Background Chronic Lymphocytic Leukemia Research Articles

Medical- and Implant-Related Complications Following Total Joint Arthroplasty in Patients Who Have Chronic Lymphocytic Leukemia

BackgroundChronic lymphocytic leukemia (CLL) is highly prevalent in the Total Joint Arthroplasty (TJA) age group but has not been properly evaluated. This study aims to assess: 1) 90-day medical complications; 2) implant-related complications; 3) healthcare utilization; and 4) time to revision in CLL and non-CLL TJA. MethodsChronic Lymphocytic Leukemia cases undergoing total knee arthroplasty (TKA) and total hip arthroplasty (THA) were identified using diagnostic and procedural codes. CLL TKA and THA patients were matched 1:5 with controls based on demographics and comorbidities. Outcomes included 90-day medical complications, 2-year implant complications, length of stay (LOS), 90-day readmission, and time to revision. ResultsThe CLL TKA patients had significantly higher odds of 90-day medical complications compared to controls, notably pneumonia (OR, 9.2; CI, 7.1 to 12.0; P < 0.001) and myocardial infarction (OR, 5.5; CI, 3.9 to 7.9; P < 0.001). Similarly, CLL THA patients had greater odds of 90-day medical complications, especially pneumonia (OR 10.0; CI 8.2 to 12.2; P < 0.001) and acute kidney injury (AKI) (OR 6.3; CI 5.1 to 7.8; P < 0.001). CLL TKA patients faced higher odds of periprosthetic fracture, mechanical loosening, and prosthetic joint infection, while THA patients had increased periprosthetic fractures. Revisions occurred earlier for THA than TKA (337 ± 547 days versus 643 ± 774 days). CLL patients had longer LOS (TKA: 5.9 ± 6.5 versus 3.1 ± 1.6 days; P < 0.001) (THA: 6.3 ± 12.9 versus 3.0 ± 2.4; P < 0.001) and higher 90-day readmission rates (OR, 1.3; CI, 1.1 to 1.5, P < 0.001). ConclusionsOrthopaedic surgeons should consider CLL status for informed patient counseling and complications mitigation.

Leukemic B cells expression of CD200 and Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1, CD305) in Chronic Lymphocytic Leukemia patients in relation to Treg frequency

BackgroundChronic lymphocytic leukemia (CLL) is characterized by a wide range of tumor-induced immune alterations. Regulatory T cells (Treg) play a central role in these immune responses. CD200 and Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1, CD305) are inhibitory markers said to be involved in Treg immune response. We aimed to analyze the expression of CD200 and LAIR-1 on leukemic cells and assess their interactions with the Treg frequency to elucidate their role in the CLL course. Subjects and methodsThis study was conducted on 70 participants: 50 newly diagnosed CLL cases classified according to Rai staging system into group 1 (n = 25) patients with stages 0, I, and II, and group 2 (n = 25) of advanced patients with stages III and IV. In addition to control group (n = 20) of healthy adults. Flow cytometry was used to investigate Treg frequency in bone marrow (BM) proportional to CD4+ T cell and to assess leukemic cell expression of CD200 and LAIR-1. Also, in-silico database analysis was performed to identify study markers interactions for future personalized target therapy. ResultsComparison between CLL groups 1 and 2 revealed increased leukemic cell percentage expressing LAIR-1 (p = 0.021) in group 1. Group 2 showed significant increase in frequency of Treg in BM and leukemic cells expressing CD200. There was a strong positive correlation between frequency of Treg and leukemic cells expressing CD200 (r = 0.669, p = 0.000). On the other hand, there was a negative correlation between frequency of Treg and leukemic cell expressing LAIR-1 (r = −0.342, p = 0.015). ROC curve analysis revealed that increased frequency of leukemic cells expressing CD200 yielded sensitivity (SN) and specificity (SP) of 96 % and 84 %, respectively in detecting CLL progression, with an AUC of 0.965. Leukemic cell percentages expressing LAIR-1 yielded a lower SN (75 %), SP (72 %), with an AUC of 0.688. ConclusionTreg frequency in BM was significantly increased in CLL advanced stages according to Rai classification. Leukemic cells CD200 and LAIR-1 expression were differently associated with Treg frequency. Increased CD200 expressions on leukemic cells can be considered a sensitive and specific biomarker in detecting CLL progression. As demonstrated by the in-silico research, CD200 blockade targeting may offer therapeutic benefits for CLL treatment through Treg suppression.

The Prevalence of Cytogenetic Abnormalities Detected by Interphase FISH Method in Chronic Lymphocytic Leukemia

Abstract Background Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia. Identification of genomic aberration provides prognostic/predictive information that is helpful in the precision medicine management of these patients. The aim of this study was to determine prevalence of the most common cytogenetic abnormalities of CLL patients in the southwest region (Shiraz) of Iran and correlate with clinical prognostic parameters to clarify their prognostic value. Materials and Methods In this cross-sectional study, 100 patients with CLL were recruited from April 2019 to October 2021. Four milliliters of anticoagulated peripheral blood was collected from each participant. The sample was used for complete blood count (CBC) test and fluorescence in situ hybridization (FISH) test. Interphase FISH (I-FISH) was performed for most common cytogenetic abnormalities, including trisomy 12, 13q14 deletion, 11q deletion, and 17p deletion on interphasic cell nuclei. Results Among 100 patients with CLL, 33 (33%) were females and 67 (67%) were males. The mean age (mean ± standard error [SE]) of the patients was 59.00 ± 1.14 years, with a ranged of 25 to 79 years. Our analysis demonstrated that 86 (86%) patients had at least one chromosomal aberration. The most commonly detected abnormality was 13q deletion (61, 61%), followed by 17q deletion (50 cases, 50%). Trisomy 12 was detected in 14 (14%) cases and 10 cases (10%) had 11q deletion. Conclusion The higher frequency of 13q14 and 17p anomalies in our study may be attributed to delayed medical consultations, leading to the emergence of secondary abnormalities. More studies are recommended for verifying the results.

