41 research outputs found
Diagnosis, treatment and supportive management of chronic lymphocytic leukemia: recommendations of the Dutch HOVON CLL working group
No full textManagement of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication
Generation of Functional CLL-Specific Cord Blood CTL Using CD40-Ligated CLL APC
No full textPMCID: PMC3526610This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Obinutuzumab pretreatment abrogates tumor lysis risk while maintaining undetectable MRD for venetoclax + obinutuzumab in CLL
No full textEarly data on venetoclax-containing regimens for the treatment of chronic lymphocytic leukemia (CLL) show promising results with deep remissions, but are hampered by potential risk for tumor lysis syndrome (TLS). Whether optimal duration of venetoclax treatment can be guided by minimal residual disease (MRD) is currently unknown. To study whether TLS risk can be mitigated in an unfit population by introducing preinduction, and whether MRD-guided duration of venetoclax treatment is a feasible and efficacious approach, we performed the Dutch-Belgian Cooperative Trial Group for Hemato-oncology (HOVON) 139/GIVE trial. The study treatment consists of 4 treatment phases: preinduction (2 cycles obinutuzumab), induction I (6 cycles obinutuzumab and venetoclax), induction II (6 cycles venetoclax), and a randomization phase (group A: maintenance with 12 additional cycles of venetoclax irrespective of MRD; group B: MRD guided venetoclax maintenance with a maximum of 12 cycles). Here we report on a planned interim safety analysis as well as preliminary efficacy and MRD data of the first 30 patients enrolled. Downgrading of TLS risk after preinduction occurred in 25 patients: 3 from high to medium, 3 from high to low, and 19 from medium to low risk. No patient remained high risk. From these 30 patients, peripheral blood MRD data were obtained for 28 patients at the end of induction II (6 months after the last obinutuzumab dose), of whom 26 had undetectable MRD levels, and for 18 patients who reached the 3-month after-randomization point, of whom 16 had undetectable MRD levels. Obinutuzumab preinduction is tolerated well in these unfit patients and results in abrogating high TLS risk in all patients. Preliminary data indicate that efficacy is maintained with a high proportion of patients with undetectable MRD levels after combination treatment
Neutropenia in cancer patients, risk prediction models of neutropenia, and supportive measures
No full textEpidemiology studies the causes and distribution of population health and disease conditions in defined populations. It identifies risk factors for disease which may help to prevent disease and promote health.
Each year, the American Cancer Society describes the epidemiology of cancer in the USA. Breast cancer and CLL are the most common cancers in women and adults, respectively. European data for CLL are limited. For both cancers, chemotherapy is an important treatment option. But side effects such as neutropenia and infections remain the principal dose-limiting toxicities, which may affect the effectiveness of cancer chemotherapy. Several studies evaluated risk factors for chemotherapy-induced neutropenia (CIN; absolute neutrophil count [ANC] <1.5x10^9/L) and febrile neutropenia (FN; ANC <0.5x10^9/L and oral temperature =38° for more than 1 hour): e.g. older age, recent infection, prior chemotherapy, and planned relative dose intensity greater than 85% of standard chemotherapy dosing. The prophylactic use of granulocyte colony-stimulating factors (G-CSFs) has been shown to be protective.
Based on the above mentioned risk factors, a number of risk prediction models have been developed over the years. Very often, the risk prediction models considered patient-related, tumour-related, treatment-related, or genetic factors. The majority of these models are not validated using an independent dataset. Systematic reviews of G-CSFs to prevent neutropenia are available, but do not include new long-acting G-CSFs or observational study designs.
To address the epidemiology of CLL, the incidence and risk factors of CIN and FN, and to develop and externally validate a risk prediction model for the occurrence of FN including a broad range of risk factors, three quantitative studies were conducted and published. The fourth published study summarised the efficacy, effectiveness and safety of G-CSFs for the prevention of CIN and FN.
For the first study, the author conducted a cohort analysis of the UK Clinical Practice Research Datalink (CPRD) to identify the epidemiology of CLL, the incidence of neutropenia, and changes in medical resource utilisation of CLL patients. Due to limited data regarding the incidence of neutropenia, the study focused on the epidemiology of CLL and medical resource utilisation of CLL patients. The incidence of CLL was 6.2 per 100’000 person-years and remained stable between 2006 and 2011. Medical resource utilisation in CLL patients increased over the time period from 2000 to 2012. Primary care data from the UK CPRD seemed to be valid to determine the incidence of CLL. These data may not reflect the total of medical resource use in CLL patients as chemotherapy and treatment of related complications such as infections and neutropenia are mainly performed in secondary or tertiary care.
