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Summary: Despite significant progress in treating chronic lymphocytic leukaemia (CLL), resistance to therapy remains challenging. NOTCH1 activation, common in CLL, confers adverse prognosis. This study explores the impact of NOTCH1 signalling on venetoclax sensitivity in vitro. Although NOTCH1 activation minimally impaired the susceptibility of CLL cells to venetoclax, ex vivo cell competition studies reveal that cells with constitutive NOTCH1 activation outgrew their wild‐type counterparts in the presence of ongoing venetoclax exposure. Our findings suggest that while NOTCH1 activation is insufficient to confer venetoclax refractoriness, there is enhanced potential for cells with NOTCH1 activation to escape and thus become fully resistant to venetoclax. [ABSTRACT FROM AUTHOR]

Abstract In chronic lymphocytic leukaemia (CLL), comorbidities assessed by the CLL comorbidity index (CLL-CI) have been associated with outcomes in Western cohorts. We conducted a retrospective analysis of an unselected Middle Eastern cohort of newly diagnosed CLL patients seen at the Kuwait Cancer Control Center (n = 300). Compared to Western studies, these Middle Eastern patients were diagnosed at a younger age (median of 59) and had a higher comorbidity burden (69% non-low risk CLL-CI). A higher CLL-CI score was independently associated with significantly shorter event-free survival and greater risk of death. Our analysis demonstrates that CLL-CI is a valuable tool for comorbidity assessment and prognostic influence in (relatively young) Middle Eastern CLL patients.

In chronic lymphocytic leukaemia (CLL), comorbidities assessed by the CLL comorbidity index (CLL-CI) have been associated with outcomes in Western cohorts. We conducted a retrospective analysis of an unselected Middle Eastern cohort of newly diagnosed CLL patients seen at the Kuwait Cancer Control Center (n = 300). Compared to Western studies, these Middle Eastern patients were diagnosed at a younger age (median of 59) and had a higher comorbidity burden (69% non-low risk CLL-CI). A higher CLL-CI score was independently associated with significantly shorter event-free survival and greater risk of death. Our analysis demonstrates that CLL-CI is a valuable tool for comorbidity assessment and prognostic influence in (relatively young) Middle Eastern CLL patients. [ABSTRACT FROM AUTHOR]

Summary: Large‐scale next‐generation sequencing (NGS) studies revealed extensive genetic heterogeneity, driving a highly variable clinical course of chronic lymphocytic leukaemia (CLL). The evolution of subclonal populations contributes to diverse therapy responses and disease refractoriness. Besides, the dynamics and impact of subpopulations before therapy initiation are not well understood. We examined changes in genomic defects in serial samples of 100 untreated CLL patients, spanning from indolent to aggressive disease. A comprehensive NGS panel LYNX, which provides targeted mutational analysis and genome‐wide chromosomal defect assessment, was employed. We observed dynamic changes in the composition and/or proportion of genomic aberrations in most patients (62%). Clonal evolution of gene variants prevailed over the chromosomal alterations. Unsupervised clustering based on aberration dynamics revealed four groups of patients with different clinical behaviour. An adverse cluster was associated with fast progression and early therapy need, characterized by the expansion of TP53 defects, ATM mutations, and 18p− alongside dynamic SF3B1 mutations. Our results show that clonal evolution is active even without therapy pressure and that repeated genetic testing can be clinically relevant during long‐term patient monitoring. Moreover, integrative NGS testing contributes to the consolidated evaluation of results and accurate assessment of individual patient prognosis. [ABSTRACT FROM AUTHOR]

Background: Metabolic dependencies of chronic lymphocytic leukaemia (CLL) cells may represent new personalized treatment approaches in patients harbouring unfavourable features. Methods: Here, we used untargeted metabolomics and lipidomics analyses to isolate metabolomic features associated with aggressive CLL and poor survival outcomes. We initially focused on profiles associated with overexpression of the adverse metabolic marker glycosyltransferase (UGT2B17) associated with poor survival and drug resistance. Results: Leukaemic B‐cell metabolomes indicated a significant perturbation in lipids, predominantly bio‐active sphingolipids. Expression of numerous enzyme‐encoding genes of sphingolipid biosynthesis pathways was significantly associated with shorter patient survival. Targeted metabolomics further exposed higher circulating levels of glucosylceramides (C16:0 GluCer) in CLL patients relative to healthy donors and an aggressive cancer biology. In multivariate analyses, C16:0 GluCer and sphinganine were independent prognostic markers and were inversely linked to treatment‐free survival. These two sphingolipid species function as antagonistic mediators, with sphinganine being pro‐apoptotic and GluCer being pro‐proliferative, tested in leukemic B‐CLL cell models. Blocking GluCer synthesis using ceramide glucosyltransferase inhibitors induced cell death and reduced the proliferative phenotype, which further sensitized a leukaemic B‐cell model to the anti‐leukaemics fludarabine and ibrutinib in vitro. Conclusions: Specific sphingolipids may serve as prognostic markers in CLL, and inhibiting enzymatic pathways involved in their biosynthesis has potential as a therapaeutic approach. [ABSTRACT FROM AUTHOR]