Gene Mutations Associated With Chronic Lymphocytic Leukemia (CLL) Among Saudi CLL Patients and Treatment Outcomes: A Single-Center Experience.

Background Chronic lymphocytic leukemia (CLL) starts in white blood cellsin the peripheral blood (stages 0 and 1). In CLL, leukemia cells often build up slowly. Many gene mutations are associated with CLL, such as trisomy 12, 13q14 deletion, and 17q deletion. Due to the lack of patients' disease characteristics, gene mutations, and treatment outcomes data among Saudi patients, this study aimed to identify the relation between the gene mutations of CLL and the treatment in King Abdulaziz Medical City (KAMC), Riyadh. Methods This cross-sectional study used data from the BESTCare hospital information system. The study included all patients diagnosed with CLL and confirmed by flow cytometry in KAMC, Riyadh, between January 2010 and October 2020. The data included demographic information, mutation type or chromosome, present comorbidity, and type of treatment. Results The study included 100 CLL patients. According to different types of clusters of differentiation (CD), CD5 was positive in 84 (84%) patients, and 88 (88%) patients were positive for CD19. Cytogenetic remarkers were tested, revealing that 21 (21%) patients with trisomy 12 and 20 (20%) were positive for 13q14 deletion. Observation of patients' disease status based on the cytogenetic remarkers showed that out of 15 patients with trisomy, 12 (80%) had not progressed and were stable and alive. Out of 20 patients with 13q14 deletion, 16 (80%) were alive and 13 (65%) patients were stable. Conclusion CLL patients in KAMC, Riyadh, displayed trisomy 12, which is characterized by the worst prognosis of disease status, as the most frequently detected cytogenetic aberration followed by 13q deletion. However, most patients were stable and alive.

Chronic Lymphocytic Leukemia (CLL) in Adolescents and Young Adults (AYA): Clinical Characteristics, Prognostic Factors and Survival for 498 Patients

Background Chronic lymphocytic leukemia (CLL) is primarily a disease of the elderly; however, it can also present in Adolescents and Young Adults (AYA) aged 15 to 39 years. Recent information of case series no larger than 227 patients each described clinical outcomes such as a 5-year Overall Survival (OS) of 90% and a 10-year OS of 78% for AYA 1-4. Data on the effect of age on OS in CLL is conflictive among studies 2,3. A higher proportion of males with CLL have been reported in the younger ages compared with olders in some series 2,4 but not in others 3. Sociodemographic characteristics and distribution between younger and older CLL patients have not been extensively reported 2-4. The objective of our study is to describe the clinical and sociodemographic characteristics, prognostic factors and survival in AYA diagnosed with CLL. Materials and Methods Cases of CLL were obtained from the Surveillance, Epidemiology, and End Results (SEER) Database from 2000 to 2020. Statistical analyses were conducted with SPSS® version 25. Patient characteristics were reported in frequencies and compared with the Chi-squared test. The Kaplan-Meier method was used to estimate the median Overall Survival (OS). Cox Regression was done to identify independent prognostic factors of survival. Results A total of 51,992 cases of CLL were identified. The median age of diagnosis was 69 years (interquartile range: 18 years). 498 AYA cases (1% of total population) were found (Table 1). For them, 66.1% were males, 70.3% were non-Hispanic whites and 90.2% lived in metropolitan areas. A median income of ≥$75,000 was noted in 45.6% of the patients. Chemotherapy was received by 32.7% and radiation therapy was given to 1.6%. The median OS for AYA population was not reached (Figure 1), with a 5-year and 10-year OS of 91% and 84%, respectively. OS was different between AYA vs older population, and age was found to be an independent prognostic factor for survival in the entire population of CLL (p&amp;lt;0.001, Figure 1). The age group comparison also found more proportion of males in AYA vs olders (66.1% vs 58.5%, p&amp;lt;0.001), more proportion of non-white patients in AYA group (29.6% vs 15.3%, p&amp;lt;0.001) and that AYA patients were more prone to receive chemotherapy (32.7% vs 14.8%, p&amp;lt;0.001). The multivariate analysis specific for AYA population found that American Indian/Alaska Native Non-Hispanic patients had poor prognosis compared with other races (HR=19.1, CI 95%: 2.2-166.5, p=0.008). Also, receiving radiotherapy (Beam radiation) was associated with poor prognosis (HR=5.5, CI 95%: 1.6-19.6, p=0.008). Compared to people with income &amp;lt;$35,000, all patients with higher income had better prognosis (for patients with ≥$75,000 median income the HR was 0.01, 95% IC: 0.001-0.11, p&amp;lt;0.001). Chemotherapy was not found to be an independent prognostic factor in this population (p=0.8). Conclusions To the best of our knowledge, this is the largest epidemiological study available for CLL in AYA to this date. Sociodemographic differences and epidemiologic prognostic factors described in this research contribute to understand this disease. Interventional studies are required to identify possible targeted therapies that could improve survival outcomes in this population. We believe that the differences in distribution and prognosis for the described variables in our study can contribute towards optimizing the randomization in interventional trials in the future.

