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Objective: Ibrutinib treatment is associated with cardiovascular side effects, in particular atrial fibrillation (AF) and hypertension, as well as increased risk of bleeding. Here, we aimed at describing the incidence of these events during long-term follow-up in patients with chronic lymphocytic leukemia treated outside clinical trials as well as identifying clinical factors predictive of developing AF. Additionally, other reasons for treatment withdrawal were analyzed., Methods: The study was retrospective, data were collected from medical records., Results: A total of 134 patients were identified. Median follow-up was 32 months (range 3-103) and median duration of ibrutinib treatment was 26 months (range 1-103). Of 110 patients with no prior history of AF, 24.5% were diagnosed during treatment. Newly diagnosed or worsening of pre-existing hypertension occurred in 15.7%. Sixty-six % of the patients experienced bleeding events, of which 7.5% grade 3-4. Treatment discontinuation and dose reduction occurred in 68% and 47% of the patients, respectively, mostly due to toxicity., Conclusions: The incidence of AF was high and at a median follow-up of 2.5 years, two-thirds of the patients discontinued treatment mostly due to bleeding and infections. Treatment-related toxicity of any grade should be regarded as a concern of prolonged ibrutinib therapy., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Objective: To determine the frequency of TP53 mutation at diagnosis of B-cell Chronic Lymphocytic Leukaemia (B-CLL) in Pakistani patients, and to investigate whether lymphocyte doubling time (LDT) of less than 1 year could be used as a surrogate marker for TP53 mutation., Study Design: A cross-sectional descriptive study. Place and Duration of the Study: Department of Haematology, Liaquat National Hospital, from January 2020 to December 2022., Methodology: Patients diagnosed with B-CLL based on the criteria set by International Workshop on Chronic Lymphocytic Leukaemia were included in the study. Clinico-haematological parameters were recorded, and TP53 mutation analysis was performed by fluorescence in situ hybridisation. Patients were followed every 3-6 months after diagnosis with the recent complete blood count (CBC) reports to record CBC parameters and calculate LDT., Results: A total of 128 B-CLL cases were evaluated, with a mean age of 62 years. Among these cases, 10 patients (7.8%) tested positive for TP53 mutation, while 118 patients (92.2%) tested negative. During the follow-up period, 26 patients were lost to follow-up, with only one patient from the TP53 positive group. In the TP53 positive group, 55.6% (n=5/9) patients had an LDT of less than 1 year, indicating aggressive disease compared to 30.1% (n=28/93) patients in the negative group (p <0.1)., Conclusion: TP53 mutations may be associated with shorter LDT, indicating aggressive disease. Further research is needed to fully comprehend the relationship between TP53 mutation and LDT in B-CLL., Key Words: TP53 mutation, B-Cell chronic lymphocytic leukaemia (B-CLL), Lymphocyte doubling time (LDT).

Introduction: Measurable residual disease (MRD) is becoming increasingly important in the chronic lymphocytic leukemia (CLL) context. It is of independent prognostic significance in terms of favorable progression-free and overall survival. The standardized methods used to assess CLL MRD are based on flow cytometry and real-time quantitative PCR. We here present a nine-color assay for CLL MRD with the ROR-1 marker antigen as recommended by the European Research Initiative (ERIC) on CLL; the sensitivity is at least 10-5., Materials and Methods: We used 54 samples to develop a new principal component analysis (PCA) method based on the Kaluza© "radar" presentation mode. We used a Navios flow cytometer (Beckman Coulter©)., Results: We confirmed the linearity of our method over more than five dilutions. The specificity limit was 1.3×10-6 and the lower limit of detection was 3.6×10-6. Compared to the Boolean method, the sensitivity, specificity, and positive and negative predictive values of our PCA method were 100%. When MRD was detectable, PCA and Boolean assays were in agreement (linear regression, R2 = 0.99)., Conclusion: We developed a new PCA-based method for detection of CLL MRD. Our method is comparable to that of the consensus method in terms of sensitivity, and it is also much easier and faster.

