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Pangalis, Gerassimos A., Theodoros P. Vassilakopoulos, Maria N. Dimopoulou, Marina P. Siakantaris, Flora N. Kontopidou, and Maria K. Angelopoulou. "B-chronic lymphocytic leukemia: practical aspects." Hematological Oncology 20, no. 3 (2002): 103–46. http://dx.doi.org/10.1002/hon.696.
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Kay, Neil E., Terry J. Hamblin, Diane F. Jelinek, Gordon W. Dewald, John C. Byrd, Sherif Farag, Margaret Lucas, and Thomas Lin. "Chronic Lymphocytic Leukemia." Hematology 2002, no. 1 (January 1, 2002): 193–213. http://dx.doi.org/10.1182/asheducation-2002.1.193.
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Abstract This update of early stage B-cell chronic lymphocytic leukemia (B-CLL) embraces current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. Emphasis on early stage is based on the rapid advancement in our understanding of the disease parameters and our increasing ability to predict for a given early stage patient whether there is a need for more aggressive management. In Section I, Dr. Terry Hamblin addresses the nature of the disease, accurate diagnostic procedures, evidence for an early “preclinical” phase, the use of newer prognostic features to distinguish who will be likely to progress or not, and whether it is best to watch or treat early stage disease. In Section II, Dr. Neil Kay and colleagues address the biologic aspects of the disease and how they may relate to disease progression. Review of the newer insights into gene expression, recurring genetic defects, role of cytokines/autocrine pathways, and the interaction of the CLL B cell with the microenvironment are emphasized. The relationship of these events to both trigger disease progression and as opportunities for future therapeutic intervention even in early stage disease is also considered. In Section III, Dr. John Byrd and colleagues review the historical and now current approaches to management of the previously untreated progressive B-CLL patient. They discuss what decision tree could be used in the initial decision to treat a given patient. The use of single agents versus newer combination approaches such as chemoimmunotherapy are discussed here. In addition, the place of marrow transplant and some of the newer antibodies available for treatment of B-CLL are considered. Finally, a challenge to utilize our growing knowledge of the biology of B-CLL in the early stage B-CLL is proffered.
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García-Muñoz, Ricardo, Verónica Roldan Galiacho, and Luis Llorente. "Immunological aspects in chronic lymphocytic leukemia (CLL) development." Annals of Hematology 91, no. 7 (April 12, 2012): 981–96. http://dx.doi.org/10.1007/s00277-012-1460-z.
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Goyal, Neha G., Kami J. Maddocks, Amy J. Johnson, John C. Byrd, Travis D. Westbrook, and Barbara L. Andersen. "Cancer-Specific Stress and Trajectories of Psychological and Physical Functioning in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia." Annals of Behavioral Medicine 52, no. 4 (February 9, 2018): 287–98. http://dx.doi.org/10.1093/abm/kax004.
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Abstract Background Chronic lymphocytic leukemia is the most prevalent adult leukemia. The disease is incurable with a cycling of treatment and relapse common. Little is known about the psychological and physical functioning of patients with relapsed/refractory chronic lymphocytic leukemia. Cancer-specific stress is an important individual difference variable that predicts psychological and physical outcomes. Purpose To examine cancer-specific stress at treatment initiation as a predictor of psychological and physical functioning trajectories in patients with relapsed/refractory chronic lymphocytic leukemia during the first 5 months of treatment. Methods Patients with relapsed/refractory chronic lymphocytic leukemia (N = 152) enrolled in a phase II clinical trial completed self-report measures at treatment initiation (baseline), 1, 2, and 5 months of treatment. Cancer-specific stress at baseline was examined as a predictor of psychological (cognitive-affective depressive symptoms, negative mood, mental health quality of life) and physical functioning (fatigue interference, sleep problems, physical health quality of life), controlling for demographic and treatment variables. Results Using multilevel modeling, higher baseline cancer-specific stress was related to worse psychological (cognitive-affective depressive symptoms, negative mood, mental health quality of life) and physical functioning (fatigue interference, sleep problems) at baseline and more rapid improvements during the next 5 months. Despite these improvements, higher baseline cancer-specific stress remained associated with poorer 5-month psychological, though not physical, functioning. Conclusions Findings suggest cancer-specific stress at treatment initiation may be a risk factor for poorer psychological functioning during treatment for patients with relapsed/refractory chronic lymphocytic leukemia.
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Rudakova, A. V., and E. A. Stadnik. "Pharmacoeconomic aspects of recurrent / refractory chronic lymphocytic leukemia treatment." Oncohematology 15, no. 1 (April 19, 2020): 73–82. http://dx.doi.org/10.17650/1818-8346-2020-15-1-73-82.
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Background. Currently, treatment of recurrent / refractory chronic lymphocytic leukemia (CLL) involves the appointment of regimens with innovative drugs, which include ibrutinib and a combination of venetoclax and rituximab. Wherein said combination provides continuing over time high frequency eradication of minimal residual disease. Thereby, this regimen can be canceled if patients do not progress after 2 years from therapy start.The objective of the study was to assess the pharmacoeconomic aspects of therapy with venetoclax and rituximab combination in patients with recurrent / refractory CLL compared with ibrutinib monotherapy.Materials and methods. Analysis was performed by a simulation method from a position of the health care system. In accordance with network meta-analysis results of clinical studies in the recurrent / refractory CLL treatment (MURANO for venetoclax + rituximab combination and RESONATE and HELIOS for ibrutinib), which showed the absence of statistically significant differences in progression-free and overall survival between these treatment options, the cost-minimization method was used in the analysis. In the basic version, the model time horizon is 4 years. The price of venetoclax, rituximab and ibrutinib in the calculation corresponded to that registered (for rituximab – the median of the registered prices) with the value-added tax and the weighted average wholesale allowance taking into account the population in Russia.When analyzing the healthcare system budget impact, the time horizon of the study was 4 years. Therapy with combination of venetoclax + rituximab starting from the first year was suggested in 100 % of newly identified recurrent / refractory CLL patients. In the base case, it was estimated that 100 patients would need therapy every year.In the basic version of analysis, the cost of therapy after progression was not taken into account. In sensitivity analysis, an option taking into account therapy cost after progression, suggesting the appointment of venetoclax in the ibrutinib group and ibrutinib in the venetoclax + rituximab group, was also evaluated. In addition, variants with disease progression were additionally evaluated in 15 % of patients per year in the venetoclax therapy group at the end of the 2-year treatment course, as well as with an increase and decrease in the disease progression rate by 15 % in both comparison groups.As part of the sensitivity analysis, an assessment is made of a 15 % decrease and increase in Venetoclax price, a 30 % decrease in Ibrutinib price compared to registered price and the option with a 3-year study time horizon. When analyzing the budget impact, options with an increase in the number of patients annually identified and requiring treatment by 10, 20, 30 and 50 % were evaluated. Clinical and economic analysis was carried out with a discount rate of 3.5 % per year. A budget impact analysis was performed without discounting.Results. According to the results of cost-effectiveness analysis in the basic version, a regimen including venetoclax can reduce costs by 46.3 % compared with ibrutinib (cost for 4 years per patient is 10.422 and 19.413 million rubles, respectively). Therapy with combination of venetoclax + rituximab in 100 newly identified recurrent / refractory CLL patients annually instead of ibrutinib monotherapy will result in a reduction in therapy costs by 29.0 %, or by 1.579 billion rubles for 4 years per 100 patients starting therapy annually. The sensitivity analysis demonstrated the high reliability of the results. Conclusion. The treatment of recurrent / refractory CLL with a combination of venetoclax and rituximab is comparable in clinical efficacy with ibrutinib monotherapy and can significantly reduce the cost of the healthcare system, and therefore increase the availability of innovative therapy for this group of patients.
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Faderl, Stefan, William Wierda, and Michael J. Keating. "New aspects of the treatment of chronic lymphocytic leukemia." Current Hematologic Malignancy Reports 1, no. 4 (December 2006): 251–57. http://dx.doi.org/10.1007/s11899-006-0006-7.
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Carlucci, F., F. Rosi, C. Di Pietro, E. Marinello, M. Pizzichini, and A. Tabucchi. "Purine nucleotide metabolism: specific aspects in chronic lymphocytic leukemia lymphocytes." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1360, no. 3 (May 1997): 203–10. http://dx.doi.org/10.1016/s0925-4439(96)00077-4.
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Vincent, AM, JC Cawley, and J. Burthem. "Integrin function in chronic lymphocytic leukemia." Blood 87, no. 11 (June 1, 1996): 4780–88. http://dx.doi.org/10.1182/blood.v87.11.4780.bloodjournal87114780.
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Integrins are central to many aspects of the tissue localization of normal and malignant lymphocytes. We examined how integrin function, rather than simple expression, might determine disease behavior in chronic lymphocyte leukemia (CLL). Using fluorescence-activated cell sorting (FACS) and immunoprecipitation, we first established the precise integrin heterodimer expression of a representative group of CLL patients (beta1 consistently present, with variable alpha 3, alpha 4, and alpha 5; alpha 4 beta 7 often expressed; alpha L beta 2 high; alpha V beta 3 absent). Regarding function, we initially examined the ability of CLL cells to interact with endothelium, because such interaction is the initial event determining the entry of CLL lymphocytes into tissues. The abnormal lymphocytes were shown to bind at low levels to unstimulated endothelium via beta 2/intercellular adhesion molecule (ICAM). However, when the endothelium was stimulated, markedly enhanced interaction with endothelium was observed in approximately half the cases; in these patients, the neoplastic population expressed alpha 4 beta 1, which conferred the ability to adhere strongly to stimulated endothelium via the alpha 4 beta 1 ligand, vascular cellular adhesion molecule-1 (VCAM-1). In relation to the migration of CLL cells within tissues, the abnormal lymphocytes showed differential binding to various adhesive proteins; they did not attach to basement membrane components, but displayed variable adhesion to fibronectin (FN). Finally, we examined the role of cell activation in these processes, and showed that activated CLL lymphocyte populations showed an increased capacity to adhere to both endothelium and matrix. Moreover, ex vivo CLL cells showed no capacity to migrate through endothelium/stroma, but were able to do so after cytokine stimulation. These studies show how the constitutive integrin expression/function, the intrinsic activation state of the cell, and the capacity of cytokines to modify integrin-mediated function all combine to determine the different patterns of clinical disease observed in CLL.