Global Perspectives of Lived Experience with CLL - Patient and Support Group Reported Insights of Access, Treatment, and Unmet Needs

Background Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, with patients facing years of monitoring and treatment. The CLL Advocates Network (CLLAN) was interested in exploring the experience of patients and support organisations to access of treatment and care. The analysis was based on the results of two surveys: the CLL Patient Advocacy and Support Survey(CLL-PAGS)conducted by CLLAN in 2021, and the Global Leukemia Patient Experience Survey (GPES) conducted in the same year in collaboration with Acute Leukemia Advocates Network and CML Advocates Network. CLL-specific data were extracted from the latter survey. Methodology The CLL-PAGSexplored the services provided by organisations for patients and their views on healthcare in their respective countries. The GPES provided data from questions completed by patients on their experience across their CLL journey. The surveys were available in 7 (CLL-PAGS) and 10 (GPES) languages and online only. Global recruitment through patient organisations, email, online forums, newsletter, and social media. Survey design was developed through literature review, patient advisory session and expert panel insights. The fieldwork of theCLL-PAGS was conducted for 12 weeks closing in August 2021. The GPES was open between September and November 2021. Building on analysis of socio demographics of age and gender, countries were segmented into High income (HIC) and Low-and-middle-income countries (LMIC), as per the Organisation for Economic Co-operation and Development´s (OECD) classification. Results 57 organisations from 40 countries (19 from LMIC and 38 from HIC) responded to the CLL-PAGS. The GPES received a total of 2,646 responses from 40 countries, 45% of whom (n=1,202 in 30 countries) corresponded to CLL. 1118 patients from HIC and 11 patients from 8 countries responded within the LMIC cohort. 73 respondents did not report a country. Because of the difficulty retrieving significant patient information from LMIC, we believe there's value in the results from our small sample. Age distribution in the GPES was similar to previous studies, with CLL predominantly in older people. 19 patients were aged 35-44 years with 2% &amp;lt;35 years. There was higher representation in LMIC of younger people (90% 35-64 years). 65% of respondents from HIC were &amp;gt;65 years. Geographical region demonstrated clear differences with HIC (34%) respondents being asymptomatic at diagnosis and all respondents from LMIC being symptomatic. Of those who sought investigation of symptoms, 36% of HIC and 33% of LMIC were diagnosed after first consult. LMIC compared to HIC had delay with 33% diagnosed within 3 and 33% within 5 or more visits. There was a difference between LMIC and HIC in treatment start. All respondents from LMIC commenced treatment within two years (42% in HIC) which may be attributed to the symptomatic presentation. Access to CLL specialist care differed as per figure 1. Variance in current treatment with 75% of LMIC on chemotherapy, while HIC reported receiving oral targeted therapy (59%) or immunotherapy (21%). Gaps were shared globally with 52% reporting they had no choice in treatment decision. LMIC were less likely at 60%. Scaled ranking identified only 54% of respondents (30% in LMIC) felt completely involved in treatment decisions. 3/4 of patients globally reported provision of information by treating team about their most recent treatment. This was lower in LMIC (50%). Further divide on patient literacy with 71% of HIC patients and only 40% in LMIC reporting information provision as well understood. 54% reported not being given the option to participate in trials. This was higher in LMIC (70%) than HIC (53%). Preference of being offered a clinical trial is shown in figure 2. Of those who had participated in a trial, 86% found this a positive experience, indicating an opportunity for the research community. Conclusion Overall, patients would like more choice in treatment decisions, increased access to clinical trials and better information. The survey responses and wider literature around CLL suggest that education for patients and HCPs around clinical trials would be beneficial, as would new methods of communicating and engaging with LMIC patients. There is opportunity to improve partnerships between patient organisations and treating teams to address the gaps. The emerging trends from the surveys merit further research.

Trends and Disparities of Chronic Lymphocytic Leukemia Mortality in the United States from 1999 to 2020

Background Chronic lymphocytic leukemia (CLL) is the most common chronic leukemia in the United States (US). In the last decade, the treatment landscape of CLL has significantly evolved, and the clinical outcomes improved. However, data on the mortality trends of CLL is not well-established. Objective This study aimed to analyze the trends in mortality rates due to CLL and to assess the disparities in the mortality rates among different sex, ages, races, and geographic locations. Methods We obtained death certificate data for CLL mortality among patients aged 35 years and above from the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database. CLL (International Classification of Diseases, Tenth Revision [ICD-10] C91.1) was listed as the underlying cause of death. Age-adjusted mortality rates (AAMRs) per 100,000 individuals were calculated, and the trends over time were analyzed by measuring the average annual percent change (AAPC) using the Joinpoint Regression Program. Subgroup analyses were conducted by sex, race, age, census region, and urbanization level. Results In the 22-year study period from 1999 to 2020, 97,186 deaths attributed to CLL were reported in the US. The CLL mortality rate decreased from 3.23 (95% CI, 3.13 - 3.32) per 100,000 individuals in 1999 to 2.05 (95% CI, 1.99 - 2.11) per 100,000 individuals in 2020 with the AAPC of -2.09 (95% CI, -2.69, -1.49). The highest AAMR was observed among non-Hispanic White men (4.14 [95% CI, 4.10 - 4.17] per 100,000 individuals), followed by non-Hispanic Black men (3.48 [95% CI, 3.37 - 3.59] per 100,000 individuals), non-Hispanic White women (1.88 [95% CI, 1.86 - 1.90] per 100,000 individuals), and non-Hispanic Black women (1.61 [95% CI, 1.55 - 1.67] per 100,000 individuals). Figure 1 shows the trends of AAMR in non-Hispanic White and non-Hispanic Black men and women over the years. Black individuals had the greatest decline in AAMR over the years with the AAPC of -2.87 (95% CI, -3.31, -2.42) whereas Hispanic individuals had the smallest decline in AAMR over the years with the AAPC of -1.50 (95% CI, -2.30, -0.69). Patients aged 75-84 years had the highest AAMR at 0.99 (95% CI, 0.98 - 1.00) per 100,000 individuals among different age groups. The greatest decline in AAMR was reported among patients aged between 45-54 years with the AAPC of -4.91 (95% CI, -6.16, -3.65). Those who lived in the Midwest region had the highest AAMR (2.93 [95% CI, 2.89 - 2.97] per 100,000 individuals), followed by the Northeast region (2.52 [95% CI, 2.49 - 2.56] per 100,000 individuals), the South region (2.48 [95% CI, 2.46 - 2.51] per 100,000 individuals), and the West region (2.38 [95% CI, 2.34 - 2.41] per 100,000 individuals). The greatest decline in AAMR over the years was observed among those who lived in the South region with the AAPC of -2.42 (95% CI, -2.68, -2.16). A higher AAMR was observed in the rural population (2.87 [95% CI, 2.83 - 2.91] per 100,000 individuals) in comparison to the urban population (2.53 [95% CI, 2.51 - 2.55] per 100,000 individuals). Conclusion CLL mortality has declined over the last two decades, likely due to the introduction of novel therapies. However, disparities among different sex, races, ages, geographic regions, and urbanization levels still exist. Our study underscores the importance of addressing these disparities and improving outcomes for susceptible individuals affected by CLL.