Summary: We explored the relevance of genomic microarrays (GM) in the refinement of prognosis in newly diagnosed low‐risk chronic lymphocytic leukaemia (CLL) patients as defined by isolated del(13q) or no lesions by a standard 4 probe fluorescence in situ hybridization (FISH) analysis. Compared to FISH, additional lesions were detected by GM in 27 of the 119 patients (22.7%). The concordance rate between FISH and GM was 87.4%. Discordant results between cytogenetic banding analysis (CBA) and GM were observed in 45/119 cases (37.8%) and were mainly due to the intrinsic characteristics of each technique. The presence of additional lesions by GM was associated with age > 65 years (p = 0.047), advanced Binet stage (p = 0.001), CLL‐IPI score (p < 0.001), a complex karyotype (p = 0.004) and a worse time‐to‐first treatment in multivariate analysis (p = 0.009). Additional lesions by GM were also significantly associated with a worse time‐to‐first treatment in the subset of patients with wild‐type TP53 and mutated IGHV (p = 0.025). In CLL patients with low‐risk features, the presence of additional lesions identified by GM helps to identify a subset of patients with a worse outcome that could be proposed for a risk‐adapted follow‐up and for early treatment including targeted agents within clinical trials. [ABSTRACT FROM AUTHOR]

Background: Alterations of plateletcrit and mean platelet volume (MPV) and pathogenesis of chronic lymphocytic leukaemia (CLL) have been linked to various inflammatory disorders. The prognostic impact of plateletcrit and MPV were evaluated. Methods: MPV and plateletcrit levels of both CLL and control group were compared and then in CLL patients, additional diseases, leukocyte count, platelet count, lactate dehydrogenase, Rai stage, progression-free and overall survival, mutations, if any, and chemotherapy, if any, were recorded. Then, the relationship between MPV and plateletcrit values and these parameters were evaluated in CLL patients. Results: Platelet and plateletcrit values were found to be significantly lower in CLL patients than the control group (p

Abstract Combination chemoimmunotherapy (CIT) consisting of anti-CD20 has improved the progression-free survival (PFS) and overall survival (OS) of patients with chronic lymphocytic leukaemia (CLL). We performed a comprehensive synthesis of prognostic factors in patients with CLL on combined CIT with anti-CD20 antibodies compared with standard chemotherapy alone or targeted therapy. We searched the MEDLINE and academic search complete electronic databases as well as clinicaltrials.gov (from inception up to 01 August 2022) for randomised controlled trials examining chemoimmunotherapy and targeted therapy in patients with CLL. The risk of bias and the quality of evidence was assessed using the quality in prognostic studies tool (QUIPS). A total of 10 prognostic factors were identified and evaluated in patients with CLL on anti-CD20 antibody-containing CIT. The predictive value of the following prognostic factors was confirmed and associated with poor patient outcomes; deletion 17p (HR = 3.39), Immunoglobulin heavy chain variable region gene mutation status (HR = 0.96) and β2-microglobulin (HR = 1.41). Conventional predictive factors may have retained prognostic value and could be useful in the stratification of patients who may be non-responsive to CIT. Trial registration: International Prospective Register of Systematic Reviews (PROSPERO) registry (CRD42021218997).

Hypocholesterolaemia is associated with elevated cancer risk and mortality, yet the relation between chronic lymphocytic leukaemia (CLL) and serum lipid profile remains unclear. Our study aims to evaluate the prognostic value of cholesterol levels in CLL and develop a prognostic nomogram that incorporates lipid metabolism. We enrolled 761 newly diagnosed CLL patients and separated them into either derivation (n = 507) or validation (n = 254) cohorts. The prognostic nomogram was constructed through multivariate Cox regression analyses, with performance evaluated using C-index, the area under the curve, calibration, and decision curve analyses. Decreased total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) at diagnosis were significantly associated with worse time to first treatment (TTFT) and cancer-specific survival (CSS), and simultaneously, low HDL-C with low LDL-C was identified as an independent prognostic indicator for both TTFT and CSS. CLL patients achieving complete or partial remission post-chemotherapy had significantly increased TC, HDL-C, and LDL-C levels compared with the baseline, and post-therapeutic HDL-C and LDL-C elevation correlated with favourable survival. The prognostic nomogram augmenting the CLL international prognostic index with low cholesterol levels yielded higher predictive accuracy and discrimination capacity for both 3-year and 5-year CSS. In conclusion, cholesterol profiles can be used as a cheap and readily accessible tool for predicting prognosis in CLL practice. [ABSTRACT FROM AUTHOR]