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C. Riches, John, and John G. Gribben. "Mechanistic and Clinical Aspects of Lenalidomide Treatment for Chronic Lymphocytic Leukemia." Current Cancer Drug Targets 16, no. 8 (September 2, 2016): 689–700. http://dx.doi.org/10.2174/1568009616666160408145741.
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Alzamora, Meritxell Garcia, Markus Schmidli, Urs Hess, Richard Cathomas, and Roger von Moos. "Minimal Change Glomerulonephritis in Chronic Lymphocytic Leukemia: Pathophysiological and Therapeutic Aspects." Oncology Research and Treatment 29, no. 4 (2006): 153–56. http://dx.doi.org/10.1159/000091644.
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Souza, Clélia Marta Casellato de, Lilian Maria Cristofani, Ana Lucia Beltrati Cornacchioni, Vicente Odone Filho, and Evelyn Kuczynski. "Comparative study of quality of life of adult survivors of childhood acute lymphocytic leukemia and Wilms’ tumor." Einstein (São Paulo) 13, no. 4 (October 30, 2015): 492–99. http://dx.doi.org/10.1590/s1679-45082015ao3231.
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Abstract Objective To analyze and compare the health-related quality of life of adult survivors of acute lymphocytic leukemia and Wilms’ tumor amongst themselves and in relation to healthy participants. Methods Ninety participants aged above 18 years were selected and divided into three groups, each comprising 30 individuals. The Control Group was composed of physically healthy subjects, with no cancer history; and there were two experimental groups: those diagnosed as acute lymphocytic leukemia, and those as Wilms’ Tumor. Quality of life was assessed over the telephone, using the Medical Outcomes Study 36-Item Short Form Health Survey. Results Male survivors presented with better results as compared to female survivors and controls in the Vitality domain, for acute lymphocytic leukemia (p=0.042) and Wilms’ tumor (p=0.013). For acute lymphocytic leukemia survivors, in Social aspects (p=0.031), Mental health (p=0.041), and Emotional aspects (p=0.040), the latter also for survivors of Wilms’ tumor (p=0.040). The best results related to the Functional capacity domain were recorded for the experimental group that had a late diagnosis of acute lymphocytic leukemia. There were significant differences between groups except for the Social and Emotional domains for self-perceived health, with positive responses that characterized their health as good, very good, and excellent. Conclusion Survivors of acute lymphocytic leukemia showed no evidence of relevant impairment of health-related quality of life. The Medical Outcomes Study 36-Item Short Form Health Survey (via telephone) can be a resource to access and evaluate survivors.
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Ramsland, Paul A., Christina R. Brock, Joshua Moses, Bruce G. Robinson, Allen B. Edmundson, and Robert L. Raison. "Structural aspects of human IgM antibodies expressed in chronic B lymphocytic leukemia." Immunotechnology 4, no. 3-4 (March 1999): 217–29. http://dx.doi.org/10.1016/s1380-2933(98)00025-6.
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Shvidel, L., M. Shtarlid, A. Klepfish, E. Sigler, and A. Berrebi. "Epidemiology and ethnic aspects of B cell chronic lymphocytic leukemia in Israel." Leukemia 12, no. 10 (October 1998): 1612–17. http://dx.doi.org/10.1038/sj.leu.2401140.
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Payandeh, Mehrdad, Edris Sadeghi, and Masoud Sadeghi. "Survival and Clinical Aspects for Patients with Chronic Lymphocytic Leukemia in Kermanshah, Iran." Asian Pacific Journal of Cancer Prevention 16, no. 17 (December 3, 2015): 7987–90. http://dx.doi.org/10.7314/apjcp.2015.16.17.7987.
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Godiwala, Neha Niranjan, Kami J. Maddocks, Travis Westbrook, John C. Byrd, Barbara L. Andersen, and Amy J. Johnson. "Covariation of psychological and inflammatory variables in patients with chronic lymphocytic leukemia receiving ibrutinib." Journal of Clinical Oncology 32, no. 15_suppl (May 20, 2014): 7057. http://dx.doi.org/10.1200/jco.2014.32.15_suppl.7057.
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Julio Delgado, Ferran Nadeu, Dolors Colomer, and Elias Campo. "Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies." Haematologica 105, no. 9 (July 3, 2020): 2205–17. http://dx.doi.org/10.3324/haematol.2019.236000.
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Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. All this knowledge has offered new perspectives that are being exploited therapeutically with novel target agents and management strategies. In this review we provide an overview of these novel advances and highlight questions and perspectives that need further progress to translate into the clinics the biological knowledge and improve the outcome of the patients.
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Morrison, Eleshia, Joseph M. Flynn, Jeffrey A. Jones, John C. Byrd, and Barbara L. Andersen. "Fatigue, Distress, and Quality of Life As Covariates for Early-Stage Chronic Lymphocytic Leukemia." Blood 120, no. 21 (November 16, 2012): 2075. http://dx.doi.org/10.1182/blood.v120.21.2075.2075.
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Abstract Abstract 2075 Objectives of the study Despite the prevalence of Chronic lymphocytic leukemia (CLL) among the leukemias (American Cancer Society, 2012), little research has examined the psychological and quality of life correlates of this disease. Virtually no research has focused on these factors as related to the experiences of monitoring through active surveillance. Further, it is unknown if the psychological distress of these patients covaries with their reports of symptoms and signs associated with this disease. Research shows that cancer diagnosis is associated with significant distress and immunologic perturbations (Andersen et al., 1998). We hypothesize that the unique nature of coping with CLL diagnosis yet receiving no subsequent therapy may be associated with increased uncertainty, worry, and other symptoms of distress. The present study is one of the first to examine adjustment and quality of life in untreated CLL. Methodology This cross-sectional study examined correlates of physical and psychological quality of life in 115 early-stage untreated CLL patients. Eligibility for this ongoing trial included patients with stage 0–2 disease aged 20 through 80 (inclusive) with no history of treatment for a prior cancer. Patients were accrued through the OSU James Division of Hematology oncology clinic. Following consent, participants completed a 45-minute telephone assessment using standardized and validated measures of psychological and physical symptoms associated with their CLL and general health. Measures included the following: Center for Epidemiological Studies-Depression Scale (CESD; Radloff, 1977) assessed depressive symptomatology; Medical Outcomes Study (MOS) SF-36 Short-Form Health Survey (SF-36; Ware et al., 1993) examined overall physical and mental quality of life. Measures of anxiety and stress were also examined. The Health Anxiety Questionnaire (HAQ; Lucock & Morley, 1996) assessed overall health-related anxiety and the Impact of Events Scale (IES; Horowitz, Wilner, & Alvarez, 1979; Weiss & Marmar, 1996) examined stress specifically related to CLL. The Fatigue Symptom Inventory (FSI; Hann et al., 1998) assessed fatigue. Hierarchical linear regression was conducted bidirectionally to examine the covarying relationship between fatigue, psychological distress, and quality of life. Results and Conclusions The demographic characteristics of this sample were similar to those found in patients participating in CLL clinical trials at the authors' institution. The majority of the sample was male (55%) with a median age of 62 (range: 37–76 years) and 100% Caucasian. Most participants in the sample had stage 0 (61.4%) disease. Mean time since diagnosis was 4.7 years (range: 0–17 years). Sociodemographic and disease variables were examined to identify appropriate statistical control variables. Age and time since diagnosis were significantly correlated with the physical and psychological variables examined. Hierarchical linear regression demonstrated that fatigue predicted greater depressive symptoms (p<.01), health anxiety manifest through worry (p<.01) and reassurance seeking (p<.05), and CLL-specific stress (p<.01). Fatigue also predicted worse physical (p<.01) and mental (p<.01) quality of life. Each regression was statistically significant when tested bidirectionally; results demonstrated the significance of distress and quality of life predicting fatigue. Significance Early-stage patients are mostly asymptomatic by definition. As such, these results highlight the importance of identifying the subset of early-stage patients for whom significant physical symptoms may be accompanied by greater distress and poorer quality of life. The bidirectional nature of the present results suggests a covariation of distress and physical symptoms, replicating previous research with other cancer patient groups. These finding also support future longitudinal research to better determine the temporal relationship of physical symptoms and distress. Identification of such predictors of worse adjustment better inform patient care both during active surveillance and treatment. These preliminary data are compelling in that they provide a perspective on the biopsychosocial characteristics of this understudied population. Further exploration on these characteristics of quality of life, distress, and physical functioning is warranted. Disclosures: No relevant conflicts of interest to declare.