Purpose of Review: The treatment paradigm of chronic lymphocytic leukemia (CLL) has dramatically changed with the advent of novel targeted agents over the past decade. Richter transformation (RT), or the development of an aggressive lymphoma from a background of CLL, is a well-recognized complication of CLL and carries significantly poor clinical outcomes. Here, we provide an update on current diagnostics, prognostication, and contemporary treatment of RT., Recent Findings: Several genetic, biologic, and laboratory markers have been proposed as candidate risk factors for the development of RT. Although a diagnosis of RT is typically suspected based on clinical and laboratory findings, tissue biopsy is essential for histopathologic confirmation of diagnosis. The standard of care for RT treatment at this time remains chemoimmunotherapy with the goal of proceeding to allogeneic stem cell transplantation in eligible patients. Several newer treatment modalities are being studied for use in the management of RT, including small molecules, immunotherapy, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy. The management of patients with RT remains a challenge. Ongoing trials show enormous promise for newer classes of therapy in RT, with the hope being that these agents can synergize, and perhaps supersede, the current standard of care in the near future., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Treatment of chronic lymphocytic leukemia (CLL) has dramatically evolved over the last decades thanks to the introduction of targeted therapies. We aimed to describe retrospectively the evolution in the frontline prescription in the CLL patients from our institution. As a secondary objective, the impact of frontline therapy on the time-to-next-treatment (TTNT) and overall survival (OS). After a median of 6.4 years (0.1-36.4) of follow-up from diagnosis, 323 of 780 CLL patients (41.4%) required therapy. Alkylating agents in monotherapy (chlorambucil) were the most used until 2012, and from then, chemoimmunotherapy. Since 2018, targeted therapies were the most common therapeutic strategy (74.1%). Patients who received targeted therapies had significantly longer TTNT compared to other regimens. In the multivariable analyses, mutated IGHV genes targeted therapies and chemoimmunotherapy regimens were related to longer TTNT, and sex female, age younger than 65, and mutated IGHV genes were associated with better OS.

Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043., (© 2023 by The American Society of Hematology.)

Background: B-Cell Lymphoproliferative Disorders (B-LPDs) are a group of heterogenous disorders characterised by the accumulation of B-cells in peripheral blood, bone marrow, lymph nodes and spleen. They have a variable disease course and outcome and many share similar features making differential diagnosis challenging. Therefore, accurate diagnosis is fundamental in particular for determining treatment options. Immunophenotyping by flow cytometry plays a crucial role in the diagnosis of B-LPDs. However, overlapping immunophenotyping patterns exist and the use of novel monoclonal antibodies has become increasingly important in immunophenotyping analysis. More recently differential expression of CD200 has been reported in various B-LPDs and that CD200 may improve the differentiation between chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). In this study CD200 expression is evaluated in different B-LPDs. Methods: A total of 100 samples were collected and analysed by immunophenotyping flow cytometry over a period of 1 year (2017-2018), by a panel of monoclonal antibodies including CD200. The percentage of CD200 and its expression intensity was evaluated and compared between different groups of B-LPDs. Results: All of the 50 cases of CLL expressed CD200 with moderate to bright intensity, 6 MCL cases lacked the expression of CD200. Furthermore, all 5 cases of hairy cell leukaemia (HCL) expressed CD200. Out of all B-LPDs evaluated, CD200 expression in HCL cases was noted to be the brightest. The other 39 cases were not found to be B-LPDs. Conclusion: CD200 has an important role in differentiating CLL from MCL, HCL has a consistent bright expression of CD200. By adding CD200 to the combinations of markers in routine testing panel, Immunophenotyping by flow cytometry can be an effective tool in the diagnosis of B-LPDs especially in cases with atypical immunophenotyping pattern. Our result support that CD200 can be added to routine testing panel as it is useful in differentiating them., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Al-Zubaidi and Hughes.)

Background/aims: Little attention is paid to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in Korea due to the rarity of the disease. With its rising incidence, we aimed to evaluate recent changes in treatment patterns and survival outcomes of patients with CLL/SLL., Methods: A total of 141 patients diagnosed with CLL/SLL between January 2010 and March 2020 who received systemic therapy were analyzed in this multicenter retrospective study., Results: The median patient age was 66 years at diagnosis, and 68.1% were male. The median interval from diagnosis to initial treatment was 0.9 months (range: 0-77.6 months), and the most common treatment indication was progressive marrow failure (50.4%). Regarding first-line therapy, 46.8% received fludarabine, cyclophosphamide, plus rituximab (FCR), followed by chlorambucil (19.9%), and obinutuzumab plus chlorambucil (GC) (12.1%). The median progression-free survival (PFS) was 49.3 months (95% confidence interval [CI], 32.7-61.4), and median overall survival was not reached (95% CI, 98.4 mo- not reached). Multivariable analysis revealed younger age (≤ 65 yr) (hazard ratio [HR], 0.46; p < 0.001) and first-line therapy with FCR (HR, 0.64; p = 0.019) were independently associated with improved PFS. TP53 aberrations were observed in 7.0% (4/57) of evaluable patients. Following reimbursement, GC became the most common therapy among patients over 65 years and second in the overall population after 2017., Conclusion: Age and reimbursement mainly influenced treatment strategies. Greater effort to apply risk stratifications into practice and clinical trials for novel agents could help improve treatment outcomes in Korean patients.