Meta-Analysis of the Efficacy and Adverse Effects of Acalabrutinib in the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia

Background Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia and is characterized by the accumulation of small and mature appearing lymphocytes in blood, lymphoid tissue, and bone marrow. Chemoimmunotherapy and targeted therapies can improve overall survival and the duration of remission; however, CLL is prone to relapse, therefore identifying new therapeutic targets has been an important aspect of CLL research and management. B-cell receptor signaling serves an integral role in the pathogenesis of CLL and kinases involved in the BCR pathway are targets of novel therapies. The Bruton tyrosine kinase (BTK) that is immediately downstream of the B-cell receptor is a mediator of cell signaling involved in B cell survival and proliferation. Moreover, BTK is involved in CLL interaction with the tumor microenvironment. Targeting BTK with ibrutinib was a transformative advance in CLL treatment and has become a front-line therapy in the management of CLL. In recent years, newer generations of Bruton tyrosine kinase inhibitors (BTKi) have been approved in the management of CLL. Acalabrutinib is an irreversible, second generation BTKi that is more selective and potent than ibrutinib. This meta-analysis investigated the efficacy, outcomes, and hematologic adverse effects of acalabrutinib in the treatment of relapsed/refractory CLL. Methods A search was conducted using the PICOS model and PRISMA guidelines to retrieve outcome, efficacy, and adverse effect data. 12 studies were chosen after literature review and screening. In the event a study was an abstract or paper providing updated data on the same patient population of a previously published study, the most up to date information was used for analysis. The random effect meta-analysis model was used for analyses. Variables for analysis were: Overall Response Rate (ORR), Overall Discontinuation Rate, Death Rate, and Discontinuation due to Adverse Effects. Grade 3 Hematologic adverse reactions were analyzed: Anemia, Neutropenia, Thrombocytopenia. Results The analysis included a total of 796 patients (450 Males &amp; 200 females; sum discrepancy due to absence of certain demographic information in particular studies). ORR pooled estimate: 82% (95% CI [0.82,0.75]; p&amp;lt;.001, I 2=81.96%), death rate: 12% (95% CI [0.06,0.19]; p&amp;lt;.001, I 2=87.23%), overall discontinuation rate: 35% (95% CI [0.20, 0.30]; p&amp;lt; .001, I 2=98.84%), discontinuation due to adverse effect: 13% (95% CI [0.10,0.15]; p=0.6, I 2=0.00), neutropenia: 18% (95% CI [0.15,0.20]; p=0.70), anemia: 9% (95% CI [0.06,0.12];p=0.18), thrombocytopenia: 7% (95% CI [0.04,0.11];p=0.09). Discussion BTK inhibitors have significantly changed the management of CLL and are utilized as either as frontline or as salvage treatment. Although, ibrutinib has shown efficacy in management of CLL, off-target toxicities and treatment resistance has been demonstrated with its use. Therefore, a greater understanding of second generation BTK inhibitors such as acalabrutinib will offer clinicians perspective in choosing a CLL management strategy. Our meta-analyses noted an ORR pooled estimate of 82% with a death rate of 12%. Deaths in the literature typically occurred either from disease progression or adverse effects. Similarly, discontinuation typically occurred due to progressive disease or adverse events. The Grade 3 hematologic adverse effects most frequently reported were anemia, thrombocytopenia, neutropenia. Clinical Grade 3 adverse effects (e.g. pneumonia, cardiac events) and baseline characteristics will be focused on in a future analysis.

Understanding Patient and Physician Perceptions Regarding Treatment-Related Adverse Events in First-Line Chronic Lymphocytic Leukemia (CLL)