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Wendtner, Clemens-Martin, Barbara Schmitt, Manuela Bergmann, Tim Röhnisch, Raymund Buhmann, and Michael Hallek. "New aspects on the pathogenesis, diagnostic procedures, and therapeutic management of chronic lymphocytic leukemia." International Journal of Hematology 73, no. 1 (January 2001): 32–38. http://dx.doi.org/10.1007/bf02981900.
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Shelby, Meghan D., Richard J. Nagle, Laura L. Barnett-Queen, Patricia D. Quattlebaum, and Donald F. Wuori. "Parental Reports of Psychological Adjustment and Social Competence in Child Survivors of Acute Lymphocytic Leukemia." Children's Health Care 27, no. 2 (April 1998): 113–29. http://dx.doi.org/10.1207/s15326888chc2702_3.
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Morrison, Eleshia J., Joseph M. Flynn, Jeffrey Jones, John C. Byrd, and Barbara L. Andersen. "Individual differences in physical symptom burden and psychological responses in individuals with chronic lymphocytic leukemia." Annals of Hematology 95, no. 12 (August 19, 2016): 1989–97. http://dx.doi.org/10.1007/s00277-016-2790-z.
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Westbrook, Travis D., Eleshia J. Morrison, Kami J. Maddocks, Farrukh T. Awan, Jeffrey A. Jones, Jennifer A. Woyach, Amy J. Johnson, John C. Byrd, and Barbara L. Andersen. "Illness Perceptions in Chronic Lymphocytic Leukemia: Testing Leventhal’s Self-regulatory Model." Annals of Behavioral Medicine 53, no. 9 (December 26, 2018): 839–48. http://dx.doi.org/10.1093/abm/kay093.
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Abstract Background Leventhal’s Self-regulatory Model proposes that somatic characteristics of a health threat (e.g., symptom severity), and prior experience with the threat (e.g., unsuccessful treatment), are determinants of illness perceptions. Chronic lymphocytic leukemia (CLL) is appropriate for test of these postulates, having three phases differing in symptom severity and prior treatment experiences: indolent disease requiring no treatment (active surveillance; AS), symptomatic disease requiring a first treatment (FT), and highly symptomatic disease in those who have relapsed and/or failed to respond to prior treatments (relapsed/refractory; RR). Purpose To test symptom severity and prior treatment experiences as determinants of illness perceptions, illness perceptions were characterized and contrasted between CLL groups. Methods Three hundred and thirty CLL patients (AS, n = 100; FT, n = 78; RR, n = 152) provided illness perception data on one occasion during a surveillance visit (AS) or prior to beginning treatment (FT, RR). Results Analysis of variance with planned comparisons revealed that consequences, identity, and concern were least favorable among RR patients, followed by FT, then AS (ps < .01). AS patients endorsed the lowest levels of coherence (ps < .01), and the most chronic illness timeline (ps < .01). FT patients endorsed the highest levels of personal and treatment control (ps < .01). Conclusions Data provide preliminary empirical support for Self-regulatory Model postulates that symptom severity and prior disease experiences influence illness perceptions. Unique knowledge needs for AS patients and elevated psychological/physical symptoms for later-stage CLL patients may warrant clinical attention.
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Deshields, Teresa L., Amylou C. Dueck, Kerry Rogers, Jennifer R. Brown, Tait Shanafelt, David Mintzer, and John C. Byrd. "Perceived risk for cancer progression and psychological status in chronic lymphocytic leukemia patients: CALGB 70603 (Alliance)." Leukemia & Lymphoma 60, no. 10 (March 27, 2019): 2580–83. http://dx.doi.org/10.1080/10428194.2019.1594218.
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Fink, Stephanie R., Sarah F. Paternoster, Stephanie A. Smoley, Heather C. Flynn, Susan M. Geyer, Tait D. Shanafelt, You Kyoung Lee, Diane F. Jelinek, Neil E. Kay, and Gordon W. Dewald. "Fluorescent-labeled DNA probes applied to novel biological aspects of B-cell chronic lymphocytic leukemia." Leukemia Research 29, no. 3 (March 2005): 253–62. http://dx.doi.org/10.1016/j.leukres.2004.07.012.
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Nabhan, Chadi, and Steven T. Rosen. "Conceptual aspects of combining rituximab and Campath-1H in the treatment of chronic lymphocytic leukemia." Seminars in Oncology 29, no. 1 (February 2002): 75–80. http://dx.doi.org/10.1053/sonc.2002.30150.
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Delgado, Julio, and Rafael F. Duarte. "Practical Aspects of Allogeneic Hematopoietic Cell Transplantation for Patients with Poor-Risk Chronic Lymphocytic Leukemia." Scientific World JOURNAL 11 (2011): 161–72. http://dx.doi.org/10.1100/tsw.2011.21.
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Allogeneic hematopoietic cell transplantation has become a viable option for younger patients with poor-risk chronic lymphocytic leukemia. The results obtained with either conventional or reduced-intensity conditioning regimens have been recently evaluated and compared with alternative nontransplant strategies. This manuscript deals with practical aspects of the procedure, including patient and donor selection, conditioning regimen, GVHD prophylaxis, disease monitoring, infectious and noninfectious complications, and timing of the procedure. Finally, we speculate on how we could improve the results obtained with the procedure and new advances currently in clinical trials.
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Eichhorst, Barbara, Moritz Fürstenau, and Michael Hallek. "Relapsed disease and aspects of undetectable MRD and treatment discontinuation." Hematology 2019, no. 1 (December 6, 2019): 482–89. http://dx.doi.org/10.1182/hematology.2019000070.
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Abstract Continuous treatment vs fixed duration of monotherapies and combinations of targeted agents are treatment options in relapsed chronic lymphocytic leukemia. The optimal choice of relapse treatment is dependent on the prior frontline therapy, duration of remission after frontline, genetic markers, and patients’ condition, including age and comorbidities. Combination therapies may result in deep responses with undetectable minimal residual disease (uMRD). Although uMRD is an excellent predictive marker for disease progression, it is rarely used in clinical practice and needs additional evaluation in clinical trials before discontinuation of therapy should be guided according to uMRD.
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Ysebaert, Loic, Mary Poupot, Yovan Sanchez-Ruiz, Camille Laurent, Guy Laurent, and Jean-Jacques Fournié. "Chronic Lymphocytic Leukemia-Associated Macrophages: Not Just Nurse Cells." Blood 116, no. 21 (November 19, 2010): 46. http://dx.doi.org/10.1182/blood.v116.21.46.46.
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Abstract Abstract 46 Introduction: CLL cells interact with many accessory cells in an environment mimicking that of normal mature B cells. Role of antigen, cytokines, adhesion pathways are critical for many aspects in the disease course (proliferation/survival, migration or homing, drug resistance, and presumably relapse). Nurse-like cells (NLC) belong to a monocytic-derived, bystander population among CLL lymph node and spleen stromal cells. Aim: To investigate the nature, functions, and location of NLC within CLL microenvironment. Methods: Gene expression profiles (GEP) from in vitro expanded NLC from patients (n=10) were produced and compared to those from normal CD14+ monocytes, M1-polarized macrophages, M2-polarized macrophages and tumor-associated macrophages (produced in the lab or downloaded from GEO datasets). Principal Component Analysis was used to categorize these five populations of cells and in-house-built GSEA software was used for functional interpretation of their relevant gene lists. Protein expression patterns were validated with multi-analyte ELISArray kits, proteome profiler arrays, flow cytometry (FC) or immunohistochemistry (IHC). Results: New insights into the physiopathological role of NLC in CLL are suggested from five lines of evidence: 1/a Òmonocytic gene signatureÓ (i.e. a set of 549 genes) is shared by the NLC and the monocyte subtypes. The genes over-represented in NLC vs normal monocytes pinpointed positive modulation of apoptotic cell clearance (scavenger, mannose and complement receptors, LXRalpha), lipid metabolism (Apolipoprotein E, PPAR signaling), extracellular matrix-receptor interactions (integrins, SPARC, Matrix MetalloProteinases) and actin cytoskeleton remodeling. 2/unsupervised clustering show that NLC represent an M2-skewed, TAM-like cell population. They down-regulate mRNA and proteins for classic M1 inflammatory markers (e.g. IL-1, IL-6, IL-12, COX2) while increase secretion of TGFbeta, IL-10, CCL17 and CCL22 soluble factors. 3/these and previously published observations suggest that B-CLL-to-NLC interactions may orchestrate immunosuppression in this disease. PBMCs from Òwatch and waitÓ CLL patients (all stage A/Rai 0, mutated IgVH, low risk cytogenetics profile) or healthy donors were stimulated with anti-CD3/CD28 beads + IL-2, either in standard RPMI+10% FCS or in conditioned medium (CM, after 14d CLL-NLC co-culture in vitro) and their proliferation/phenotype were compared after 2 weeks. Significant expansion of T cells with Treg (CD4+CD25+FoxP3+) phenotype was observed only from CLL PBMCs grown in conditioned medium (mean % Treg: 2.85 vs 3.05 in CM for normal PBMCs, and 1.54 vs 15.9 in CM for CLL PBMCs, P< 0.05). 4/although NLC make immune synapses with live B-CLL, they do not phagocytose them. Over-expression of CD47 (ÒdonÕt eat meÓ signal) by B-CLL cells (mfi= 3490 vs 2581 on normal cells, P< 0.05, n=18) may provide them with a protective signal against NLC. 5/from our GEP, flow cytometric and IHC analyses, we propose CD163 (classic M2 marker) as a reliable tool to identify NLC in vivo. Although in vitro, CLL cells can pervert healthy donor monocytes into NLC, only CLL-derived NLC are truly CD14+ CD163+. In vivo, CD163 staining reveals putative NLC in CLL lymph nodes(LN)/spleen sections but not in bone marrow. In LN from all patients, NLC reside in the subcapsular areas and line vessel structures, suggesting a role in CLL cells trafficking. Most interestingly, NLC infiltrate pseudofollicles structures only in a subset of cases. We will present updated IHC and clinical presentation correlation studies. Conclusions: Our results suggest that the role of NLC in CLL might be broader than initially thought. Beside of nursing and conferring drug resistance, NLC may also be crucial in the setting of immunosuppression, of CLL cells recruitment, and should thus be considered as therapeutic targets. Disclosures: Off Label Use: GA101 is not currently approved for CLL treatment.