Aim: Chronic lymphocytic leukemia (CLL) is a highly heterogenous hemopathy. Genetic stratification of CLL patients has important prognostic and therapeutic values - mainly immunoglobulin heavy chain variable region gene ( IGHV ) mutational status and the presence of cytogenetic abnormalities. The genetics of CLL in Lebanon is scarcely described in the literature. Patients & methods: In this work, we studied the genetic biomarkers of 312 Lebanese CLL patients. Results: Prominent IGHV genes were IGHV4-34 , IGHV1-69 and IGHV3-30 ; and CLL #1 and #5 presented major subsets. Some similarities as well as major differences were highlighted when comparing our data with previously published data. Conclusion: The distribution of IGHV alleles in our series differed from previously described distributions, suggesting involvement of antigenic selection and regional variables in CLL pathogenesis.

Objectives: To assess the spectrum and clinico-haematological profile of chronic lymphoproliferative disorders in patients presenting with lymphocytosis., Methods: The cross-sectional, retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data related to cases of bone marrow aspirate and trephine from January to November 2020. Patients for whom the bone marrow was done for lymphocytosis were studied for the presence of lymphoproliferative disorders, sub-types and patients'characteristics. The diagnosis and classification were based on the World Health Organisation criteria for tumours of haematopoietic and lymphoid tissues. Data was analysed using SPSS 21., Results: Of the 3,334 bone marrow specimenstested, 103(3%) were related to lymphocytosis. Of these, 84(82%) were diagnosed with lymphoproliferative disorders, while diagnosisremained undetermined in 19(18%) cases. Male:female ratio was 3.6:1 and median age was 60 years (range: 21-85 years). Constitutional symptoms were found in 61(73%) patients. Median absolute lymphocyte count was 45x109/L (range: 5.3-480). All 84(100%) patients were classified as B-cell lymphoproliferative disorder. Chronic lymphocytic leukaemia wasthe most common form, 61(73%), and 31(51%) of them presented with advanced stage disease., Conclusions: A huge majority of patients presenting with lymphocytosis had underlying lymphoproliferative disorders of which B-cell chronic lymphocytic leukaemia was found to be the most common.

Patients with chronic lymphocytic leukaemia can have an indolent or aggressive clinical course. Current guidelines recommend performing immunoglobin heavy chain testing, four-colour probe fluorescence in situ hybridization testing and mutational analysis for TP53 mutations as part of routine prognostic testing to determine if high-risk genomic features are present. Rigolin et al. demonstrate that genomic microarray testing can identify high-risk genomic features in patients deemed low risk by current testing standards and is independently associated with shorter time to first treatment in their cohort. Commentary on: Rigolin et al. Additional lesions identified by genomic microarrays are associated with an inferior outcome in low-risk chronic lymphocytic leukaemia patients. Br J Haematol 2023;202:953-959., (© 2023 The Author. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in Australia and New Zealand (ANZ). Considerable changes to diagnostic and management algorithms have occurred within the last decade. The availability of next-generation sequencing and measurable residual disease assessment by flow cytometry allow for advanced prognostication and response assessments. Novel therapies, including inhibitors of Bruton's tyrosine kinase (BTKi) and B-cell lymphoma 2 (BCL2) inhibitors, have transformed the treatment landscape for both treatment-naïve and relapsed/refractory disease, particularly for patients with high-risk genetic aberrations. Recommendations regarding appropriate supportive management continue to evolve, and special considerations are required for patients with CLL with respect to the global SARS-CoV-2 pandemic. The unique funding and treatment environments in Australasia highlight the need for specific local guidance with respect to the investigation and management of CLL. This consensus practice statement was developed by a broadly representative group of ANZ experts in CLL with endorsement by peak haematology bodies, with a view to providing this standardised guidance., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Session 3 of the lymphoma workshop of the XXI joint meeting of the European Association for Haematopathology and the Society for Hematopathology took place in Florence, Italy, on September 22, 2022. The topics of this session were splenic and nodal marginal zone lymphomas, transformation in marginal zone lymphomas, and pediatric nodal marginal zone lymphomas and their differential diagnosis as well as related entities. Forty-two cases in these categories were submitted to the workshop, including splenic lymphomas (marginal zone and diffuse red pulp lymphomas), transformed marginal zone lymphomas (splenic and nodal), nodal marginal zone lymphomas with increased TFH-cells, and pediatric nodal marginal zone lymphomas. The case review highlighted some of the principal problems in the diagnosis of marginal zone lymphomas, including the difficulties in the distinction between splenic marginal zone lymphoma, splenic diffuse red pulp lymphoma, and hairy cell leukemia variant/splenic B-cell lymphoma with prominent nucleoli which requires integration of clinical features, immunophenotype, and morphology in blood, bone marrow, and spleen; cases of marginal zone lymphoma with markedly increased TFH-cells, simulating a T-cell lymphoma, where molecular studies (clonality and mutation detection) can help to establish the final diagnosis; the criteria for transformation of marginal zone lymphomas, which are still unclear and might require the integration of morphological and molecular data; the concept of an overlapping spectrum between pediatric nodal marginal zone lymphoma and pediatric-type follicular lymphoma; and the distinction between pediatric nodal marginal zone lymphoma and "atypical" marginal zone hyperplasia, where molecular studies are mandatory to correctly classify cases., (© 2023. The Author(s).)