The second study addressed the identification of risk factors and the development of a risk prediction model for FN in a hospital-based breast cancer cohort. Risk factors for FN were lower platelet count and haemoglobin, higher alanine aminotransferase (ALT), and specific allele variants of two single nucleotide polymorphisms (SNPs) in a gene involved in multidrug resistance. Genetic testing beforehand might be helpful to identify patients at a very high risk of FN. Predictive performance of the model was improved by adding genetic information but overall remained limited.
The third study used an available risk prediction model for FN in Non-Hodgkin lymphoma (NHL) patients and applied its prediction rules to an independent dataset of NHL patients. Age, weight, baseline white blood cell count, and planned chemotherapy dose were confirmed to predict the risk of FN. However, there was a decrease of the predictive performance in the independent validation dataset. This limits its use in clinical practice. But if successful risk prediction models are developed and externally validated, these may help to optimally target prophylaxis with G-CSFs to those patients at high risk of FN.
Finally, a systematic literature review was conducted to identify studies evaluating the efficacy, effectiveness and safety of G-CSFs in the prevention of CIN and FN. Most studies showed better efficacy and effectiveness for the long-acting pegfilgrastim than daily filgrastim. Efficacy and safety profiles of new long-acting G-CSFs such as lipegfilgrastim and balugrastim were comparable to pegfilgrastim. In times of increasing health care costs and scarce resources, the cost-efficient use of supportive measures is necessary.
The studies this work is based on showed that the availability of and access to appropriate data sources are necessary to develop and systematically validate risk prediction models. The findings contribute to the development of an evidence-based, efficient and cost-efficient approach to prevent neutropenia in cancer patients
Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial
No full textBackground Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.Methods We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27).Findings Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35.2 months (IQR 31.5-41.3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths.Interpretation Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. Copyright (C) 2022 Elsevier Ltd. All rights reserved
Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
No full text\ua9 2018, The Author(s). The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies
The Risk of Venous Thromboembolism Is High in Chronic Lymphocytic Leukemia Because of Additional Cancers:A Danish National Cohort Study
No full textBackground: Venous thromboembolism (VTE) is a frequent yet potentially preventable complication that increases morbidity and mortality among cancer patients. Chronic Lymphocytic Leukemia (CLL) is a heterogeneous hematological cancer. Patient specific factors (age, gender, performance status) and CLL specific markers (e.g. IgHV mutational status, Binet stage, and beta 2-microglobulin (B2M) levels) influence the clinical course of CLL. A considerable proportion of CLL patients are diagnosed with additional cancer after the CLL diagnosis. The risk of VTE in CLL is higher than the background population throughout the clinical course of CLL in contrast to solid tumors where VTE typically develops within the first few months after cancer diagnosis.Aim: To investigate the risk of VTE in CLL patients according to patient specific factors, CLL specific markers, CLL treatment and additional cancer after the CLL diagnosis.Methods: The Danish National CLL Registry provided prospectively collected clinical data from all CLL patients diagnosed in Denmark since 2008. These data were linked at person level by the unique civil registration number to the Danish National Patient Registry for information on VTE and additional cancers, to the Danish National Prescription Database for information on prescribed and reimbursed anticoagulation treatment and to the Danish Civil Registration System for information on vital status and emigration. Study entry was date of CLL diagnosis; subjects were followed until VTE, death, emigration or administrative censoring. Cumulative incidence of VTE according to Binet stage, B2M levels, IgHV mutational status and additional cancers diagnosed later than CLL were calculated. Additional cancer after the CLL diagnosis was defined as a time-varying exposure. Subjects contributed to the number being at risk of VTE in the "no additional cancer" group until the possible date of additional cancer at which they shifted to the "additional cancer after CLL" group. Death and additional cancer were treated as competing risks by use of the Aalen-Johansen estimator. In Cox proportional hazard models, we estimated the hazard ratios (HR) of VTE; WHO-performance score, previous VTE and sex were included in the models as categorical variables, age was included as a continuous variable and anticoagulation treatment and additional cancer were included as time-varying covariates in the appropriate models.Results: From 2008 through 2015, 3609 subjects were diagnosed with CLL, 60.1% were males and the median age at CLL diagnosis was 70.4 years. Median follow-up was 2.6 years. During the study period, 12.7% (461) were diagnosed with an additional cancer and 19.9% (721) died. Anticoagulation treatment was given to 6.3% (227) of