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Pérez-Carretero, Claudia, Isabel González-Gascón-y-Marín, Ana E. Rodríguez-Vicente, Miguel Quijada-Álamo, José-Ángel Hernández-Rivas, María Hernández-Sánchez, and Jesús María Hernández-Rivas. "The Evolving Landscape of Chronic Lymphocytic Leukemia on Diagnosis, Prognosis and Treatment." Diagnostics 11, no. 5 (May 10, 2021): 853. http://dx.doi.org/10.3390/diagnostics11050853.
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The knowledge of chronic lymphocytic leukemia (CLL) has progressively deepened during the last forty years. Research activities and clinical studies have been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease, improving CLL diagnosis, prognosis and treatment. Whereas the diagnostic criteria for CLL have not substantially changed over time, prognostication has experienced an expansion with the identification of new biological and genetic biomarkers. Thanks to next-generation sequencing (NGS), an unprecedented number of gene mutations were identified with potential prognostic and predictive value in the 2010s, although significant work on their validation is still required before they can be used in a routine clinical setting. In terms of treatment, there has been an impressive explosion of new approaches based on targeted therapies for CLL patients during the last decade. In this current chemotherapy-free era, BCR and BCL2 inhibitors have changed the management of CLL patients and clearly improved their prognosis and quality of life. In this review, we provide an overview of these novel advances, as well as point out questions that should be further addressed to continue improving the outcomes of patients.
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Borowitz, M. J., B. L. Dowell, J. M. Boyett, D. J. Pullen, W. M. Crist, F. M. Quddus, J. M. Falletta, and R. S. Metzgar. "Clinicopathologic aspects of E rosette negative T cell acute lymphocytic leukemia: a Pediatric Oncology Group study." Journal of Clinical Oncology 4, no. 2 (February 1986): 170–77. http://dx.doi.org/10.1200/jco.1986.4.2.170.
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The Pediatric Oncology Group has studied 1,367 patients with non-B cell acute lymphocytic leukemia (ALL) of whom 186 (14%) had blasts that reacted with previously well-characterized heteroantisera, recognizing a T-lymphocyte specific surface membrane antigen (PT+). In 87 of these T cell cases, the leukemic cells failed to form at least 20% of sheep erythrocytic rosettes at 4 degrees C. Comparison of clinicopathologic features among PT-, E-PT+, and E+ groups of patients revealed significant differences among them. E-PT+ patients were older than PT- patients, had higher white blood cell counts (WBCs) and were more likely to have a mediastinal mass, and thus contained a higher proportion of poor-risk patients. However, the E-PT+ patients were also significantly different from the more traditionally-defined E+ patients in that they had lower WBCs and hemoglobin levels, and less frequent lymphadenopathy or mediastinal mass. In many respects, then, E-PT+ patients were intermediate in character between PT- and E+ patients. Our findings support the notion that further subclassification of ALL using antibodies recognizing lineage-specific surface determinants will permit recognition of groups of patients with distinct clinicopathologic features that may differ in prognosis or response to therapy. Such classification also focuses future biological studies on the pathogenesis of leukemias to immunologically well-defined subgroups of lymphoid neoplasms.
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Delgado, Raquel, Karoline Kielbassa, Johanna ter Burg, Christian Klein, Christine Trumpfheller, Koen de Heer, Arnon P. Kater, and Eric Eldering. "Co-Stimulatory versus Cell Death Aspects of Agonistic CD40 Monoclonal Antibody Selicrelumab in Chronic Lymphocytic Leukemia." Cancers 13, no. 12 (June 21, 2021): 3084. http://dx.doi.org/10.3390/cancers13123084.
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Objectives: Chronic lymphocytic leukemia (CLL) is a common form of leukemia with a heterogeneous clinical course that remains incurable due to the development of therapy resistance. In lymph node proliferation centers, signals from the microenvironment such as CD40 ligation through interaction with follicular T helper cells shield CLL cells from apoptosis. Previous observations have shown that, despite CD40-induced changes in apoptotic mediators resulting in cell survival, CD40 activation also increases sensitivity to cell death by CD20 mAbs rituximab and obinutuzumab. To further investigate these observations, we here studied the activity of the fully human agonistic CD40 mAb selicrelumab in primary CLL cells in relation to cell activation, induced pro-survival profile, and sensitization for cell death by aCD20 mAbs, in vitro. Methods: CLL cells from peripheral blood were isolated by the Ficoll density method. The expression of activation markers and cytokine production following CD40 stimulation was quantified by flow cytometry and ELISA. The anti-apoptotic profile of CLL induced by stimulation was evaluated by the expression of BCL-2 proteins with Western blot, and resistance to venetoclax with flow cytometry. Cell death induced by the combination of selicrelumab and aCD20 mAbs was quantified by flow cytometry. Results: CLL cells treated with selicrelumab upregulated co-stimulatory molecules such as CD86, TNF-α and death receptor CD95/Fas. In contrast to the CD40 ligand-transfected NIH3T3 cells, induction of resistance to venetoclax by selicrelumab was very moderate. Importantly, selicrelumab stimulation positively sensitized CLL cells to CD20-induced cell death, comparable to CD40 ligand-transfected NIH3T3 cells. Conclusions: Taken together, these novel insights into selicrelumab-stimulatory effects in CLL may be considered for developing new therapeutic strategies, particularly in combination with obinutuzumab.
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Rice, Julia, Ryan David Nipp, Daniel E. Lage, Ashley M. Nelson, Richard Newcomb, Mitchell W. Lavoie, Carlisle E. W. Topping, Christine Ritchie, Areej El-Jawahri, and Patrick Connor Johnson. "Association between baseline geriatric domains and survival in older adults with chronic lymphocytic leukemia (CLL)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 12041. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.12041.
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12041 Background: CLL is a disease that commonly affects older adults. Although the value of geriatric assessment is increasingly being recognized in older adults with cancer, few studies have examined the relationship between baseline geriatric domains and clinical outcomes in older adults with CLL. Methods: We conducted a secondary data analysis of 369 adults diagnosed with CLL and treated in a phase 3 randomized trial of patients age ≥65 with bendamustine plus rituximab versus ibrutinib plus rituximab versus ibrutinib alone. We evaluated geriatric domains of functional status (activities of daily living [ADL], instrumental activities of daily living [IADL], Timed “Up and Go,” and number of falls in last 6 months), psychological status (Mental Health Inventory), social activity (Medical Outcomes Study [MOS] Social Activity Survey), cognition (Blessed Orientation Memory Concentration Test), social support (MOS Social Support Tangible and Emotional/Informational subscales), and nutritional status ( > 5% weight loss in the preceding 6 months). We examined associations among baseline geriatric domains with overall survival (OS) and progression-free survival (PFS) using multivariable Cox regression models. Results: The median age of patients was 71 years (range: 65-89). Most were male (67.1%) and had an ECOG performance status of 0 or 1 (96.9%). In multivariable models, the following geriatric domains were significantly associated with OS: better functional status (ADL score: HR 0.67, p = 0.012; IADL score: HR 0.98, p = 0.007); social activity score (HR 0.97, p = 0.004); and nutritional status (HR 2.58, p = 0.008). Similarly, functional status (ADL score: HR 0.77, p = 0.028; IADL score: HR 0.99, p = 0.007); social activity score (HR 0.97, p < 0.001); and nutritional status (HR 2.87, p < 0.001) were all associated with PFS. Additionally, the number of impaired geriatric domains was also associated with OS (HR 1.50, p = 0.004) and PFS (HR 1.45, p < 0.001). Timed “Up and Go”, number of falls in last 6 months, psychological status, cognition, and social support were not significantly associated with clinical outcomes. Conclusions: Geriatric domains of functional status, social activity, and nutritional status were associated with OS and PFS in this cohort of older adults with CLL. These findings highlight the importance of assessing geriatric domains to identify high-risk patients with CLL who may benefit from additional support during their treatment.
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Kasteng, Frida, Patrik Sobocki, Christer Svedman, and Jonas Lundkvist. "Economic evaluations of leukemia: A review of the literature." International Journal of Technology Assessment in Health Care 23, no. 1 (January 2007): 43–53. http://dx.doi.org/10.1017/s0266462307051562.
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Objectives:Leukemia, together with lymphoma and multiple myeloma, are hematological malignancies, malignancies of the blood-forming organs. There are four major types of leukemia: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). There is a growing amount of literature of the health economic aspects of leukemia. However, no comprehensive review is yet performed on the health economic evidence for the disease. Hence, our aim was to review and analyze the existing literature on economic evaluations of the different types of leukemia.Methods:A systematic literature search used electronic databases to identify published cost analyses and economic evaluations of leukemia treatments. After reviewing all identified studies, sixty studies were considered relevant for the purpose of the review.Results:The identified studies were published after 1990, with a few exceptions. Many of the identified economic evaluations in leukemia, particularly for ALL and AML, may be defined as cost-minimization analyses, where only the costs of different treatment strategies are compared. In CML, a new treatment, imatinib, was introduced in 2001 and several cost-effectiveness analyses have since then been conducted comparing imatinib with previous first line treatments.Conclusions:This review indicates that there is a shortage of cost-effectiveness information in leukemia. The introduction of new therapies will stress the need for new economic evaluations in this group of diseases. More information about the total costs, that is, including indirect costs, and quality of life effects would be valuable in future evaluations in leukemia.