In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), research is focused on developing fixed-duration strategies to improve long-term outcomes while sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach in which after obinutuzumab-ibrutinib induction for 9 months, patients (n = 10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n = 115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 84 of 135 (62.2%) patients enrolled achieved CR with a BM MRD <0.01%. Here, we report follow-up at median 63 months. Peripheral blood (PB) MRD was assessed 6 monthly beyond the end of treatment using a highly sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in the PB MRD status were apparent per to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Opinion Statement: Treatment of chronic lymphocytic leukemia (CLL) has evolved dramatically during the last decade, from chemoimmunotherapy (CIT)-based therapies to newer B-cell receptor (BCR) signaling targeting agents, which are sometimes given as continuous schemes. Response to treatment was traditionally defined according to clinical variables designed to assign a response category. Interest in assessing for deeper responses in CLL by the means of measurable residual disease (MRD) testing has been the subject of research during the last several years. Analyses and sub-analyses of clinical trials have shown that achieving undetectable MRD (uMRD) in CLL is an important prognostic factor. In this review, we summarize the available evidence about MRD in CLL, from the various assays available for measurement, the compartment to test, the impact of reaching uMRD according to the treatment regimen, and the results of fixed duration treatment guided by MRD trials. Finally, we summarize how MRD can be incorporated in clinical practice and how it may guide fixed duration treatment in the future should evidence continue to accumulate in that direction., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Age-related comorbid conditions are exceedingly common in patients with chronic lymphocytic leukemia (CLL). As the prevalence of type 2 diabetes (T2D) is predicted to double during the next two decades, a better understanding of the interplay between CLL and T2D is of increasing importance. In this study, analyses were performed in parallel in two separate cohorts, based on Danish national registers and the Mayo Clinic CLL Resource. The primary outcomes were overall survival (OS) from time of CLL diagnosis, OS from time of treatment, and time to first treatment (TTFT), studied using Cox proportional hazard regression analysis and Fine-Gray regression analysis. In the Danish CLL cohort, the prevalence of T2D was 11%, in the Mayo CLL cohort, it was 12%. Patients with CLL and T2D had shorter OS both from time of diagnosis and from first-line treatment for were less likely to receive treatment for CLL compared with patients with CLL and without T2D. The increased mortality was largely driven by an increased risk of death due to infections, especially in the Danish cohort. The findings of this study emphasize a substantial subgroup of CLL patients with co-occurring T2D with an inferior prognosis and a possible unmet treatment need requiring additional interventions and further research., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Undetectable measurable residual disease (MRD) is associated with favourable clinical outcomes in chronic lymphocytic leukaemia (CLL). While assessment is commonly performed using multiparameter flow cytometry (MFC), this approach is associated with limitations including user bias and expertise that may not be widely available. Implementation of unsupervised clustering algorithms in the laboratory can address these limitations and have not been previously reported in a systematic quantitative manner. We developed a computational pipeline to assess CLL MRD using FlowSOM. In the training step, a self-organising map was generated with nodes representing the full breadth of normal immature and mature B cells along with disease immunophenotypes. This map was used to detect MRD in multiple validation cohorts containing a total of 456 samples. This included an evaluation of atypical CLL cases and samples collected from two different laboratories. Computational MRD showed high correlation with expert analysis (Pearson's r > 0.99 for typical CLL). Binary classification of typical CLL samples as either MRD positive or negative demonstrated high concordance (>98%). Interestingly, computational MRD detected disease in a small number of atypical CLL cases in which MRD was not detected by expert analysis. These results demonstrate the feasibility and value of automated MFC analysis in a diagnostic laboratory., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