the CLL patients in the study period. The majority of the CLL patients had mutated IgHV, and B2M levels below 4mg/L (Table 1). A VTE was registered in 92 CLL patients during the study period. The cumulative incidence of VTE was highest in CLL patients exposed to additional cancer followed by CLL patients with B2M levels above 4 mg/L and unmutated IgHV. (Figure 1). CLL patients with additional cancer after the CLL diagnosis had a 3-4 fold higher risk of VTE compared with CLL patients without additional cancer. Previous VTE increased the risk of VTE after the CLL diagnosis by 5 fold. This was to some extent because a larger proportion of CLL patients with previous VTE were exposed to an additional cancer after the CLL diagnosis (23.9 compared with the total study population (12.8. The HR of VTE in case of previous VTE however, remained high after adjustment for additional cancer cancer and other risk factors (Table 1). Unmutated IgHV and B2M level gt;4 mg/L increased the risk of VTE, these associations persisted after adjustment for additional cancer (Table 1). CLL treatment tended to increase the risk of VTE, patient related factors and CLL specific markers did not affect the association markedly.Conclusion: The risk of VTE was especially high in CLL patients with additional cancer. Previous VTE was also a substantial (expected) risk factor whereas high age and CLL specific markers (B2M level gt; 4 mg/L, unmutated IgHV) were significant but less strong risk factors of VTE.Disclosures No relevant conflicts of interest to declare.↵* Asterisk with author names denotes non-ASH members
Modelling water quality for water distribution systems
No full textThis thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Maintaining water quality in distribution systems has become a prominent issue in the study of water networks. This thesis concentrates on disinfectant and particle counts as two important indicators of water quality. The models discussed in this work are based on data collected by the author. The experimental set-up and procedure are described and observations of particle counts, particle counter size distributions, monochloramine as disinfectant, temperature, heterotrophic plate counts and epifluorescence microscopy counts are reported. A model of the response of particle counts to an increase in flow is developed. This model is obtained from specification derived from the data and assumptions, and is validated by its interpretability and its fit to data. A local shear-off density and an initial biofilm shedding profile were introduced and thus a linear model for this part of the water quality dynamics could be obtained. A procedure for the identification of the parameters of the local shear-off function and for the determination of the biofilm shedding profile is presented. This profile can be used to provide information about the status of the distribution system in terms of shear-off from the biofilm on the pipe walls. Monochloramine decay dynamics are investigated. The chlorine meter data is preprocessed with the help of titration data to correct meter drift. The data is then used in calibrating two different possible chlorine models: a model with a single decay coefficient and a model with bulk decay coefficient and wall demand (as used in Epanet). Important difficulties in identifying these parameters that come about because of the structure of the models are highlighted. Identified decay coefficients are compared and tested for flow, inlet chlorine and temperature dependence. The merits and limits of the approach to modelling taken in this work and a possible generalisation are discussed. The water industry perspective and an outlook are provided
A new approach for automatic classification of non-Hodgkin lymphoma using deep learning and classical learning methods on histopathological images
No full textLymph cancer, also known as lymphoma, refers to the uncontrolled proliferation of the body's defensive cells, resulting in their transformation into cancerous cells. Lymphoma belongs to the group of blood cancers and exhibits a higher incidence compared to other cancers within this category. Early and accurate diagnosis plays a crucial role in managing this disease. In this particular investigation, an expert support system was developed employing histopathological images of lymph cancer. The data set comprised images of various lymphomas, including chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). The initial approach involved utilizing the GLCM method to extract features from these images, while subsequent approaches adopted transfer learning architectures. Additionally, principal component analysis was employed for feature selection and dimension reduction. For the classification stage, a combination of machine learning algorithms such as random forests, k-nearest neighbors (KNN), naive Bayes, and decision trees, as well as deep learning methods including VGG16, ResNet50, and DenseNet201 architectures were employed. The models were trained separately for double and triple classes, and their performance was evaluated. The highest accuracy values in binary classification are: 94% for CLL and FL, 92% for FL and MCL, and 82% for MCL and CLL. In triple classification, the highest accuracy rate is 82%. The lowest accuracy values in binary classification are: 52% for CLL and FL, 57% for FL and MCL, and 49% for MCL and CLL. The methods by which these accuracy values were obtained are stated in "Results" section. However, due to the difficulty in distinguishing between MCL- and CLL-type lymphomas, the classification accuracy for these lymphomas was lower compared to the other classifications. On the other hand, the classification accuracy for FL was higher, as it exhibits more distinctive features than the other two lymphomas. The lowest success in the study was achieved at 36% as a result of the use of the KNN algorithm in triple classification. Notably, the DenseNet201 method achieved the highest success in the study, accurately classifying FL and CLL with a 94% accuracy rate. © The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature 2024.Tekirdağ Namık Kemal Üniversitesi, TNKU, (NKUBAP.06, 21.317); Tekirdağ Namık Kemal Üniversitesi, TNK