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Gordon, Max J., and Alexey V. Danilov. "The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia." Therapeutic Advances in Hematology 12 (January 2021): 204062072198958. http://dx.doi.org/10.1177/2040620721989588.
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Ibrutinib, the first in class of the oral covalent Bruton tyrosine kinase (BTK) inhibitors, has profoundly changed the treatment landscape of chronic lymphocytic leukemia (CLL). The phase III RESONATE and RESONATE-2 trials first demonstrated the superiority of ibrutinib over ofatumumab in the relapsed/refractory setting and over chlorambucil in older patients with de novo disease. The phase III ECOG–ACRIN trial extended these results to young, fit patients, demonstrating a significant survival advantage to ibrutinib plus rituximab over fludarabine, cyclophosphamide, and rituximab. Similarly, the Alliance trial demonstrated the superiority of ibrutinib over bendamustine with rituximab as frontline in elderly patients. Challenges with ibrutinib include toxicity, development of resistance, and need for indefinite therapy. The second generation BTK inhibitor acalabrutinib may cause less off-target toxicity. The ELEVATE TN trial demonstrated the superiority of acalabrutinib with or without obinutuzumab over chlorambucil and obinutuzumab as frontline therapy for elderly or comorbid patients. Promising early results from the phase II CAPTIVATE and CLARITY trials, which combined ibrutinib with venetoclax, suggest a future role for minimal residual disease (MRD) testing to determine treatment duration. The ongoing phase III GAIA/CLL13, ECOG EA9161, Alliance A041702, CLL17, and [ClinicalTrials.gov identifier: NCT03836261] trials will assess various combinations of ibrutinib/acalabrutinib, venetoclax, and anti-CD20 antibodies. These trials will answer key questions in the treatment of CLL: should novel agents in CLL be used in combination or sequentially? What is the best frontline agent? Can treatment be safely stopped with BTK inhibitors? Can undetectable MRD be used to determine treatment duration? In this review, we will discuss these and other aspects of the evolving role of BTK inhibition in CLL.
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Castoldi, Gian Luigi, Francesco Lanza, and Antonio Cuneo. "Cytogenetic aspects of B-cell chronic lymphocytic leukemia: Their correlation with clinical stage and different polyclonal mitogens." Cancer Genetics and Cytogenetics 26, no. 1 (May 1987): 75–84. http://dx.doi.org/10.1016/0165-4608(87)90135-x.
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Juliusson, G., I. Christiansen, M. M. Hansen, S. Johnson, E. Kimby, A. Elmhorn-Rosenborg, and J. Liliemark. "Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia." Journal of Clinical Oncology 14, no. 7 (July 1996): 2160–66. http://dx.doi.org/10.1200/jco.1996.14.7.2160.
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PURPOSE Purine analogs have wide potential indications in the treatment of hematologic malignancies, but intravenous administration has been required. We previously established that the oral bioavailability of cladribine is 50%. Our aim was to evaluate the efficacy and toxicity of oral cladribine to previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS Sixty-three patients with symptomatic but previously untreated CLL received cladribine solution 10 mg/m2/d orally for 5 consecutive days in monthly courses. RESULTS Complete remission (CR) was achieved in 24 patients (38%), and 23 patients (37%) had a partial response (PR). Most patients, including those in whom there was no remission (NR) achieved normal blood lymphocyte counts. Failure to meet response criteria was mostly due to thrombocytopenia. The median response duration was not reached at 2 years. The median survival time among 13 deceased patients was 322 days, whereas the median observation time of surviving patients is 760 days. The overall survival rate at 2 years is 82%. Response rate was associated with clinical stage. Grade III to IV infectious toxicity occurred in one third of patients. CONCLUSION Orally administered cladribine is an effective and feasible therapy for CLL, and produces durable remissions in three quarters of the patients. However, significant toxicity may occur and further studies are required to assess long-term effects and quality-of-life aspects.
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Davi, Frédéric, Anton W. Langerak, Anne Langlois de Septenville, P. Martijn Kolijn, Paul J. Hengeveld, Anastasia Chatzidimitriou, Silvia Bonfiglio, et al. "Immunoglobulin gene analysis in chronic lymphocytic leukemia in the era of next generation sequencing." Leukemia 34, no. 10 (June 19, 2020): 2545–51. http://dx.doi.org/10.1038/s41375-020-0923-9.
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Abstract Twenty years after landmark publications, there is a consensus that the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is an important cornerstone for accurate risk stratification and therapeutic decision-making in patients with chronic lymphocytic leukemia (CLL). The IGHV SHM status has traditionally been determined by conventional Sanger sequencing. However, NGS has heralded a new era in medical diagnostics and immunogenetic analysis is following this trend. There is indeed a growing demand for shifting practice and using NGS for IGHV gene SHM assessment, although it is debatable whether it is always justifiable, at least taking into account financial considerations for laboratories with limited resources. Nevertheless, as this analysis impacts on treatment decisions, standardization of both technical aspects, and data interpretation becomes essential. Also, the need for establishing new recommendations and providing dedicated education and training on NGS-based immunogenetics is greater than ever before. Here we address potential and challenges of NGS-based immunogenetics in CLL. We are convinced that this perspective helps the hematological community to better understand the pros and cons of this new technological development for CLL patient management.
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Herishanu, Yair, and Aaron Polliack. "Chronic lymphocytic leukemia: A review of some new aspects of the biology, factors influencing prognosis and therapeutic options." Transfusion and Apheresis Science 32, no. 1 (February 2005): 85–97. http://dx.doi.org/10.1016/j.transci.2004.10.012.
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Cochrane, Tara, Tatiana Chagorova, Tadeusz Robak, Su-Peng Yeh, Evgeny Nikitin, Madlaina Breuleux, Abdullah Masud, Kavita Sail, Viktor Komlosi, and Mary Ann Anderson. "Venetoclax Improves Quality of Life for Patients with Elapsed/Refractory Chronic Lymphocytic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 4858. http://dx.doi.org/10.1182/blood-2018-99-117127.
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Abstract INTRODUCTION: Patients with chronic lymphocytic leukemia (CLL) have significantly decreased health related quality of life (HRQoL), particularly related to severe and progressive fatigue. Side effects of chemotherapies and the emotional burden of living with an often poor prognosis disease also negatively impact patient HRQoL. Venetoclax, an oral agent that targets the anti-apoptotic protein BCL2, has demonstrated high rates of deep and durable response in patients with relapsed/refractory (R/R) CLL, including those with 17p deletions, and has been shown to facilitate clinically relevant improvement in several key aspects of functioning and HRQoL. We evaluated the impact of venetoclax monotherapy on the quality of life of patients with R/R CLL. METHODS: VENICE II is an ongoing open-label, phase 3b, multicenter study (NCT02980731) that assessed patient-reported HRQoL in patients who were ≥18 years old with R/R CLL, including those with 17p deletion, TP53 mutations, and/or prior experience with B-cell receptor pathway inhibitor-containing (BCRi) therapy, treated with venetoclax monotherapy (5-week dose-titration, starting at 20mg once daily, then increased weekly to 50 mg, 100 mg, 200 mg, and 400 mg, followed by 400mg once daily). The primary endpoint was the mean change from baseline to Week 48 in the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) subscale. HRQoL subscales analyzed included: Global Health Status, Role Functioning, Emotional Functioning, Cognitive Functioning, Social Functioning, and Fatigue. The impact on QoL was also assessed on the CLL Module (EORTC QLQ-CLL16). Relevance of mean changes in HRQoL measures from baseline were analyzed based on minimum important difference (MID); a 5-10 point change was defined as MID, and >10 points was considered clinically meaningful.(Osoba, D., et al. J Clin Oncol. 1998;16:139-44. Osoba, D., et al. Qual Life Res. 1994;3:353-64.) Safety and adverse events (AEs) were also monitored. RESULTS: As of the data cutoff, April 30, 2018, the median time on study was 28 weeks (range: 1 - 73) and the median time on therapy was 23 weeks (range: 0.1 - 69) in this ongoing study. Of the 169 treated patients, 70% were male; the median age was 65 years (range: 24 - 86). Among those with available data, 17p deletions and TP53 mutations were confirmed in 34% (41/122) and 38% (19/50) of patients, respectively. Overall, 38%, 20%, and 42% of patients had one, two, and three (or more) prior lines of therapy respectively; 21% of patients had prior BCRi therapy. Clinically meaningful improvements from baseline were observed by week 12 and were sustained through week 48 in the EORTC-QLQ-C30 global health status and the role function, social function, and fatigue subscales (Table and Figure 1A) and EORTC-QLQ-CLL16 future health and disease effect subscales (Table and Figure 1B). Eighty-two percent of patients had at least 1 AE; most commonly observed AEs (≥10% of patients) were neutropenia (35%), diarrhea (17%), thrombocytopenia (15%), anemia (12%), nausea (12%), and upper respiratory infection (11%). Twenty-eight percent of patients had a serious AE, of which the most common were pneumonia (5%), febrile neutropenia (4%) and pyrexia (3%). Five percent of patients discontinued the study due to an AE. CONCLUSIONS: Preliminary data from this ongoing study suggest that patients with R/R CLL experienced improvement in several key aspects of functioning and quality of life with venetoclax monotherapy within the first 12 weeks which is sustained over time. Venetoclax monotherapy was well tolerated in R/R CLL patients. These findings are consistent with previous studies of R/R CLL patients who received venetoclax monotherapy. Disclosures Cochrane: Janssen: Membership on an entity's Board of Directors or advisory committees; Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Calgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; MSD: Honoraria. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Nikitin:AbbVie, Inc: Speakers Bureau. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Masud:AbbVie, Inc: Employment, Equity Ownership. Sail:AbbVie, Inc: Employment, Equity Ownership. Komlosi:AbbVie, Inc: Employment, Equity Ownership. Anderson:Walter and Eliza Hall: Employment, Patents & Royalties; AbbVie, Inc: Research Funding; Genentech: Research Funding.