The GIMEMA phase II LLC1518 VERITAS trial investigated the efficacy and safety of front-line, fixed-duration venetoclax and rituximab (VenR) in combination in young (≤65 years), fit patients with chronic lymphocytic leukemia and unmutated IGHV and/or TP53 disruption. Treatment consisted of the venetoclax ramp-up, six monthly courses of the VenR combination, followed by six monthly courses of venetoclax as a single agent. A centralized assessment of minimal residual disease (MRD) was performed by allele-specific oligonucleotide polymerase chain reaction assay on the peripheral blood and bone marrow at the end of treatment (EOT) and during the follow-up. The primary endpoint was the complete remission rate at the EOT. Seventy-five patients were enrolled; the median age was 54 years (range, 38-65), 96% had unmutated IGHV, 12% had TP53 disruption, and 4% had mutated IGHV with TP53 disruption. The overall response rate at the EOT was 94.7%, with a complete remission rate of 76%. MRD was undetectable in the peripheral blood of 69.3% of patients and in the bone marrow of 58.7% of patients. The 12-month MRD-free survival in the 52 patients with undetectable MRD in the peripheral blood at the EOT was 73.1%. After a median follow-up of 20.8 months, no cases of disease progression were observed. Three patients had died, two due to COVID-19 and one due to tumor lysis syndrome. The first report of the VERITAS study shows that front-line VenR was associated with a high rate of complete remissions and durable response with undetectable MRD in young patients with chronic lymphocytic leukemia and unfavorable genetic characteristics. ClinicalTrials.gov identifier: NCT03455517.

The era of AI-based methods to improve flow cytometry diagnostics in haematology is now at the beginning. The study by Nguyen and colleagues explored an emerging machine learning approach to assess phenotypic MRD in chronic lymphocytic leukaemia patients, showing that such AI-driven computational analysis may represent a robust and feasible tool for advanced diagnostics of haematological malignancies. Commentary on: Nguyen et al. Computational flow cytometry provides accurate assessment of measurable residual disease in chronic lymphocytic leukaemia. Br J Haematol 2023;202:760-770., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

TP53 aberrations, including mutations and deletion of 17p13, are important adverse prognostic markers in chronic lymphocytic leukemia (CLL) but are less studied in high count monoclonal B-cell lymphocytosis (HCMBL), an asymptomatic pre-malignant stage of CLL. Here we estimated the prevalence and impact of TP53 aberrations in 1,230 newly diagnosed treatment-naïve individuals (849 CLL, 381 HCMBL). We defined TP53 state as: wild-type (no TP53 mutations and normal 17p), single-hit (del(17p) or one TP53 mutation), or multi-hit (TP53 mutation and del(17p), TP53 mutation and loss of heterozygosity, or multiple TP53 mutations). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time to first treatment and overall survival by TP53 state. We found 64 (7.5%) CLL patients and 17 (4.5%) HCMBL individuals had TP53 mutations with variant allele fraction >10%. Del(17p) was present in 58 (6.8%) of CLL and 11 (2.9%) of HCMBL cases. Most individuals had wild-type (N=1,128, 91.7%) TP53 state, followed by multi-hit (N=55, 4.5%) and then single-hit (N=47, 3.8%) TP53 state. The risk of shorter time to therapy and death increased with the number of TP53 abnormalities. Compared to wild-type patients, multi-hit patients had 3-fold and single-hit patients had 1.5-fold increased risk of requiring therapy. Multi-hit patients also had 2.9-fold increased risk of death compared to wild-type. These results remained stable after accounting for other known poor prognostic factors. Both TP53 mutations and del(17p) may provide important prognostic information for HCMBL and CLL that would be missed if only one were measured., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Adult T-cell leukemia/lymphoma (ATLL) has aggressive clinical behaviors, and improving its prognosis is a great challenge. A disease progression model from asymptomatic human T-cell leukemia virus type 1 carrier to aggressive-type ATLL has been proposed, and indolent ATLL comprising a smoldering or favorable chronic type is located at the midpoint. Even the most favorable smoldering type has a 4-year overall survival rate of <60%. Although watchful waiting is pervasive in patients with indolent ATLL, early therapeutic intervention is discussed among hematologists. Indolent ATLL was once termed T-cell-derived chronic lymphocytic leukemia (CLL). Unlike indolent ATLL, several molecular-targeted agents at the initial treatment have dramatically improved CLL prognosis. Recent studies on CLL have revealed a similar progression model involving premalignant monoclonal B-cell lymphocytosis (MBL). In particular, individuals with high-count MBL have an increased lymphoma risk. Considering the unsatisfactory long-term prognosis of indolent ATLL, further treatment strategies, including precision medicine, are warranted., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Chronic lymphocytic leukemia (CLL) is a malignant blood disorder in which there is an excess of white blood cells (lymphocytes) in blood and lymphoid tissues. CLL patients experience different clinical behaviors with diversity in disease course and outcome. Accordingly, prognostic markers are crucial for employing appropriate therapy protocols. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor. Soluble CD163 (sCD163) is an emerging prognostic player in the field of hematopoietic neoplasms. This study aimed to assess the prognostic potential of sCD163 as a serological marker in CLL. The study included 41 CLL patients and 44 apparently normal healthy volunteers as controls. Expression of CD38 and cytoplasmic ZAP 70 in CLL cells was assessed using flow cytometry. Beta 2 microglobulin (B2M), sCD23, and sCD163 serological markers were measured by ELISA. Serum levels of sCD163 were statistically significantly higher in CLL cases compared to controls (p=0.000). sCD163 levels were positively correlated with absolute lymphocyte count, sCD23, and B2M levels (p= 0.027, p=0.01, and p=0.004, respectively). In conclusion, levels of sCD163 in CLL is a promising prognostic tool for evaluating disease progression., (Copyright© by the Egyptian Association of Immunologists.)