Neoplasias de células linfoides maduras B: avaliação dos casos diagnosticados e acompanhados no hospital universitário da Universidade Federal de Santa Catarina entre 2011 e 2014
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2015.De acordo com a classificação da OMS (2008), as neoplasias de células maduras B (NCLM-B) abrangem os linfomas de células B (LCB) e as neoplasias de células plasmocitárias (NCP). O diagnóstico das NCLM-B é baseado nos exames morfológicos, fenotípicos e genéticos, associados aos dados clínicos do paciente. No entanto, mesmo com essas ferramentas diagnósticas, em alguns casos não é possível definir o subtipo de NCLM-B. Assim, o objetivo do presente estudo foi avaliar os casos de NCLM-B diagnosticados entre 2011 e 2014 e acompanhados no HU-UFSC a fim de traçar o perfil desses pacientes. Foram incluídos no estudo 93 pacientes adultos portadores de NCLM-B. Os subtipos mieloma múltiplo (MM), leucemia linfocítica crônica de células B (LLC/LLP), linfoma difuso de grandes células B (LDGCB), linfoma folicular (LF) e linfoma de Burkitt (LB) foram os mais frequentes, representando 23,7%, 15,1%, 12,9%, 11,8% e 7,5% dos casos, respectivamente. A idade mediana dos pacientes no momento do diagnóstico foi de 58 anos, com uma relação entre os gêneros masculino e feminino de 1,3:1. Foi observada diferença significativa entre os subtipos de LCB em relação aos parâmetros idade, atividade da LDH e expressão de Ki-67. De acordo com os índices prognósticos, observou-se que a maioria dos pacientes portadores de MM foi estratificada como de alto risco, enquanto que a maioria dos portadores de LLC/LLP foi estratificada como de baixo risco. Os pacientes portadores de LB foram os que apresentaram maiores índices de recidiva/progressão. Para todos os pacientes, a frequência de óbito durante o período de estudo foi de 31,2% e a média de sobrevida global (SG) foi de 27,6 meses. Foi observada diferença significativa entre os tempos de SG dos pacientes portadores de LB daqueles com LLC/LLP, LF e LDGCB. A concordância entre os exames de imunofenotipagem (IMF) e de imuno-histoquímica foi de 100%, 47,5%, 93,2%, 71,7% e 46,9%, para os subtipos MM, LLC/LLP, LDGCB, LF e LB, respectivamente. Em relação à expressão fenotípica, para auxílio diagnóstico, destaca-se a expressão dos marcadores CD200, CD81 e CD62L nas células de LLC/LLP; CD10, CD43 e CD81 nas células de LB; CD10 e CD95 nas células de LF; e CD39 nas células de LDGCB. Em conclusão, o perfil dos pacientes diagnosticados com NCLM-B no HU-UFSC é semelhante àquele observado na literatura e a IMF se mostrou uma excelente ferramenta diagnóstica, concordante com a IHQ.Abstract : According to the World Health Organization (WHO) classification (2008), mature B-cell neoplasms (MBCN) are a heterogeneous group of diseases that comprises B-cell lymphomas (BCL) and plasma cell disorders (PCD). MBCN current diagnosis is usually based on a combination of morphology, immunophenotype, recurrent cytogenetic aberration and clinical features. However, even with these diagnostic tools, in some cases aberrant and overlapping phenotypes often can make the definitive diagnosis difficult. In this view, the aim of this study was to assess the profile of patients diagnosed with MBCN and monitored at the University Hospital of UFSC between 2011 and 2014. The study included 93 adult patients with MBCN diagnosis. The most frequent subtypes were multiple myeloma (MM), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Burkitt lymphoma (BL), representing 23.7%, 15.1%, 12.9%, 11.8%, and 7.5% of the cases, respectively. The median age at diagnosis was 58 years with a male-to-female ratio of 1.3:1. There were statistical differences in terms of age at diagnosis, LDH levels and Ki-67 expression among BCL subtypes. According to the prognostic indexes, it was observed that the majority of MM patients was stratified as high risk, while the majority of CLL patients was classified as low risk. LB patients showed the highest rates of recurrence/progression. Regarding all patients, the incidence of death during the study period was 31.2% and the average overall survival (OS) was 27.6 months. Statistical differences were found in terms of OS between BL and CLL, BL and FL, and BL and DLBCL. The concordance between immunophenotypic and immunohistochemical methods were 100%, 47.5%, 93.2%, 71.7% e 46.9%, for MM, CLL, DLBCL, FL, and BL, respectively. Regarding phenotypic expression, the expression of CD200, CD81 and CD62L markers by CLL cells; CD10, CD43 and CD81 by BL cells; CD10 and CD95 by FL cells; and CD39 by DLBCL cells, were considered as relevant in order to assist diagnosis. In conclusion, the profile of MBCN patients diagnosed and monitored at our Institution is similar to that observed in the literature, besides, immunophenotyping showed good concordance with immunohistochemistry