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Irwanto, Mia Ratwita, Rendi Prihaningtyas, and Muhammad Mustakim. "Impact of Caregiver’s Psychological Aspects towards Quality of Life of Children with Acute Lymphoblastic Leukemia (ALL)." Asian Pacific Journal of Cancer Prevention 21, no. 9 (September 1, 2020): 2683–88. http://dx.doi.org/10.31557/apjcp.2020.21.9.2683.
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Arab, Mansour, Colleen Bernstein, Aboutaleb Haghshenas, and Hadi Ranjbar. "Factors associated with caregiver burden for mothers of children undergoing Acute Lymphocytic Leukemia (ALL) treatment." Palliative and Supportive Care 18, no. 4 (November 15, 2019): 405–12. http://dx.doi.org/10.1017/s1478951519000853.
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AbstractObjectiveThe present study examined the extent to which social support (SS) availability and satisfaction could predict the extent of caregiver burden (CB) among mothers of children with Acute Lymphocytic Leukemia (ALL).MethodThe study was a cross-sectional, descriptive-correlative study. It was conducted on a sample of 117 mothers whose children were undergoing treatment in a public hospital in Bam, Iran. The Norbeck Social Support Scale and the Caregiver Burden Scale were used to measuring study variables. The data were analyzed using Pearson's correlations, t-tests, ANOVAs, and linear regressions.ResultsSignificant correlations were observed between CB and SS availability (r = −0.499, p < 0.001), SS satisfaction (r = −0.543, p < 0.001), the age of the child with cancer (r = −0.22, p = 0.01), and duration of treatment (r = 0.336, p < 0.001). Married mothers experienced less CB than those that were widowed or divorced. Within the regression equation, SS satisfaction, SS availability, marital status, and duration of treatment were the predictors of CB.Significance of resultsBased on the results of the current study, mothers who have less SS, especially those who are single mothers, with younger children, and who have taken care of their child for an extended duration should be given special attention. Furthermore, it appears that there are distinct cultural variations amongst Iranian mothers which suggest that culture may impact upon SS availability. Results also suggest a need for interventions that enhance nurses' ability to provide support to caregivers and the broader family unit as a whole. Nurses in cancer care need to have psychological competencies to help family members of cancer patients especially mothers and more so those that are single mothers. As integral members of the patient care experience, nurses may be uniquely positioned to provide this needed psychosocial support.
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Schrag, Janelle, Ellen Kendall, Monique D. Dawkins, Leigh Boehmer, and Brian Koffman. "Using Data Visualization to Support the Need for Chronic Lymphocytic Leukemia Provider Education." Blood 134, Supplement_1 (November 13, 2019): 5827. http://dx.doi.org/10.1182/blood-2019-128710.
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Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Due to its less common occurrence and slow progression, however, community-based oncology providers are less likely to regularly diagnose and treat patients with CLL. In addition, these providers may have unique difficulties in treating patients with CLL due to limited access to clinical trials, innovative therapies, and/or local/regional experts for referral or consults. Given these barriers, the Association of Community Cancer Centers (ACCC) developed educational resources to support community-based providers treating patients diagnosed with CLL, including the development of a national CLL heatmap. The primary objective of the CLL heatmap was to increase awareness of the current national CLL landscape as well as facilitate peer-to-peer networks. Thus, the heatmap was designed as an incidence-to-provider profile that highlights where CLL is most frequently diagnosed with an overlay of where specialist providers are located. CLL incidence data was extracted from the National Association of Central Cancer Registries, and a list of CLL experts was gathered from the CLL Society. The term "expert" was loosely defined by recommendations from the CLL Society medical advisory board, executive team, and CLL patient and caregiver community. Once the data was input into the heatmap, additional filters were added for unique data visualization, including raw case numbers, crude case rates per 100,000, and age adjusted rates per 100,000. The heatmap was launched on the ACCC website in May 2019. The final heatmap highlights significant gaps and disparities related to CLL incidence and expertise. For example, when viewing raw CLL case rates, highly populated states like California, New York, Texas, and Florida show the highest incidence. However, when adjusting for the crude rate or age, the highest incidence shifts to states such as Montana, Maine, and the North-Central region. Most importantly, in both scenarios, there are many geographic areas where CLL experts are extremely limited or lacking altogether. Overall, this data visualization tool provides an invaluable resource to community-based cancer providers, patients and caregivers, advocacy groups and educators, and health services researchers. Not only is it useful in quickly assessing where additional educational programming may be needed, but also provides important context for CLL diagnosis, treatment, and quality improvement. In the future, additional research could benefit from expansion of the CLL heatmap to account for other aspects of care or inform the replication of the heatmap for other less common cancers. Disclosures Koffman: NOVARTIS: Membership on an entity's Board of Directors or advisory committees; TGTX: Equity Ownership; MGEN: Equity Ownership; Gilead: Equity Ownership; Verastem: Equity Ownership, Honoraria; BGNE: Equity Ownership; AZN: Equity Ownership, Honoraria; PTLA: Equity Ownership; MEIP: Equity Ownership; JNJ: Equity Ownership, Honoraria; SNSS: Equity Ownership; Abbvie: Equity Ownership; BMY: Equity Ownership, Honoraria.
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Weigel, Christoph, Yassen Assenov, Charles Imbusch, Qi Wang, Renée Beekman, Brian Giacopelli, Yue-zhong Wu, et al. "Recurrent Mutations in EGR2 Direct Specific Epigenetic Reconfiguration in Chronic Lymphocytic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 650. http://dx.doi.org/10.1182/blood-2018-99-119070.
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Abstract Epigenetic alterations are universal in cancer and are important in establishing the malignant phenotype. Dissection of the factors that shape the tumor-specific epigenome may reveal insight into key aspects of tumorigenesis and therapeutic resistance. In chronic lymphocytic leukemia (CLL), we have previously found that broad changes in epigenetic patterns co-occur with the evolution of genetic alterations. We have also uncovered that aberrant patterning of DNA methylation in CLL involves excessive activity of a defined group of transcription factors (TFs), including the early growth response (EGR) TF family. Recent work has further revealed that recurrent mutations in EGR2 are associated with exceptionally poor clinical outcomes in CLL. The basis for the adverse association of EGR2 mutations in CLL is unclear. To explore the role of EGR2 mutations in CLL, we initially performed genome-wide DNA methylation analysis using Illumina arrays on CLL patients harboring EGR2 mutations (n=27) compared to EGR wild-type cases (n=265). We found that the three most common recurrent mutations, occurring at amino acid positions E356K, H384N and D411H within the DNA binding domain, are each associated with an exclusive subset of tumor-specific hypomethylated CpG sites. A search for TF sequence motifs at these loci revealed a strong enrichment of novel derivative EGR2 motifs that differ only marginally (usually by a single nucleotide) from the canonical EGR2 recognition sequence. Each recurrent mutation led to specific enrichment of a different derivative EGR2 motif. Furthermore, the canonical (wild-type) recognition sequence was not enriched, suggesting that mutations re-localize binding activity to derivate sequence motifs rather than simply altering binding affinity. Luciferase enhancer, proximity ligation and electrophoretic mobility shift assays confirmed that each EGR2 mutant protein specifically binds and enhances transcriptional activity only when the matched EGR2 derivative recognition motif is present. These results establish that derivative motif sequences may function as novel cryptic enhancers in the presence of the cognate EGR2 mutant TF. We performed multiomics profiling (DNA methylome, ATAC-seq, ChIP-seq and RNA-seq) to examine the nature of the epigenetic reconfiguration and the phenotypic impact of individual EGR2 mutations. Whole genome bisulfite sequencing of E356K- and H384N-mutated CLL samples (n=4 each) was used to reveal the full complement of recurrent differentially methylated regions (DMRs) across the genome, and recapitulated the mutually-exclusive pattern of DMRs between mutations. Overlaying DMRs with data from ChIP-seq and ATAC-seq experiments in the same samples revealed the nature of EGR2 mutation-specific chromatin reconfiguration to be remarkably mutation-specific. For E356K, hypomethylated DMRs are often associated with foci of accessible chromatin, EGR2 binding, and flanked by gains of H3K4me1 and H3K27ac, indicative of the acquisition of active enhancer function. Conversely, H384N mutations generated fewer DMRs and mainly directed the deposition of H3K4me1 only, indicative of gain of poised enhancers at these loci. RNA-sequencing analyses revealed that a subset of epigenetically reconfigured regions was associated with mutation-specific altered gene expression, and differences were virtually always associated with proximal gene activation. E356K and H384N mutations displayed highly differential gene expression patterns, with E356K exhibiting a greater impact on gene expression. Integrated analyses indicated that E356K mutations may specifically involve activated Notch signaling, revealed by the aberrant activation of Notch target genes and the mutual exclusivity of NOTCH1 mutations, further highlighted by enriched co-mutation of NOTCH1 in H384N-mutated CLL. Together these findings provide an exceptional example of the precise role that a singular TF may play in programming the epigenetic landscape. As there are no known TFs that naturally bind derivative EGR2 motifs, these mutant proteins provide insight into aberrant enhancer generation and the phenotypic impact of (re)directed TF binding in a human disease setting. Although these recurrent mutations are presently only known in CLL, these findings provide insight into the mechanisms that may surround other gain-of-function TF activity in various malignancies. Disclosures Kipps: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees.