Background Chronic Lymphocytic Leukemia (CLL) patients have various treatment options which are all associated with different adverse events. A limited number of studies have explored how patients and physicians perceive these adverse events in the frontline treatment setting. Understanding the similarities and differences in perceptions between physicians and CLL patients is an important factor in supporting shared decision-making. Aims The objective of this multi-country study was to understand the differences in patients' and physicians' perception on treatment-related adverse events in CLL. Methods CLL patients and physicians managing CLL (oncologists, hematologist-oncologists, and hematologists) were invited to complete an online survey. Participants were recruited from the US, UK, Germany, France, and Australia. The survey included a best-worst scaling (BWS) exercise to assess how ‘bothersome’ 14 potential adverse events associated with 1L CLL treatments were perceived. In a series of 18 BWS choice tasks, participants chose which was most ‘bothersome’ and which was ‘least bothersome’ among subsets of 4 adverse events. A hierarchical Bayesian (HB) model was used to estimate BWS scores for each treatment-related adverse event: BWS scores sum to 100 for each participant and a higher score indicates that an adverse event is relatively more ‘bothersome’. Results The study included 192 patients and 259 physicians. The top four most bothersome adverse events were the same for both patients and physicians, however, these were ranked in a different order (Table 1). Physicians ranked the ‘risk of cardiac events/atrial fibrillation/flutter that may require medical treatment and/or hospitalization’ and ‘risk of bleeding (hemorrhage) that requires medical intervention and/or hospitalization’ as their 2 most bothersome adverse events while patients ranked ‘Risk of infection, such as pneumonia or blood infections (sepsis) requiring medical intervention and/or hospitalization’ and ‘Risk of tumor lysis syndrome (TLS) which requires hospitalization’ as their 2 most bothersome adverse events (Table 1). The 2 least bothersome adverse events for both physicians and patients were ‘Risk of mild-to-moderate muscle, joint or bone pain (mild-to-moderate pain not interfering with daily activities) that might go away with medication’ and ‘Risk of mild-to-moderate headache (not limiting daily activities or limiting only instrumental activities such as cooking, cleaning, transportation, laundry, etc.) that might go away with medication’ (Table 1). Among patients who had experienced an adverse event (N=111), 62 (56%) reported that it had impacted their quality of life. These patients rated the following adverse events as more bothersome compared to those who had not experienced adverse events impacting quality of life: ‘risk of infection, such as pneumonia or blood infections requiring medical intervention and/or hospitalization’ (BWS scores=13.88 vs. 11.79) and ‘a side effect resulting in stopping the medication’ (9.46 vs. 6.00). These patients also rated the following adverse events as least bothersome: ‘risk of severe headache that might lead to hospitalization’ (9.55 vs. 11.68), ‘risk of severe vomiting that might lead to hospitalization’ (8.97 vs. 10.70), and ‘risk of severe muscle joint or bone pain’ (7.32 vs. 10.59), compared to those not experiencing adverse events impacting quality of life. Conclusions Patients' and physicians' perceptions were generally aligned on what adverse events related to 1L CLL treatments are most and least bothersome. However, the rank-ordering of the most bothersome adverse events varied between patients and physicians: patients were more concerned about a risk of infection or tumor lysis syndrome whereas physicians thought that a risk of cardiac event and the risk of bleeding were the most bothersome adverse events. Patients expressed hardly any concern about a risk of mild-to-moderate headache that could be resolved with medication. Interestingly, patients who had experienced a prior adverse event had differing results to patients who had not. These results should further inform and facilitate conversations between physicians and patients and improve shared decision-making when selecting a 1L regimen to treat CLL.

Lifetime exposure to brominated trihalomethanes in drinking water and swimming pool attendance are associated with chronic lymphocytic leukemia: a Multicase-Control Study in Spain (MCC-Spain)

BackgroundChronic lymphocytic leukemia (CLL) etiology is poorly understood, and carcinogenic chemicals in drinking and recreational water are candidates.ObjectiveTo evaluate the association between drinking-water exposure to trihalomethanes (THMs) and nitrate as well as lifetime swimming pool attendance and CLL.MethodsDuring 2010–2013, hospital-based CLL cases and population-based controls were recruited in Spain, providing information on residential histories, type of water consumed and swimming pool attendance. Average THMs and nitrate levels in drinking water were linked to lifetime water consumption. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using mixed models.ResultsFinal samples for residential tap water analyses and swimming pool attendance analyses were 144 cases/1230 controls and 157 cases/1240 controls, respectively. Mean (SD) values for average lifetime residential brominated THMs and chloroform in tap water (μg/L), and ingested nitrate (mg/day) were 48.1 (35.6), 18.5 (6.7) and 13.7 (9.6) respectively in controls; and 72.9 (40.7), 17.9 (5.4), and 14.1 (8.8) in CLL cases. For each 10 μg/L increase of brominated THMs and chloroform lifetime-average levels, the ORs (95% CI) were 1.22 (1.14, 1.31) and 0.54 (0.34, 0.87), respectively. For each 5 mg/day increase of ingested nitrate, the OR of CLL was 0.91 (0.80, 1.04). The OR of lifetime pool users (vs. non-users) was 2.38 (1.61, 3.52). Upon performing annual frequency of attending pools analysis through categorization, the second and third categories showed an ORs of 2.36 (1.49, 3.72) and 2.40 (1.51, 3.83), respectively, and P-trend of 0.001.Impact statementThis study identifies an association of long-term exposure to THMs in drinking water, at concentrations below the regulatory thresholds and WHO guidelines, and swimming pool attendance, with chronic lymphocytic leukemia (CLL). These unprecedented findings are highly relevant since CLL is an incurable cancer with still unknown etiology and because the widespread exposure to chlorination by-products that remain in drinking and recreational water worldwide. Despite the demonstrated carcinogenicity in animals of several chlorination by-products, little is known about their potential risks on human health. This study makes a significant contribution to the search for environmental factors involved in the etiology of CLL and to the evidence of the health impact of these high prevalent water contaminants.

Trends of chronic lymphocytic leukemia incidence and mortality in the United States: a population-based study over the last four decades

ABSTRACT Background Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults, and its incidence is higher in elderly individuals. This study aims to examine the burden of CLL in the United States (US) by exploring the incidence-based rates (IBR) and incidence-based mortality (IBMR) across four decades. Research design and methods CLL incidence data were obtained from the SEER-8 registry, covering 8.3% of the US population. Cases were identified using specific diagnostic codes and excluded if diagnosed on autopsy or death certificate. Age-standardized IBR and IBMR were calculated based on age, sex, and ethnicity/race. Joinpoint Regression Program was used to analyze changing trends in incidence and mortality. Results Since 2011, males’ and females’ IBRs declined by −1.72%/year (p = 0.028) and −1.07%/year (p = 0.222), respectively. IBR of patients > 75 years increased by 4.01%/year (p < 0.001) form 1998–2010, then declined by 2.02%/year (p = 0.011). IBR of Blacks increased by 0.96%/year (p < 0.001) throughout the study period. CLL IBMR stabilized at −0.38%/year (p = 0.457) since 2012. Whites’ IBMR plateaued at a rate of −0.10%/year (p = 0.857) form 2012–2019, while blacks’ IBMR increased by 1.40%/year (p = 0.056) between 2000–2019. Conclusions The analysis revealed a decline in CLL incidence since 2013, with stable mortality rates since 2012, indicating advancements in CLL management.