Chronic Lymphocytic Leukaemia (CLL) is the most common adult B‐cell leukaemia and despite improvement in patients' outcome, following the use of targeted therapies, it remains incurable. CLL supportive microenvironment plays a key role in both CLL progression and drug resistance through signals that can be sensed by the main components of the focal adhesion complex, such as FAK and PYK2 kinases. Dysregulations of both kinases have been observed in several metastatic cancers, but their role in haematological malignancies is still poorly defined. We characterized FAK and PYK2 expression and observed that PYK2 expression is higher in leukaemic B cells and its overexpression significantly correlates with their malignant transformation. When targeting both FAK and PYK2 with the specific inhibitor defactinib, we observed a dose–response effect on CLL cells viability and survival. In vivo treatment of a CLL mouse model showed a decrease of the leukaemic clone in all the lymphoid organs along with a significant reduction of macrophages and of the spleen weight and size. Our results first define a possible prognostic value for PYK2 in CLL, and show that both FAK and PYK2 might become putative targets for both CLL and its microenvironment (e.g. macrophages), thus paving the way to an innovative therapeutic strategy. [ABSTRACT FROM AUTHOR]

Introduction: The B‐cell lymphoma/leukaemia 11A (BCL11A) gene encodes a Krüppel‐like transcription factor involved in lymphocyte development during normal haematopoiesis. Aberrant expression of BCL11A has been observed in several haematological malignancies, including chronic lymphocytic leukaemia (CLL). However, its functions in the regulatory networks of malignant B lymphocytes are poorly understood, as are the relations to clinical course and outcome of B‐cell malignancies, particularly CLL. Methods: The expression of BCL11A was analysed in peripheral blood mononuclear cells of 87 newly‐diagnosed CLL patients by quantitative reverse‐transcriptase polymerase chain reaction (qRT‐PCR), and association with clinical and molecular variables was assessed. Results: BCL11A was significantly overexpressed in CLL samples compared to control samples (p < 0.001). BCL11A expression level exhibited no association with age, sex, leukocyte, lymphocyte and platelet counts, haemoglobin level, serum β2‐microglobulin, CD38 status and cytogenetic abnormalities. On the other hand, high BCL11A expression was associated with low serum lactate dehydrogenase (p = 0.031), Binet A stage (p = 0.047) and mutated IGHV (p = 0.028). In addition, a positive correlation with BCL2/BAX mRNA ratio was observed (r = 0.36; p < 0.001). Regarding the association with the time to first treatment (TTFT), a trend towards longer median TTFT in BCL11A high‐ versus BCL11A low‐expressing cases was detected (21 vs. 6 months; p = 0.164). Conclusion: The results of this study show that BCL11A is upregulated in CLL patients, and that high BCL11A expression at diagnosis may be associated with better prognosis. These data are consistent with the role of BCL11A expression in CLL biology, and imply its potential prognostic relevance. [ABSTRACT FROM AUTHOR]

Combination chemoimmunotherapy (CIT) consisting of anti-CD20 has improved the progression-free survival (PFS) and overall survival (OS) of patients with chronic lymphocytic leukaemia (CLL). We performed a comprehensive synthesis of prognostic factors in patients with CLL on combined CIT with anti-CD20 antibodies compared with standard chemotherapy alone or targeted therapy.We searched the MEDLINE and academic search complete electronic databases as well as clinicaltrials.gov (from inception up to 01 August 2022) for randomised controlled trials examining chemoimmunotherapy and targeted therapy in patients with CLL. The risk of bias and the quality of evidence was assessed using the quality in prognostic studies tool (QUIPS).A total of 10 prognostic factors were identified and evaluated in patients with CLL on anti-CD20 antibody-containing CIT. The predictive value of the following prognostic factors was confirmed and associated with poor patient outcomes; deletion 17p (HR = 3.39), Immunoglobulin heavy chain variable region gene mutation status (HR = 0.96) and β2-microglobulin (HR = 1.41).Conventional predictive factors may have retained prognostic value and could be useful in the stratification of patients who may be non-responsive to CIT.Trial registration: International Prospective Register of Systematic Reviews (PROSPERO) registry (CRD42021218997). [ABSTRACT FROM AUTHOR]

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression. Synopsis: Combined perturbation by microenvironmental stimuli and drugs of chronic lymphocytic leukaemia cells annotated for genetic alterations reveals distinct response patterns and molecular modulators. CLL samples fall into four subgroups with distinct progression dynamics based on their microenvironmental response.Trisomy 12 enhances the response to microenvironmental stimulation and has a distinct transcription factor activity profile which is inhibited by IBET‐762 treatment.Linear modelling reveals different types of drug ‐ stimuli interactions, the most common being drug resistance induced by microenvironmental stimulation.IL4 and TLR signalling is more active in CLL infiltrated lymph nodes, and higher IL4 signalling activity correlates with faster disease progression. [ABSTRACT FROM AUTHOR]