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Hasan, Kawa M. "Clinical Aspects, Immunophenotypic Analysis and Survival Rate of Chronic Lymphocytic Leukaemia Patients in Erbil City, Iraq." Sultan Qaboos University Medical Journal [SQUMJ] 18, no. 4 (March 28, 2019): 461. http://dx.doi.org/10.18295/squmj.2018.18.04.006.
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Objectives: Chronic lymphocytic leukaemia (CLL) is characterised by an accumulation of clonal B cells in the blood, bone marrow and lymphatic tissue. This study aimed to evaluate the clinical and immunophenotypic characteristics and survival rate of CLL patients. Methods: This retrospective study was conducted at the Nanakaly Hospital for Blood Diseases & Oncology in Erbil, Iraq, between January 2011 and December 2017. A total of 105 CLL patients were assessed to determine clinical presentation and staging, immunophenotype and survival rate. Results: The median age of the patients was 65 years and 63.8% were male. The main clinical presentations were splenomegaly (64.8%), pallor (61.9%) and lymphadenopathy (60%). More than half of the patients presented at an advanced clinical stage according to the Rai and Binet staging systems (59.1% and 55.2%, respectively). All CLL cases expressed both cluster of differentiation (CD)19 and CD5, 67.6% had monoclonal kappa light chains and 21% expressed CD38. The five-year overall survival (OS) rate was 61.3%. The mean duration of five-year survival was 41.3 months (95% confidence interval: 36.4–46.3 months). There were no correlations between survival and sociodemographic, clinical or laboratory characteristics. Conclusion: In comparison to the existing Western literature, Iraqi CLL patients more frequently presented with hepatosplenomegaly and at a more advanced clinical stage. In addition, the five-year OS rate was much lower.Keywords: Lymphoproliferative Disorders; Chronic Lymphocytic Leukemia; Immunophenotyping; Survival Rates; Iraq.
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Kantorova, Barbara, Jitka Malcikova, Jana Kminkova, Veronika Navrkalova, Barbora Dvorakova, Boris Tichy, Jana Smardova, et al. "Mutational Analysis of TP53 Gene in Chronic Lymphocytic Leukemia: Comparison of Different Methodological Approaches." Blood 120, no. 21 (November 16, 2012): 3911. http://dx.doi.org/10.1182/blood.v120.21.3911.3911.
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Abstract Abstract 3911 Background The adverse prognostic significance of p53 aberrations (gene deletion at locus 17p13.1 and/or TP53 mutations) has been already proven in chronic lymphocytic leukemia (CLL). In contrast to the standardized examination of the gene deletion by interphase FISH, various methodologies with different detection efficiency are applied for mutation analysis. To reduce inter-laboratory variability, the European Research Initiative on CLL (ERIC) has recently released recommendations for p53 mutational testing (Pospisilova et al., 2012). However, the optimal detection methodology has not been established yet. Aim To compare molecular-biological methods for exact determination of TP53 mutational status in CLL patients. Methodology The analyzed cohort included 100 high-risk CLL patients with unfavorable disease prognosis represented by unmutated IgVH gene status, 17p and 11q deletions and/or chemotherapy resistence. Mutational screening of TP53 gene was performed in all patients by the combination of the following methods: (1) direct Sanger sequencing (DNA and/or cDNA), (2) denaturing high-performance liquid chromatography (DHPLC; Varian), (3) functional analysis (FASAY), (4) CLL custom resequencing microarray (Affymetrix), (5) Roche AmpliChip p53 Test (Roche Molecular Systems). In the selected samples, the presence of mutations was confirmed by ultra-deep next generation sequencing (NGS; GS Junior System, Roche). Results The parallel p53 analysis using all five above mentioned detection techniques revealed totally 66 mutations in 47/100 patients. The predominant proportion of the identified alterations was represented by prognostically adverse missense substitutions (67%), mainly localized in p53 DNA-binding domain (5–8 exons). Other clinically relevant sequencing variants included frameshift mutations (15%), splice-site mutations (8%), nonsense mutations (6%) and in-frame deletions (4%). Although the used detection methods reached comparable sensitivity (with the exception of direct sequencing), some inconsistent results were observed. In comparison with DNA-based methodologies, the FASAY failed in recognition of nonsense mutations leading to RNA degradation (nonsense-mediated decay phenomenon). On the other hand, the technical aspects of chip arrays have not facilitated the proper determination of deletions and insertions. From this perspective, DHPLC in connection with direct sequencing enabled the most specific recognition of the present gene alterations. Using this methodic combination, 57/66 mutations covering all mutation types were clearly identified. Nevertheless, for the correct evaluation of the biological importance and the clinical consequences of the detected mutations, the DNA screening should be supplemented with functional analysis. Conclusion The heterogeneous biological properties of TP53 mutations require sensitive and specific detection methodology. Although many different methods are currently used for mutation analysis, each of them has some advantages and shortcommings. The combination of DNA testing with functional analysis offers the most efficient tool for improved prediction of the disease course and the response of patients to therapy. Disclosures: No relevant conflicts of interest to declare.
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Falchi, Lorenzo, Jessica M. Baron, Carrie Anne Orlikowski, and Alessandra Ferrajoli. "BCR SIGNALING INHIBITORS: AN OVERVIEW OF TOXICITIES ASSOCIATED WITH IBRUTINIB AND IDELALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA." Mediterranean Journal of Hematology and Infectious Diseases 8 (February 10, 2016): 2016011. http://dx.doi.org/10.4084/mjhid.2016.011.
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The B-cell receptor signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment landscape of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology of these agents, as well as clinical experience regarding their use for the treatment of patients with CLL. Our foci will be both the most common and the most clinically significant toxicities associated with these drugs.
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Refeno, Valéry, Nomeharisoa R. E. Hasiniatsy, Andriatsioharana V. N. Ramahandrisoa, Fanomezantsoa A. Rakoto, Aimée O. Rakoto Alson, and Florine Rafaramino. "Epidemiology and clinical aspects of hematological malignancies at the military hospital of Antananarivo." International Journal of Research in Medical Sciences 7, no. 6 (May 29, 2019): 2037. http://dx.doi.org/10.18203/2320-6012.ijrms20192478.
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Background: Malignant hemopathies constitute a group of pathologies having in common the anomalies of the bone marrow or of the lymphatic system cells. In developed countries, the number and actual distribution of cancers is provided by cancer registries. In Madagascar there is no effective cancer registry and only two studies on malignant hemopathies have been carried out to date, but neither has described their epidemiology and clinical aspects. Thus, we aimed to describe the epidemiology and clinical aspects of malignant hemopathies managed in the Medical Oncology Unit of the Military Hospital of Antananarivo.Methods: It was a cross-sectional and descriptive study carried out at this unit from 1st December 2012 to 31st August 2015 (33 months). Authors included all patients followed, then excluded those without pathologic evidence, cases of monoclonal gammapathy of unknown significance and cases of solid cancers.Results: We followed up 57 cases of malignant hemopathies. The mean age was 49.39±15.46 years and the sex ratio was 1.71. Superficial lymphadenopathy was the most frequent warning signs (31.58%) and lymphomas were most represented (52.63%). There was a significant association between warning signs and diagnosis (p value <0.001).Conclusions: Present results are grossly similar to those of other African authors. Present results are distinguished by a low proportion of chronic myeloid leukemia and a very low proportion of chronic lymphocytic leukemia compared to literature data. The effectiveness of the cancer registry will allow us to improve the knowledge about frequency and current distribution of cancer in Madagascar.
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Radhakrishnan, Neetu, and Mark A. Hoffman. "Hypercalcemia in B-Cell Chronic Lymphocytic Leukemia: Report of a Case and Review of the Literature." Blood 106, no. 11 (November 16, 2005): 5009. http://dx.doi.org/10.1182/blood.v106.11.5009.5009.