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.

Acalabrutinib monotherapy (A) and acalabrutinib plus obinutuzumab (A + O) demonstrated improved efficacy and safety versus chlorambucil plus obinutuzumab (C + O) among treatment-naive patients with chronic lymphocytic leukaemia (CLL) in the ELEVATE-TN trial. The relative risk-benefit at a median follow-up of 47 months was assessed using Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) methodology. Patient data were partitioned into 3 states: time with toxicity (TOX); time without symptoms or toxicity (TWiST); and time after relapse (REL). Mean Q-TWiST was estimated by summing the mean time in each state, multiplied by its respective utility weight. Patients receiving A or A + O experienced significantly longer Q-TWiST versus C + O when toxicity was defined as grade 3-4 adverse events (AEs) (41.79 vs 34.56 months; 42.07 vs 34.56 months) and grade 2-4 AEs (35.07 vs 30.64 months; 34.21 vs 30.64 months). Overall, patients with treatment-naive CLL treated with A or A + O experienced significant gains in Q-TWiST compared with C + O.

The comprehensive epidemiology and global disease burdens reported recently suggest that chronic lymphocytic leukemia (CLL) constitutes 25-30% of leukemias thus being the most common leukemia subtype. However, there is an insufficient presence of artificial intelligence (AI)-based techniques for CLL diagnosis. The novelty of this study is in the investigation of data-driven techniques to leverage the intricate CLL-related immune dysfunctions reflected in routine complete blood count (CBC) alone. We used statistical inferences, four feature selection methods, and multistage hyperparameter tuning to build robust classifiers. With respective accuracies of 97.05%, 97.63%, and 98.62% for Quadratic Discriminant Analysis (QDA), Logistic Regression (LR), and XGboost (XGb)-based models, CBC-driven AI methods promise timely medical care and improved patient outcome with lesser resource usage and related cost.

Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet need. Though Bruton tyrosine kinase (BTK) and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL on ibrutinib (49 relapsing after an initial response and 49 still responding after ≥1 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital polymerase chain reaction (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32 of 49 relapsing cases (65%) carried at least 1 hotspot BTK and/or PLCG2 mutation(s); in 6 of 32, BTK mutations were only detected by ddPCR (variant allele frequency [VAF] 0.1% to 1.2%). BTK/PLCG2 mutations were also identified in 6 of 49 responding patients (12%; 5/6 VAF <10%), of whom 2 progressed later. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, whereas BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n = 11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut and BTKwt relapsing cases, and ibrutinib treatment did not favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

