Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF.

Real-world experience of pegcetacoplan in paroxysmal nocturnal hemoglobinuria.

Pegcetacoplan significantly improves outcomes for patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing extravascular hemolysis (EVH) on eculizumab, leading to approval in 2021/2022 (USA/Europe). We report the first collaborative real-world evidence on pegcetacoplan use in UK and France. A total of 48 patients were either currently receiving or previously received pegcetacoplan (2019-2023). A total of 12 patients had participated in the PEGASUS clinical trial, continuing treatment after trial completion. Five patients were on combination treatment of C5 inhibition and pegcetacoplan. Mean pegcetacoplan duration was 20.2 months. Indication for pegcetacoplan was EVH on C5 inhibitors (Eculizumab, n = 29, Ravulizumab n = 16, others n = 3) with 35/48 patients requiring blood transfusion within the previous 12 months. Mean hemoglobin and reticulocyte count at pegcetacoplan commencement and after 3 months: 91 g/L and 205 × 109/L and 115.8 g/L and 107 × 109/L, respectively, resulting in mean Hb change of 22.3 g/L. Mean LDH pre- and post-pegcetacoplan was unchanged. Six patients have stopped pegcetacoplan. A total of 32 breakthrough hemolysis (BTH) events occurred in 13/48 patients. A total of 14 events were within clinical trials (reported separately). Six patients experienced 18 acute BTH events outside clinical trials, 7/18 associated with complement activating conditions. Successful clinical management included daily pegcetacoplan subcutaneously for 3 days or single eculizumab doses; these events are manageable with prompt intervention. Pegcetacoplan is effective for patients with PNH experiencing EVH. In this large patient cohort, treatment was well tolerated with improved hemoglobin and reticulocytes and maintained LDH control. Although BTH occurs, this is manageable by acute dose modification, with the majority of patients being maintained on pegcetacoplan.

Cardiac Involvement in Vasculotoxic and Neurotoxic Snakebite - A not so Uncommon Complication.

BACKGROUND: Cardiac toxicity following snakebite envenomation has been previously observed, but not studied in detail, especially the involvement in neurotoxic bites. This prospective observational case study evaluates the incidence of cardiac toxicity along with the difference between vasculotoxic and neurotoxic bites and analysing the predictors for development of cardiotoxicity. METHOD: 96 patients who had snake bite envenomation were evaluated for features of cardiotoxicity with clinical features, ECG, echocardiogram and troponin-I levels. RESULTS: Cardiac toxicity was observed in 42.7% of patients, the majority were either ECG changes, noted in 34.3% and rise in troponin-I, noted in 21.9% of patients. Other changes included echocardiographic changes in 4.2%, and Takotsubo cardiomyopathy in 1%. There was no significant difference in the incidence of cardiotoxicity between the neurotoxic (41.7%) and vasculotoxic (42.9%) (p value =1) snake bites, even though the predominant changes seen in neurotoxic snake bites were ECG changes. There were no deaths in the current study. None of the demographic or clinical parameters studied could predict the development of cardiac events. CONCLUSION: Cardiac toxicity is a well defined complication of poisonous snake bite and incidence is more frequent than previously thought. Both vasculotoxic and neurotoxic snake bites are associated with cardiac toxicity and is not associated with increase in mortality.

Minimal residual disease is an independent predictor for 10-year survival in CLL.

Minimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemia (CLL) cell detectable per 10 000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here, we retrospectively analyzed, with up to 18 years follow-up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach. MRD negativity correlated with both progression-free survival (PFS) and overall survival (OS) independent of the type and line of treatment, as well as known prognostic factors including adverse cytogenetics. The greatest impact of achieving MRD negativity was seen in patients receiving frontline treatment, with 10-year PFS of 65% vs 10% and 10-year OS of 70% vs 30% for MRD-negative vs MRD-positive patients, respectively. Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL.

Eradication of minimal residual disease improves overall and progression-free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: a phase II trial assessing alemtuzumab consolidation.

With immunochemotherapy, remission duration and survival in patients with chronic lymphocytic leukaemia is dependent on the level of minimal residual disease (MRD) after treatment. This phase II trial assessed alemtuzumab consolidation post-chemotherapy in patients who responded with persistent low levels of detectable disease. Blood was screened for MRD using multi-parameter flow cytometry, 6-24 months post-chemotherapy. MRD-positive participants received alemtuzumab 30 mg subcutaneously 3 times weekly for 6 weeks. Following a marrow assessment, MRD-negative participants or non-responders stopped therapy and MRD-positive participants with 1 + log reduction had 6 more weeks of alemtuzumab. Alemtuzumab consolidation was received by 47 participants. One death and 19 of 22 serious adverse events reported from 17 (36%) participants were alemtuzumab-related. MRD eradication from blood and bone marrow was achieved in 39 (83%) participants at the end of consolidation, with 18 (38%) remaining MRD-negative in the blood 6 months later. Of the 18 participants who were MRD-negative at 6 months, the median time to MRD relapse was 46 months, which was similar to patients who were MRD-negative at baseline and were followed up. The 5-year progression-free survival (PFS) and overall survival (OS) of participants who were MRD-negative at 6 months was significantly better than MRD-positive participants [PFS: 78% vs. 39% (P = 0·010), OS: 89% vs. 64% (P = 0·029)].