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Abstract A 53 year old man with Rai stage IV CLL was being treated with R-HyperCVAD when he presented between cycles with fatigue, lethargy and pancytopenia. Clinical examination revealed diffuse adenopathy and splenomegaly. Serum calcium was 13.6 mg/dl, phosphorus level was 2.7 mg/dl, and alkaline phosphatase was 54 U/L. PTH was 4 Units/L (10–65), PTHrP < 0.2 pmole/L (0–1.9), 1–25 (OH) Vitamin D < 10pgm/ml (22–67). Quantitative immunglobulins: IgA 10 mg/dl, IgG 252 mg/dl, IgM 50 mg/dl. Immunofixation revealed a faint IgG lambda paraprotein. There were no lytic lesions on skeletal survey. Bone marrow biopsy revealed focal large cell transformation (Richter’s syndrome). Cytogenetics revealed 3 metaphases with complex cytogenetic abnormalities, indicating clonal evolution. The hypercalcemia resolved with appropriate therapy, but despite subsequent treatment with CAMPATH, he died 2 weeks after diagnosis. A review of reported patients with CLL and hypercalcemia in the literature was performed from 1980 onwards using MEDLINE and PubMed; only those cases in which clinical aspects, biochemistry, PTH levels, imaging studies and concurrent pathology (if obtained) were documented, are summarized in this analysis (n=13). Rai stage: I n=1, II n=4, III n=3, IV n=5. Immunoreactive PTH levels were low or normal in 100% of patients. In 5 cases in which it was measured, 1–25 (OH) Vitamin D levels were not elevated. PTHrP was normal in 2 cases and elevated in 1. In nine patients, multiple lytic bone lesions were present on skeletal radiology. Two patients had osteopenia without lytic lesions. Two had no lytic lesions. Six of ten patients had evidence of transfomation on lymph node and/or bone marrow biopsy performed at the time of evaluation for hypercalcemia. Prognosis was poor (range 0.5–12 months) with only one patient surviving post allo-transplant. In conclusion, hypercalcemia in CLL is rare. Osteolytic lesions are present in the majority of cases. PTH levels are low, and thus this hormone is not mediating the hypercalcemia. The evidence is also against a role of elevated Vitamin D. Histological transformation is seen in half of the cases. Survival is poor after diagnosis of hypercalcemia. The mechanisms(s) of the osteolysis and hypercalcemia remain to be defined.
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Kiss, Richárd, Donát Alpár, Ambrus Gángó, Noémi Nagy, Dora Aczel, Andras Matolcsy, Judit Csomor, Zoltán Mátrai, and Csaba Bödör. "Spatial Convergent Clonal Evolution Leading to Ibrutinib Resistance and Disease Progression in Chronic Lymphocytic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 5539. http://dx.doi.org/10.1182/blood-2018-99-115937.
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Abstract Introduction: Bruton tyrosine kinase inhibitor ibrutinib has altered the therapeutic landscape of chronic lymphocytic leukemia (CLL) with remarkable responses in relapsed or refractory CLL. Despite mostly durable responses, approximately 20% of patients experience disease progression with, in many cases, BTK or phospholipase Cg2 (PLCG2) resistance mutations predating the clinical progression by up to 15 months. Longitudinal studies have shed some light on the temporal aspects of clonal evolution processes leading to ibrutinib resistance, however, the spatial heterogeneity within the various environmental niches has not been described in detail yet. Here, we report the case of a CLL patient in which we are able to document, for the first time, an example of ibrutinib driven spatial convergent evolution leading to disease progression. The patient developed ibrutinib resistance after 21 months of treatment with simultaneous lymphadenomegaly and lymphocytosis. Sanger sequencing revealed a canonical BTK p.C481S mutation in peripherial blood and a PLCG2 p.D993H mutation in the lymph node with the absence of the BTK p.C481S mutation present in the peripherial blood suggesting convergent evolution in terms of the BTK and PLCG2 variants with both commonly associated with ibrutinib resistance. The patient was subsequently treated with venetoclax but due to further progression despite of high-dose salvage chemotherapy and autologous stem cell transplantation the patient died. Methods: Serial samples at ten different timepoints during the disease course were analysed. Genomic DNA was isolated from peripheral blood mononuclear cells and native lymph node tissue. Circulating cell-free DNA (ccfDNA) was isolated from peripheral blood samples. The fraction of tumor cells was determined by flow cytometry. During the Sanger sequencing BTK exons 11, 15, 16, and PLCG2 exon 12, 19, 20, 24, 27 and 30 were examined. Targeted ultra-deep next-generation sequencing (NGS) analysis of the BTK and PLCG2 genes was performed on a MiSeq platform (Illumina). Abundances of the PLCG2 p.P993H and BTK p.C481S variants were quantified using custom assays on a QX200 droplet digital PCR system (ddPCR, BioRad). Results: To dissect this spatial heterogeneity, BTK and PLCG2 mutations were screened by NGS which confirmed the Sanger finding and in addition to the dominant PLCG2 p.D993H variant, identified the BTK p.C481S mutation as a minor clone in the lymph node, with the BTK p.C481S mutation remaining the exclusive for the peripheral blood. Next, we tested the presence of these mutations in the circulating ccfDNA with ddPCR. Notably, both mutations were identified in the ccfDNA with a VAF of 1%. The ddPCR analysis revealed that both variants were absent in the pre-ibrutinib peripheral blood sample, however their emergence predated the clinical progression by 15 months. We observed a gradual expansion of these variants in the sequential samples, demonstrating clonal selection under the selective pressure of ibrutinib. Of note, the ddPCR assay identified the PLCG2 p.D993H mutation as a minor clone (VAF: 0.2%), previously unseen in the peripheral blood by NGS at the time of ibrutinib relapse. Intriguingly, the two subclones displayed differential sensitivity to the venetoclax therapy. In the peripheral blood, we observed a reduction of the BTK p.C481S positive subclone accompanied by expansion of the subclone harbouring PLCG2 p.D993H which was previously dominant in the lymph node. With these dynamic changes in the subclonal architecture, the disease progressed and ultimately led to death of the patient. Conclusions: Clonal evolution is a major driving force of disease progression in CLL. Several studies have traced the effect of treatment on temporal evolutionary trajectories in the context of standard and targeted therapies and identified subclonal heterogeneity and active clonal selection. However, the spatial aspect of subclonal dynamics has not been appreciated until recently. Here, we presented a unique case of CLL, developing ibrutinib resistance via multiple routes simultaneously, with the observed spatial heterogeneity leading to progression and aggressive transformation of the disease. This case highlights the importance of genetic profiling of multiple affected sites as investigations restricted to peripheral blood may underestimate the repertoire of clinically relevant genetic alterations. Disclosures No relevant conflicts of interest to declare.
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Grander, D., M. Heyman, K. Brondum-Nielsen, Y. Liu, E. Lundgren, S. Soderhall, and S. Einhorn. "Interferon system in primary acute lymphocytic leukemia cells with or without deletions of the alpha-/beta-interferon genes." Blood 79, no. 8 (April 15, 1992): 2076–83. http://dx.doi.org/10.1182/blood.v79.8.2076.2076.
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Abstract Various aspects of the interferon (IFN) system were studied in malignant cells from 37 unselected patients with acute lymphocytic leukemia (ALL). It was found that leukemic cells from two of 37 patients had a complete loss of alpha- and beta-IFN genes, whereas cells from four of 37 had lost one of the alpha-/beta-IFN alleles. In 25 cases, viable cells were also available for functional studies. Cell clones with loss of one of the alpha-/beta-IFN alleles produced low amounts of IFN after virus induction in vitro. Some clones with an apparently normal set of IFN genes were unable to produce detectable amounts of IFN. All clones studied were found to carry high-affinity alpha-IFN receptors. In clones carrying deletions of IFN genes, the cells were sensitive to IFN in vitro as measured by alpha-IFN-induced enhancement of 2′,5′-oligoadenylate synthetase (2′,5′-A synthetase). Cells from four patients with an apparently normal set of IFN genes were insensitive to this effect of IFN. We conclude that of the 17 patients in which IFN genes, IFN production, alpha-IFN receptors, and IFN-induced enhancement of 2′,5′-A synthetase were studied, nine (53%) showed some abnormality in their IFN system. This finding may add some support to the hypothesis that defects in the IFN system could be a step on the path to malignant transformation in ALL. Moreover, patients whose malignant cells carry IFN gene deletions or other defects in their IFN-producing capacity, but are still sensitive to exogenous IFN, could represent a subgroup of ALL with a greater likelihood of responding to IFN therapy.
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Grander, D., M. Heyman, K. Brondum-Nielsen, Y. Liu, E. Lundgren, S. Soderhall, and S. Einhorn. "Interferon system in primary acute lymphocytic leukemia cells with or without deletions of the alpha-/beta-interferon genes." Blood 79, no. 8 (April 15, 1992): 2076–83. http://dx.doi.org/10.1182/blood.v79.8.2076.bloodjournal7982076.
Full textAbstract:
Various aspects of the interferon (IFN) system were studied in malignant cells from 37 unselected patients with acute lymphocytic leukemia (ALL). It was found that leukemic cells from two of 37 patients had a complete loss of alpha- and beta-IFN genes, whereas cells from four of 37 had lost one of the alpha-/beta-IFN alleles. In 25 cases, viable cells were also available for functional studies. Cell clones with loss of one of the alpha-/beta-IFN alleles produced low amounts of IFN after virus induction in vitro. Some clones with an apparently normal set of IFN genes were unable to produce detectable amounts of IFN. All clones studied were found to carry high-affinity alpha-IFN receptors. In clones carrying deletions of IFN genes, the cells were sensitive to IFN in vitro as measured by alpha-IFN-induced enhancement of 2′,5′-oligoadenylate synthetase (2′,5′-A synthetase). Cells from four patients with an apparently normal set of IFN genes were insensitive to this effect of IFN. We conclude that of the 17 patients in which IFN genes, IFN production, alpha-IFN receptors, and IFN-induced enhancement of 2′,5′-A synthetase were studied, nine (53%) showed some abnormality in their IFN system. This finding may add some support to the hypothesis that defects in the IFN system could be a step on the path to malignant transformation in ALL. Moreover, patients whose malignant cells carry IFN gene deletions or other defects in their IFN-producing capacity, but are still sensitive to exogenous IFN, could represent a subgroup of ALL with a greater likelihood of responding to IFN therapy.