For patients with non-Hodgkin lymphoma (NHL), formal comorbidity assessment is recommended but is rarely conducted in routine practice. A simple, validated measure of comorbidities that standardizes their assessment could improve adherence to guidelines. We previously constructed the 3-factor risk estimate scale (TRES) among patients with chronic lymphocytic leukemia (CLL). Here, we investigated TRES in multiple NHL subtypes. In the surveillance, epidemiology, and end results-Medicare database, patients with NHL diagnosed from 2008 to 2017 were included. Upper gastrointestinal, endocrine, and vascular comorbidities were identified using ICD-9/ICD-10 codes to assign TRES scores. Patient characteristic distributions were compared using χ2 or t test. Association of mortality and TRES score was assessed using Kaplan-Meier and multivariable Cox regression model for competing risk. A total of 40 486 patients were included in the study. Median age was 77 years (interquartile range [IQR], 71-83 years). The most frequent NHL subtypes were CLL (28.2%), diffuse large B-cell (27.6%), and follicular lymphoma (12.6%). Median follow-up was 33 months (IQR, 13-60 months). TRES was low, intermediate, and high in 40.8%, 37.0%, and 22.2% of patients, corresponding to median overall survival (OS) of 8.2, 5.3, and 2.9 years (P < .001), respectively. TRES was associated with OS in all NHL subtypes. In multivariable models, TRES was associated with inferior OS and NHL-specific survival. TRES is clinically translatable and associated with OS and lymphoma-specific survival in older adults with NHL., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is a heterogeneous disease with variable patient outcomes. A multidisciplinary technical evaluation, including flow cytometry, immunohistochemistry, molecular and cytogenetic analyses, can comprehensively characterize a patient's leukemia at diagnosis, identify important prognostic biomarkers, and track measurable residual disease; all of which can impact patient management. This review highlights the key concepts, clinical significance, and main biomarkers detectable with each of these technical approaches; the contents are a helpful resource for medical practitioners involved in the workup and management of patients with CLL., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Session 3 of the 2021 Workshop of the Society for Hematopathology/European Association for Haematopathology examined progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and B-cell prolymphocytic leukemia (B-PLL)., Methods: Thirty-one cases were reviewed by the panel. Additional studies such as immunohistochemistry and molecular genetic testing, including whole-exome sequencing and expression profiling, were performed in select cases., Results: Session 3 included 27 CLL/SLL cases and miscellaneous associated proliferations, 3 cases of B-PLL, and 1 case of small B-cell lymphoma. The criteria for -accelerated CLL/SLL are established for lymph nodes, but extranodal disease can be diagnostically challenging. Richter transformation (RT) is a broad term and includes true transformation from original CLL/SLL clone(s) and clonally unrelated neoplasms. The morphologic, immunophenotypic, and genetic spectrum is diverse with classical and highly unusual examples. T-cell proliferations can also be encountered in CLL/SLL. B-cell prolymphocytic leukemia is a rare, diagnostically challenging disease due to its overlaps with other lymphoid neoplasms., Conclusions: The workshop highlighted complexity of progression and transformation in CLL/SLL and B-PLL, as well as diagnostic caveats accompanying heterogeneous presentations of RT and other manifestations of disease progression. Molecular genetic studies are pivotal for diagnosis and determination of clonal relationship, and to predict response to treatment and identify resistance to targeted therapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Somatic hypermutation status of the IGHV gene is essential for treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Unlike the conventional low-throughput method, assessment of somatic hypermutation by next-generation sequencing (NGS) has potential for uniformity and scalability. However, it lacks standardization or guidelines for routine clinical use. We critically assessed the performance of an amplicon-based NGS assay across 458 samples. Using a validation cohort (35 samples), the comparison of two platforms (Ion Torrent versus Illumina) and two primer sets [leader versus framework region 1 (FR1)] in their ability to identify clonotypic IGHV rearrangement(s) revealed 97% concordance. The mutation rates were identical by both platforms when using the same primer set (FR1), whereas a slight overestimation bias (+0.326%) was found when comparing FR1 with leader primers. However, for nearly all patients this did not affect the stratification into mutated or unmutated categories, suggesting that use of FR1 may provide comparable results if leader sequencing is not available and allowing for a simpler NGS laboratory workflow. In routine clinical practice (423 samples), the productive rearrangement was successfully detected by either primer set (leader, 97.7%; FR1, 94.7%), and a combination of both in problematic cases reduced the failure rate to 1.2%. Higher sensitivity of the NGS-based analysis also detected a higher frequency of double IGHV rearrangements (19.1%) compared with traditional approaches., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Examine physical function and T-cell phenotype in patients with chronic lymphocytic leukemia (CLL) before and after a physical activity (PA) intervention., Methods: Physical function measures and blood samples were collected from CLL patients (Rai stage 0-4, 50% receiving targeted therapy, N = 24) enrolled in a 16-week intervention of at-home aerobic and/or resistance exercise. Flow cytometry characterized T-cells in cryopreserved peripheral blood cells. Wilcoxon signed-rank test compared physical function and T-cell phenotype at baseline and 16-weeks; Kendall's Tau assessed associations between variables., Results: Godin leisure-time PA score increased from baseline to 16-weeks (mean difference: 14.61, p < .01) and fatigue decreased (mean difference: 6.71, p < .001). At baseline, lower fatigue correlated with a lower proportion of CD8+ T-cells (τ = 0.32, p = .03) and cardiorespiratory fitness (CRF) inversely correlated with the percentage of PD-1+CD8+ T-cells (τ -0.31, p = .03). At 16-weeks, CRF inversely correlated with the proportion of PD-1+CD4+ T-cells (τ -0.34, p = .02). Reduced fatigue at 16-weeks correlated with an increased CD4:CD8 ratio (τ = 0.36, p = .02) and lower percentage of HLA-DR+PD-1+CD4+ T-cells (τ = -0.37, p = .01)., Conclusions: This intervention increased leisure-time PA and decreased fatigue in CLL patients. These changes correlated with an increased CD4:CD8 T-cell ratio and reduced proportion of T-cells subsets previously associated with poor outcomes in CLL patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02194387., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: little is known regarding the prognostic value of soluble CD200 (sCD200)in  chronic lymphocytic leukemia patients. Therefore, the objective of our study is  to address the prognostic value of sCD200 antigen concentration on  CLL patients outcome., Methods: Determination of  serum sCD200 was done using ELISA kit in 158 CLL patients at diagnosis  before start of therapy beside 21 healthy controls., Results: sCD200 concentration levels was significantly higher in CLL patients as compared to healthy controls.  High sCD200 was associated with poor prognostic markers (high expression of CD38+% and ZAP70+, high LDH, high risk Rai stages, unfavorable cytogenetic finding, time to first treatment (TTT) as well as patients outcome (P<0.001 for All). sCD200 at cut-off value ( 752.5 pg/ml) could predicts TTT with specificity 83.4%., Conclusion: Determination of sCD200 concentration levels at diagnosis could be used as a prognostic biomarker in CLL patients.

