and worsen COVID-19 disease. However, ACE2 is protective against lung injury while ANG II (which is catabolised by ACE2) is associated with lung injury both in mice and humans. We propose that medications which inhibit the RAS ACE-dependent pathway may be beneficial in treating COVID-19 and should be explored in animal models and clinical trials. Here we give an overview of the RAS pathway with respect to COVID-19 and argue that strategies which manipulate this pathway might reduce the destructive lung manifestations of COVID-19 and improve patient outcomes.

Chloroquine and COVID-19 - a potential game changer?

The novel coronavirus SARS-CoV-2, causing the disease COVID-19, first emerged in Wuhan, China in December 2019 and has now spread to 203 countries or territories, infected over 2 million people and caused over 133,000 deaths. There is an urgent need for specific treatments. One potential treatment is chloroquine and its derivatives, including hydroxychloroquine, which have both antiviral and anti-inflammatory effects. These compounds are effective against SARS-CoV-2 in vitro, but in vivo data are lacking. Although some encouraging outcomes have been reported, and these results have been received enthusiastically, we recommend careful and critical evaluation of current evidence only when all methods and data are available for peer review. Chloroquine is safe and cheap. However, further evidence from coordinated multicentre trials is required before it can be confidently said whether it is effective against the current pandemic.

Chronic Lymphocytic Leukaemia in 2020: the Future Has Arrived.

PURPOSE OF REVIEW: Chronic lymphocytic leukaemia is now recognised as a heterogenous disease with a variety of clinical outcomes. Here we summarise the way it is currently stratified according to genetic risk and patient characteristics and the treatment approaches used for these different subgroups. RECENT FINDINGS: Certain patients appear to sustain MRD negativity after combination chemoimmunotherapy, leading to the suggestion that their CLL may be cured. However, 17p-deleted, p53-mutated or IGHV-UM subgroups are generally resistant to FCR, and much better responses are seen with ibrutinib and venetoclax, frequently inducing MRD negativity that hopefully will be translated into durable remissions. Small molecule inhibitors have already revolutionised CLL treatment. Going forward, we anticipate their use in the majority of patients, early after diagnosis and with curative intent.