SYT7 regulates the progression of chronic lymphocytic leukemia through interacting and regulating KNTC1

BackgroundChronic lymphocytic leukemia (CLL) is one of the most frequent occurring types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course. At present, the molecular mechanism driving the pathogenesis and progression of CLL is not fully understood. The protein Synaptotagmin 7 (SYT7) encoded by the SYT7 gene has been found to be closely related to the development of various solid tumors, but its role in CLL is unclear. In this study, we investigated the function and molecular mechanism of SYT7 in CLL.MethodsThe expression level of SYT7 in CLL was determined by immunohistochemical staining and qPCR. The role of SYT7 in promoting CLL development was verified by in vivo and in vitro experiments. The molecular mechanism of SYT7 in CLL was elucidated by methods such as GeneChip analysis and Co-immunoprecipitation assay.ResultsMalignant behaviors such as proliferation, migration, and anti-apoptosis of CLL cells were significantly inhibited after SYT7 gene knockdown. In contrast, SYT7 overexpression promoted CLL development in vitro. Consistently, the knockdown of SYT7 also inhibited xenograft tumor growth of CLL cells. Mechanistically, SYT7 promoted CLL development by inhibiting SYVN1-mediated KNTC1 ubiquitination. The KNTC1 knockdown also attenuated the effects of SYT7 overexpression on development of CLL.ConclusionsSYT7 regulates the progression of CLL through SYVN1-mediated KNTC1 ubiquitination, which has potential value for molecular targeted therapy of CLL.

Elevated serum ELABELA and SERPINA3 as novel biomarkers to predict poor prognosis in Egyptian chronic lymphocytic leukemia patients

Abstract Background Chronic lymphocytic leukemia (CLL) is the most common kind of adult leukemia worldwide. Increased expressions of serpin peptidase inhibitor, clade A member 3 (SERPINA3) and apelin receptor early endogenous ligand (ELABELA) have been observed in various malignancies. However, there is little information on their clinical importance in CLL. Patients and methods The study included 67 newly diagnosed CLL patients and 66 healthy individuals as a control group. This study was conducted at the Oncology Center, Mansoura University, Mansoura, Egypt from April 2020 to March 2022. Serum levels of SERPINA3 and ELABELA were determined using an enzyme-linked immunosorbent assay. Results This study found that serum levels of SERPINA3 and ELABELA were significantly higher in CLL patients than in the control group with P less than 0.001 and P=0.001, respectively. SERPINA3 and ELABELA were found to be independent risk factors for CLL. In CLL patients, increased serum levels of SERPINA3 and ELABELA were associated with advanced staging, reduced progression-free survival, and overall survival. Conclusion Serum SERPINA3 and ELABELA could be used as prognostic biomarkers to predict poor prognosis in CLL patients. So, inhibition of SERPINA3 and ELABELA may be a promising therapeutic target for CLL treatment.

Competing endogenous RNA networks related to prognosis in chronic lymphocytic leukemia: comprehensive analyses and construction of a novel risk score model

BackgroundChronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy that lacks specific biomarkers and drug targets. Competing endogenous RNAs (ceRNAs) play vital roles in oncogenesis and tumor progression by sponging microRNAs (miRNAs). Nevertheless, the regulatory mechanisms of survival-related ceRNA networks in CLL remain to be uncovered.MethodsWe included 865 de novo CLL patients to investigate RNA expression profiles and Illumina sequencing was performed on four CLL patients, two CLL cell lines and six healthy donors in our center. According to univariate Cox regression, LASSO regression as well as multivariate Cox regression analyses, we established a novel risk score model in CLL patients. Immune signatures were compared between the low- and high-risk groups with CIBERSORT and ESTIMATE program. Afterwards, we analyzed the relationship between differentially expressed miRNAs (DEmiRNAs) and IGHV mutational status, p53 mutation status and del17p. Based on the survival analyses and differentially expressed RNAs with targeting relationships, the lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed. In addition, the circRNA circ_0002078/miR-185-3p/TCF7L1 axis was verified and their interrelations were delineated by dual-luciferase reporter gene assay.ResultsTotally, 57 differentially expressed mRNAs (DEmRNAs) and 335 DEmiRNAs were identified between CLL patient specimens and normal B cells. A novel risk score model consisting of HTN3, IL3RA and NCK1 was established and validated. The concordance indexes of the model were 0.825, 0.719 and 0.773 in the training, test and total sets, respectively. The high-risk group was related to del(13q14) as well as shorter overall survival (OS). Moreover, we identified DEmiRNAs that related to cytogenetic abnormality of CLL patients, which revealed that miR-324-3p was associated with IGHV mutation, p53 mutation and del17p. The survival-related lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed to further facilitate the development of potential predictive biomarkers. Besides, the expression of circ_0002078 and TCF7L1 were significantly elevated and miR-185-3p was obviously decreased in CLL patients. Circ_0002078 regulated TCF7L1 expression by competing with TCF7L1 for miR-185-3p.ConclusionsThe comprehensive analyses of RNA expression profiles provide pioneering insights into the molecular mechanisms of CLL. The novel risk score model and survival-related ceRNA networks promote the development of prognostic biomarkers and potential therapeutic vulnerabilities for CLL.

Identifying a novel ferroptosis-related prognostic score for predicting prognosis in chronic lymphocytic leukemia.

BackgroundChronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Although the treatment landscape for CLL is rapidly evolving, there are still some patients who develop drug resistance or disease refractory. Ferroptosis is a type of lipid peroxidation–induced cell death and has been suggested to have prognostic value in several cancers. Our research aims to build a prognostic model to improve risk stratification in CLL patients and facilitate more accurate assessment for clinical management.MethodsThe differentially expressed ferroptosis-related genes (FRGs) in CLL were filtered through univariate Cox regression analysis based on public databases. Least absolute shrinkage and selection operator (LASSO) Cox algorithms were performed to construct a prognostic risk model. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were performed to estimate the immune infiltration score and immune-related pathways. A total of 36 CLL patients in our center were enrolled in this study as a validation cohort. Moreover, a nomogram model was established to predict the prognosis.ResultsA total of 15 differentially expressed FRGs with prognostic significance were screened out. After minimizing the potential risk of overfitting, we constructed a novel ferroptosis-related prognostic score (FPS) model with nine FRGs (AKR1C3, BECN1, CAV1, CDKN2A, CXCL2, JDP2, SIRT1, SLC1A5, and SP1) and stratified patients into low- and high-risk groups. Kaplan–Meier analysis showed that patients with high FPS had worse overall survival (OS) (P<0.0001) and treatment-free survival (TFS) (P<0.0001). ROC curves evaluated the prognostic prediction ability of the FPS model. Additionally, the immune cell types and immune-related pathways were correlated with the risk scores in CLL patients. In the validation cohort, the results confirmed that the high-risk group was related to worse OS (P<0.0001), progress-free survival (PFS) (P=0.0140), and TFS (P=0.0072). In the multivariate analysis, only FPS (P=0.011) and CLL-IPI (P=0.010) were independent risk indicators for OS. Furthermore, we established a nomogram including FPS and CLL-IPI that could strongly and reliably predict individual prognosis.ConclusionA novel FPS model can be used in CLL for prognostic prediction. The model index may also facilitate the development of new clinical ferroptosis-targeted therapies in patients with CLL.

Explainable machine learning for chronic lymphocytic leukemia treatment prediction using only inexpensive tests

BackgroundChronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in the western world which affects mainly the elderly population. Progress of the disease is very heterogeneous both in terms of necessity of treatment and life expectancy. The current scoring system for prognostic evaluation of patients with CLL is called CLL-IPI and predicts the general progress of the disease but is not a measure or a decision aid for the necessity of treatment. Due to the heterogeneous behavior of CLL it is important to develop tools that will identify if and when patients will necessitate treatment for CLL. Recently, Machine Learning (ML) has spread to many public health fields including diagnosis and prognosis of diseases. ObjectiveExisting machine learning methods for CLL treatment prediction rely on expensive tests, such as genetic tests, rendering them useless in peripheral or low-resource clinics such as those in developing countries. We aim to develop a model for predicting whether a patient will need treatment for CLL within two years of diagnosis using a machine learning model based on only on demographic data and routine laboratory tests. MethodWe conducted a single center study that included adult patients (above the age of 18) that were diagnosed with CLL according to the IWCLL criteria and were under observation at the hematology unit of the Bnai-Zion medical center between 2009 and 2019. Patient data include demographic, clinical and laboratory measures that were extracted from patients’ medical records anonymously. All laboratory results, during the observation period, were extracted for the entire cohort. Multiple ML approaches for classifying whether a patient will require treatment during a predetermined period of 2 years were evaluated. Performance of the ML models was measured using repeated cross validation. We evaluated the use of SHapley Additive exPlanation (SHAP) for explaining what influences the models decision. Additionally, we employ a method for extracting a single decision tree from the ML model which enables the doctor to understand the main logic governing the model prediction. ResultsThe study included 109 patients of them 67 males (61%). Patients were under observation for a median of 44 months and the median age was 65 (age range: 45–87). 64% of the cohort received therapy during follow-up. A Gradient Boosting Model (GBM) model using all of the extracted variables to identify the need for treatment in the coming two years among patients with CLL achieved the AUPRC of 0.78 (±0.08). An identical GBM model, without genetic/FISH and flowcytometry (FACS) data, such that it can be used in peripheral clinics, scored an AUPRC of 0.7686 (±0.0837). A Generalized Linear Model (GLM) using the same features, scored an AUPRC of 0.7535 (±0.0995). All the models described above surpassed the performance of CLL-IPI that was evaluated using the CLL-TIM model. According to the SHAP results, red blood cell (RBC) count was the most predictive value for the necessity for treatment, where a high value is associated with a low probability of requiring treatment in the coming two years. Additionally, the SHAP method was used for estimating the personal risk of a random patient and showed sensible results. A simple Decision Tree classifier showed that patients who had a hemoglobin level of less than 13 gm/dL and a Neutrophil to Lymphocyte Ratio (NLR) less than 0.063, which constituted 34% percent of the patients included in our study, had a high probability (76%) of requiring treatment. ConclusionsMachine Learning algorithms that were evaluated in this work for predicting the necessity of treatment for patients with CLL achieved reasonable accuracy which surpassed that of CLL-IPI which was evaluated using the CLL-TIM model. Furthermore, we found that a machine learning model trained exclusively using inexpensive features only incurred a modest decrease in performance compared to the model trained using all of the features. Due to the small number of patients in this study it is necessary to validate the results on a larger population.

BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion

BackgroundChronic lymphocytic leukemia (CLL) results in increased susceptibility to infections. T cell dysfunction is not associated with CLL in all patients; therefore, it is important to identify CLL patients with T cell defects. The role of B-cell lymphoma-2 (BCL-2) in CLL has been explored; however, few studies have examined its role in T cells in CLL patients. Herein, we have investigated the regulatory role of BCL-2 in T cells in the CLL tumor microenvironment.MethodsThe expression of BCL-2 in T cells was evaluated using flow cytometry. The regulatory roles of BCL-2 were investigated using single-cell RNA sequencing (scRNA-seq) and verified using multi-parameter flow cytometry on CD4 and CD8 T cells. The clinical features of BCL-2 expression in T cells in CLL were also explored.ResultsWe found a significant increase in BCL-2 expression in the T cells of CLL patients (n = 266). Single cell RNA sequencing (scRNA-seq) indicated that BCL-2+CD4+ T cells had the gene signature of increased regulatory T cells (Treg); BCL-2+CD8+ T cells showed the gene signature of exhausted cytotoxic T lymphocytes (CTL); and increased expression of BCL-2 was associated with T cell activation and cellular adhesion. The results from scRNA-seq were verified in peripheral T cells from 70 patients with CLL, wherein BCL-2+CD4+ T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2−CD4+ T cells. BCL-2 expression in CD8+T cells was associated with exhausted cells (PD-1+Tim-3+) and weak expression of granzyme B and perforin. T cell–associated cytokine profiling revealed a negative association between BCL-2+ T cells and T cell activation. Decreased frequencies and recovery functions of BCL-2+T cells were observed in CLL patients in complete remission after treatment with venetoclax.ConclusionBCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion.

Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia

BackgroundChronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB).MethodsA retrospective chart review was conducted for patients treated with obinutuzumab from January 1, 2014 to December 31, 2017 at CCMB. A minimum data set was extracted for patients treated with other front-line therapies. Descriptive statistics were used to evaluate patient demographics, toxicity, duration and dosing of obinutuzumab treatment. Kaplan–Meier curves were used to evaluate time-to-next-treatment (TTNT), overall survival (OS) and PFS for patients treated with obinutuzumab. A multivariable logistic regression model was used to investigate associations between infusion related reactions (IRRs) and age at treatment, pre-treatment lymphocyte count, cumulative illness rating scale (CIRS) and receipt of prior chemotherapy.ResultsForty seven percent of patients receiving frontline therapy received chlorambucil and obinutuzumab. Sixty-seven patients were treated with obinutuzumab and consisted of 36 males (53.7%) and 31 females (46.3%) with 29 patients (43.3%) over age 75 years. Rates of grade 3 and 4 obinutuzumab IRRs were lower (6%) compared to the CLL11 clinical trial (20%) due to local practices including slower infusion rates and using chlorambucil before starting obinutuzumab treatment. Many patients had difficulty tolerating the full dosage of chlorambucil. Only 26 patients (38.8%) had their dose of chlorambucil escalated to the full dose of 0.5 mg/kg. In addition, only 18 patients (26.9%) received all doses of obinutuzumab and all 12 doses of chlorambucil.ConclusionsIn summary, first dose infusion reactions with obinutuzumab can be markedly reduced by using chlorambucil to decrease the lymphocyte count before obinutuzumab and by using a very slow initial obinutuzumab infusion rate. Modifications in chlorambucil dosing and obinutuzumab administration can improve tolerance without significant loss in efficacy.

Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia

BackgroundChronic lymphocytic leukemia (CLL) is the most frequent, and still incurable, form of leukemia in the Western World. It is widely accepted that cancer results from an evolutionary process shaped by the acquisition of driver mutations which confer selective growth advantage to cells that harbor them. Clear examples are missense mutations in classic RAS genes (KRAS, HRAS and NRAS) that underlie the development of approximately 13% of human cancers. Although autonomous B cell antigen receptor (BCR) signaling is involved and mutations in many tumor suppressor genes and oncogenes have been identified, an oncogenic driver gene has not still been identified for CLL.MethodsConditional knock-in mice were generated to overexpress wild type RRAS2 and prove its driver role. RT-qPCR analysis of a human CLL sample cohort was carried out to measure RRAS2 transcriptional expression. Sanger DNA sequencing was used to identify a SNP in the 3’UTR region of RRAS2 in human CLL samples. RNAseq of murine CLL was carried out to identify activated pathways, molecular mechanisms and to pinpoint somatic mutations accompanying RRAS2 overexpression. Flow cytometry was used for phenotypic characterization and shRNA techniques to knockdown RRAS2 expression in human CLL.ResultsRRAS2 mRNA is found overexpressed in its wild type form in 82% of the human CLL samples analyzed (n = 178, mean and median = 5-fold) as well as in the explored metadata. A single nucleotide polymorphism (rs8570) in the 3’UTR of the RRAS2 mRNA has been identified in CLL patients, linking higher expression of RRAS2 with more aggressive disease. Deliberate overexpression of wild type RRAS2 in mice, but not an oncogenic Q72L mutation in the coding sequence, provokes the development of CLL. Overexpression of wild type RRAS2 in mice is accompanied by a strong convergent selection of somatic mutations in genes that have been identified in human CLL. R-RAS2 protein is physically bound to the BCR and mediates BCR signals in CLL.ConclusionsThe results indicate that overexpression of wild type RRAS2 is behind the development of CLL.

The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019

BackgroundChronic lymphocytic leukemia (CLL) is the most prevalent subtype of leukemia in Western countries, causing a substantial health burden on patients and society. Comprehensive evaluation of the epidemiological characteristics of CLL is warranted, especially in the current context of global population aging. The main objective of this study is evaluating the disease burden of CLL at global, regional, and national levels from 1990 to 2019. As secondary objectives, we studied the influence of demographic factors and performed risk factor analysis. We hope this study could provide evidence for the evaluation of the effectiveness of previous prevention strategies and the formulation of future global health policies.ResultsBased on data of CLL between 1990 to 2019 from the Global Burden of Disease (GBD) study 2019, we depicted the age, gender, and regional structure of the CLL burden population and described the impact of social development on the disease burden of CLL. The distribution and changing trends of attributable risk factors were also investigated. The global burden of CLL has increased dramatically. A high incidence has been achieved in males and elder people. Countries and territories with high social-demographic index (SDI) tended to have higher global burden than low-SDI region. Of risk factors, high body mass index and smoking were the major contributors for CLL-related mortality and disability adjusted life-years (DALYs).ConclusionIn summary, the global CLL burden continues to rise over the past 30 years. The relocation of medical resource should be considered on a global scale.Graphical