Ibrutinib has dramatically changed the treatment landscape for chronic lymphocytic leukemia (CLL) since its availability in British Columbia (BC), Canada in 2014. We analyzed patterns of use and real-world survival outcomes in 370 patients who received ibrutinib for first-line (1 L, n  = 35) and relapsed/refractory (R/R, n  = 335) CLL between 2014-2018 in BC. Dose reductions and interruptions were frequent in 32% and 27%, respectively. With a median follow-up of 27.6 months, 35% of patients discontinued ibrutinib, primarily for adverse events (AEs) rather than progressive disease. Over the course of treatment, 87% of patients experienced at least one adverse event. The 2-year overall survival (OS) and event-free survival (EFS) were excellent at 83.9% and 76.1%, respectively, with medians not reached. However, patients who discontinued ibrutinib had a median OS of 32.5 months and median EFS of only 3.8 months from time of discontinuation, highlighting the need to minimize toxicity in the real-world.

The monoclonal B-cell lymphocytosis (MBL) introduced as new entities in the 2008 WHO classification, are defined by circulating B-cell clone < 5.109/L without organomegaly and previous and/or simultaneous lymphoproliferative disorders. The MBL were subclassified in MBL CLL type (the most frequent), MBL atypical CLL type and MBL non-CLL type (rarely reported in literature). Here the clinic, cytologic, immunologic and genetic features of MBL non-CLL type were described from a series of 34 cases. As previously reported, present cases presented immunologic and genetic similarities to MZL and could be associated to the new proposed entity CBL-MZ (clonal B-cell lymphocytosis of marginal zone origin). In addition, few cases presented similarities to splenic diffuse red pulp lymphoma (SDRPL). In conclusion, according to the literature, MBL with non-CLL type (assimilated to CBL-MZ) may be a premalignant state of MZL and/or SDRPL.

Chilblain-like lesions (CLL) coinciding with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have been described in the literature. Available reviews of the literature suggest that CLL are associated with younger age, an equal sex ratio, negative testing for SARS-CoV-2, and mild to no extracutaneous manifestations (ECM) associated with COVID-19 infection. This systematic review aims to provide a summary of reports of CLL associated with the early SARS-CoV-2 pandemic in children to clarify the prevalence, clinical characteristics, and resolution outcomes of these skin findings. Sixty-nine studies, published between May 2020 and January 2022, met inclusion criteria and were summarized in this review, representing 1,119 cases of CLL. Available data showed a slight male predominance (591/1002, 59%). Mean age was 13 years, ranging from 0 to 18 years. Most cases had no ECM (682/978, 70%). Overall, 70/507 (14%) of patients tested positive for COVID-19 using PCR and/or serology. In the majority the clinical course was benign with 355/415 (86%) of cases resolving, and 97/269 (36%) resolving without any treatment. This comprehensive summary of pediatric CLL suggests these lesions are rarely associated with COVID-19 symptoms or test positivity.