Degradation of acephate by Enterobacter asburiae, Bacillus cereus and Pantoea agglomerans isolated from diamondback moth Plutella xylostella (L), a pest of cruciferous crops.

Acephate-degrading bacterial isolates were isolated from the larval gut of diamondback moth Plutella xylostella, a notorious pest of cruciferous crops worldwide that has developed resistance to insecticides. Partial 16S rRNA gene sequencing identified the isolates as Bacillus cereus (PX-B.C.Or), Enterobacter asburiae (PXE), and Pantoae agglomerans (PX-Pt.ag.Jor). All isolates grew on minimal media (MM) in the presence of acephate at 100 and 200 ppm, with maximum growth at 200 ppm. LC-MS analyses of spent medium showed that E. asburiae degraded acephate to methamidophos and O, O-dimethyl phosporamidate and B. cereus O,S-dimethyl to phosphorothioate but P. agglomerans to an unnamed compound. All three isolates used acephate as a source of carbon and energy for growth; however, P. agglomerans used it also as source of sulphur. Strong evidence revealed that the bacterial communities present in the gut of diamondback moth might aid in acephate degradation and play a role in the development of insecticide resistance.

B-vitamin status in relation to bone mineral density in treated celiac disease patients.

OBJECTIVES: Patients with celiac disease (CD) are at increased risk of osteoporosis and compromised B-vitamin status. Emerging evidence supports a beneficial role of folate and the metabolically related B-vitamins in bone health in generally healthy adults, but no previous study has investigated this in CD patients. The aim of the current study was to examine the relationship of folate, vitamins B12, B6 and B2 (riboflavin), and the related metabolite homocysteine, with bone mineral density (BMD) in CD patients. MATERIALS AND METHODS: Of the 400 treated adult CD patients invited to participate, 110 responded and met the eligibility criteria for study participation. BMD was measured using dual energy X-ray absorptiometry scanning at the lumbar spine (L1-L4), femoral neck, and total hip sites. Biomarker status of the relevant B-vitamins and homocysteine, and dietary B-vitamin intakes, were measured. RESULTS: The significant predictors of low BMD were increasing age (B = 0.080, p < 0.001) and decreasing weight (B = 0.072, p = 0.004), whereas no significant relationship with serum 25-hydroxyvitamin D (B = 0.093, p = 0.928) was observed. Following adjustment for these predictors, serum vitamin B12 (but no other B-vitamin biomarker) was found to be a significant determinant of BMD at the femoral neck (ß = 0.416, p = 0.011) and total hip (ß = 0.327, p = 0.049) in men only. No significant relationships were found between any of the B-vitamin biomarkers investigated and BMD (at any measured site) in women. CONCLUSION: These findings add to current evidence suggesting a potential role of vitamin B12 in BMD, particularly in men, and show such a relationship for the first time in CD patients.

Post-vaccination Symptoms of Covishield Vaccine among Frontline Workers of a Tertiary Care Center in Pathanamthitta District.

Introduction: The COVID-19 pandemic, which began in late 2019 and is still ongoing, has affected health and life across the world. Widespread vaccination with highly effective vaccines is an important tool in the efforts to control this pandemic. To determine post-vaccination symptoms after the first dose of Covishield vaccine among health care workers at a tertiary care centre in Pathanamthitta District. Materials and Methods: A descriptive cross-sectional study in a tertiary care hospital in Pathanamthitta District. Data on adverse effects following vaccination with the first dose of Covishield vaccine were collected from health care workers through online surveys and interviews. Baseline characteristics were described with frequency, percentages, and mean. Associations between categorical variables were assessed using the Chi-square test. Results: Of the 1,115 health care workers who participated in the study, the majority were medical students (28.3%), followed by nurses (24.8%), and doctors (19.1%). Post-vaccination symptoms were reported by the majority of the participants (95.1%). The most common symptoms were pain at the site of injection (79.8%), followed by myalgia (67.2%), and tiredness (64.6%). Hospitalization was required for six (0.5%) of the participants. Conclusion: The symptoms reported in the study were those already known to be the general side effects associated with vaccines. The information obtained from this study will aid in health promotion activities related to COVID-19 vaccination.

Development and validation of the CoV19-OM intensive care unit score: An early ICU identification for laboratory-confirmed SARS-CoV-2 patients from a retrospective cohort study in Oman.

OBJECTIVE: To develop and validate a clinical score that will identify potential admittance to an intensive care unit (ICU) for a coronavirus disease 2019 (COVID-19) case. MATERIALS AND METHODS: The clinical scoring system was developed using a least absolute shrinkage and selection operator logistic regression. The prediction algorithm was constructed and cross-validated using a development cohort of 313 COVID-19 patients, and was validated using an independent retrospective set of 64 COVID-19 patients. RESULTS: The majority of patients were Omani in nationality (n = 181, 58%). Multivariate logistic regression identified eight independent predictors of ICU admission that were included in the clinical score: hospitalization (OR, 1.079; 95% CI, 1.058-1.100), absolute lymphocyte count (OR, 0.526; 95% CI, 0.379-0.729), C-reactive protein (OR, 1.009; 95% CI, 1.006-1.011), lactate dehydrogenase (OR, 1.0008; 95% CI, 1.0004-1.0012), CURB-65 score (OR, 2.666; 95% CI, 2.212-3.213), chronic kidney disease with an estimated glomerular filtration rate of less than 70 (OR, 0.249; 95% CI, 0.155-0.402), shortness of breath (OR, 3.494; 95% CI, 2.528-6.168), and bilateral infiltrates in chest radiography (OR, 6.335; 95% CI, 3.427-11.713). The mean area under a curve (AUC) for the development cohort was 0.86 (95% CI, 0.85-0.87), and for the validation cohort, 0.85 (95% CI, 0.82-0.88). CONCLUSION: This study presents a web application for identifying potential admittance to an ICU for a COVID-19 case, according to a clinical risk score based on eight significant characteristics of the patient (http://3.14.27.202/cov19-icu-score/).

A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia.

Combination fludarabine (F), cyclophosphamide (C) and rituximab (R) is the standard front-line therapy in chronic lymphocytic leukaemia (CLL), but appropriate treatment of relapsed/refractory CLL is less clear. Combined FC and mitoxantrone (M) has been reported to be effective in a single arm study, and rituximab when added to chemotherapy in CLL is synergistic. A randomized, two-stage, Phase II trial of FCM and FCM-R was conducted in relapsed CLL. The primary endpoint was response rate 2 months after therapy, assessed according to the 2008 International Workshop CLL criteria. In addition, minimal residual disease (MRD) in the marrow was studied 2 months after therapy, with MRD negativity defined as <0·01% CLL cells. Fifty-two patients were entered, 26 in each arm. The overall response rates to FCM and FCM-R were 58% and 65% respectively. Combined complete response (CR) and CR with incomplete marrow recovery [CR(i)] was 15% (95% confidence interval [CI]:4-35%) for FCM and 42% (95%CI:23-63%) for FCM-R, with eight patients achieving MRD negativity (3 FCM; 5 FCM-R). The toxicity of both regimens was acceptable. In conclusion, the addition of rituximab to FCM improves the response rates in relapsed CLL, resulting in more complete remissions and without additional safety concerns. Efficacy and safety should be fully tested in a randomized Phase III trial.

Acalabrutinib in management of chronic lymphocytic leukemia: An Indian perspective.

The treatment landscape of chronic lymphocytic leukemia (CLL) has witnessed immense changes in the past decade. Several newer target therapies and their combinations with anti-CD 20 therapies have got approval for management of CLL in the treatment-naïve and relapsed/refractory setting. Also, the availability of newer diagnostic techniques has helped differentiate the disease into high- and low-risk CLL which acts not just as a prognostic marker but also helps decide the best drug management that can be administered to the patients. Targeted therapy has largely overtaken chemoimmunotherapy in the management of CLL, except for a small subset of the population (young and fit with IGHV mutation). However, with targeted therapy, there is also an issue of previously uncommon treatment-emergent adverse events, the duration of therapy, and financial toxicity. The aim of this review article is to gather results from all landmark CLL trials and discuss the feasibility of incorporating Acalabrutinib in the CLL landscape from an Indian perspective.

Management of Chronic Lymphocytic Leukemia in Less-Resourced Countries.

ABSTRACT: Despite the practice-changing advances achieved in the prognostic stratification and treatment of chronic lymphocytic leukemia (CLL), a large fraction of the world population resides in countries where access to many of these advances remains unavailable or subject to severe constraints. Although some of these countries display incidence rates of CLL that are lower than those of developed Western countries, a large number of patients are expected to be diagnosed with CLL in these regions every year. In this article, we review issues regarding management of CLL in some less-resourced countries, with a focus on the evidence basis for epidemiological and clinical information on this disease, the availability of diagnostic and therapeutic resources, and participation in clinical trials. Going forward, challenges that still need to be addressed include the development of unified countrywide registries, guidelines for management applicable to each country, wider availability of prognostic tools, access to new drugs, and policies that ensure these drugs are affordable to all patients worldwide.

SEAMHCRD deterministic compartmental model based on clinical stages of infection for COVID-19 pandemic in Sultanate of Oman.

The present novel coronavirus (COVID-19) infection has engendered a worldwide crisis on an enormous scale within a very short period. The effective solution for this pandemic is to recognize the nature and spread of the disease so that appropriate policies can be framed. Mathematical modelling is always at the forefront to understand and provide an adequate description of the transmission of any disease. In this research work, we have formulated a deterministic compartmental model (SEAMHCRD) including various stages of infection, such as Mild, Moderate, Severe and Critical to study the spreading of COVID-19 and estimated the model parameters by fitting the model with the reported data of ongoing pandemic in Oman. The steady-state, stability and final pandemic size of the model has been proved mathematically. The various transmission as well as transition parameters are estimated during the period from June 4th to July 30th, 2020. Based on the currently estimated parameters, the pandemic size is also predicted for another 100 days. Sensitivity analysis is performed to identify the key model parameters, and the parameter gamma due to contact with the symptomatic moderately infected is found to be more significant in spreading the disease. Accordingly, the corresponding basic reproduction number has also been computed using the Next Generation Matrix (NGM) method. As the value of the basic reproduction number (R0) is 0.9761 during the period from June 4th to July 30th, 2020, the disease-free equilibrium is stable. Isolation and tracing the contact of infected individuals are recommended to control the spread of disease.

Ethnic and geographic diversity of chronic lymphocytic leukaemia.

East Asians, Asian Indians and Amerindians have a five to ten-fold lower age-adjusted incidence rate (AAIR) of chronic lymphocytic leukaemia (CLL) compared with persons of predominately European descent. The data we review suggest a genetic rather than environmental basis for this discordance. All these populations arose from a common African Black ancestor but different clades have different admixture with archaic hominins including Neanderthals, Denisovans and Homo erectus, which may explain different CLL incidences. There are also some differences in clinical laboratory and molecular co-variates of CLL between these populations. Because the true age-adjusted incidence rate in African Blacks is unknown it is not possible to determine whether modern Europeans acquired susceptibility to CLL or the other populations lost susceptibility and/or developed resistance to developing CLL. We also found other B-cell lymphomas and T- and NK-cell cancers had different incidences in the populations we studied. These data provide clues to determining the cause(s) of CLL.

Assessment of bone marrow response in Waldenström's macroglobulinemia.

In this study we used bone marrow flow cytometry and immunohistochemistry to evaluate response to fludarabine therapy in patients with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma. Responses in serum M protein were typically delayed with a median time to maximum response of 6 months following the completion of therapy (range, 0-18 months). In contrast, bone marrow responses occurred promptly in responding patients such that there were no detectable clonal B cells at the end of therapy in 55% of patients assessed. Persistent monoclonal plasma cells were, however, readily identified by CD138 immunohistochemistry, explaining the persistence of serum M protein in these patients. This simple observation has significant implications for the assessment of responses in WM as well as the design of future therapeutic strategies.

Capillary leak syndrome in Daboia russelii bite-a complication associated with poor outcome.

Background: Capillary leak syndrome (CLS) has been previously observed as a complication of Daboia russelii bite but not clearly defined or studied in length. This observational case-control study evaluates the mortality along with associated clinical and laboratory features. Methods: Twenty-five patients who developed CLS were compared with 25 patients without CLS following Daboia russelii (Russell's viper) bite. Results: Development of CLS is associated with a significantly high risk of mortality; 11 (44%) patients with CLS died compared with 1 (4%) control (odds ratio 18.8 [95% confidence interval 2.2 to 161.99], p=0.002). Disease-defining manifestations included myalgia (22 [88%]), thirst (20 [80%]), parotid swelling (15 [60%]), conjunctival chemosis (19 [76%]) and hypotension (22 [88%]), which were unobserved in controls. Although several clinical and laboratory parameters were found to be predictive for development of CLS in univariate analysis, none of them had independent predictive value in multivariate analysis. Similarly, development of parotid swelling was the only factor with independent predictive value for mortality in multivariate analysis. Even though the number of vials of snake antivenom used is more in CLS, it seems unlikely to improve the mortality in CLS. Conclusions: This study proves that CLS is a well-defined complication of Russell's viper bite with high mortality but with clear predictors for the development of CLS and mortality.