Limited data exists to show the correlation of (tumour protein 53) TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (≥10%) and low burden mutations (<10%). TP53 aberrations (17p [del(17p)] and/or TP53 mutation) were detected in 320/2332 patients (13.7%). Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Of these 238 (79%) and 65 (21%) were cases with high burden and low burden mutations respectively. In our cohort, 2012 cases did not demonstrate a TP53 aberration (86.3%). A total of 159 cases showed TP53 mutations in the absence of del(17p) (49/159 with low burden TP53 mutations) and 144 cases had both TP53 mutation and del(17p) (16/144 with low burden mutations). Only 17/2332 (0.7%) cases demonstrated del(17p) with no TP53 mutation. Validated NGS protocols should be used in clinical decision making to avoid missing low-burden TP53 mutations and can detect the vast majority of TP53 aberrations. [ABSTRACT FROM AUTHOR]

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice.

Limited data exists to show the correlation of (tumour protein 53) TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (≥10%) and low burden mutations (

Hypocholesterolaemia is associated with elevated cancer risk and mortality, yet the relation between chronic lymphocytic leukaemia (CLL) and serum lipid profile remains unclear. Our study aims to evaluate the prognostic value of cholesterol levels in CLL and develop a prognostic nomogram that incorporates lipid metabolism. We enrolled 761 newly diagnosed CLL patients and separated them into either derivation (n = 507) or validation (n = 254) cohorts. The prognostic nomogram was constructed through multivariate Cox regression analyses, with performance evaluated using C-index, the area under the curve, calibration, and decision curve analyses. Decreased total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) at diagnosis were significantly associated with worse time to first treatment (TTFT) and cancer-specific survival (CSS), and simultaneously, low HDL-C with low LDL-C was identified as an independent prognostic indicator for both TTFT and CSS. CLL patients achieving complete or partial remission post-chemotherapy had significantly increased TC, HDL-C, and LDL-C levels compared with the baseline, and post-therapeutic HDL-C and LDL-C elevation correlated with favourable survival. The prognostic nomogram augmenting the CLL international prognostic index with low cholesterol levels yielded higher predictive accuracy and discrimination capacity for both 3-year and 5-year CSS. In conclusion, cholesterol profiles can be used as a cheap and readily accessible tool for predicting prognosis in CLL practice.

Chronic lymphocytic leukaemia is one of the most common types of adult leukaemia. Cancer-related systemic inflammation response has been characterized to correlate with therapeutic outcome in patients with cancer. The C-reactive protein-to-albumin (CRP/ALB) ratio (CAR), which is an inflammatory marker, has been reported as a novel prognostic factor in several cancers. The aim of our study was to evaluate the prognostic value of the CAR in patients with chronic lymphocytic leukaemia (CLL). We retrospectively reviewed the clinical characteristics of 322 newly diagnosed CLL patients, investigated the correlations among pretreatment CAR, treatment-free survival (TFS) and overall survival (OS), assessed the prognostic effect of the CAR to compare with other inflammation-related prognostic index by the area under the curve (AUC), and combined CAR and CLL-international prognostic index (CLL-IPI) together to improve the current prognostic system. The results showed that CAR was an independent prognostic factor for OS. Furthermore, the predictive and discriminatory capacity of CLL-IPI together with CAR level was superior to that of CLL-IPI alone for OS. In conclusion, serum CRP and ALB levels are both simple and easily accessible parameters, whose ratio CAR may be good candidates for predicting prognosis in the future clinical practice of CLL.

Summary: The manageable toxicity profile of obinutuzumab (GA101; G) alone or with chemotherapy in first‐line (1L; fit and non‐fit) and relapsed/refractory (R/R) patients with chronic lymphocytic leukaemia (CLL) was established in the primary analysis of the Phase IIIb GREEN trial (Clinicaltrials.gov: NCT01905943). The final analysis (cut‐off, 31 January 2019) is reported here. Patients received G (1000 mg) alone (G‐mono; fit and non‐fit patients) or with chemotherapy [fludarabine and cyclophosphamide (FC; fit patients); chlorambucil (non‐fit patients); bendamustine (any patient)]. Study endpoints were safety (primary) and efficacy (secondary). Subgroup analyses were performed on prognostic biomarkers in 1L CLL. Overall, 630 patients received 1L and 341 received R/R CLL treatment. At the final analysis, no new safety signals were observed [Grade ≥ 3 adverse events (AEs): 1L 82·7%, R/R 84·5%; serious AEs: 1L 58·1%, R/R 62·5%]. Neutropenia (1L 50·5%, R/R 53·4%) and thrombocytopenia (1L 14·6%, R/R 19·1%) were the most common Grade 3–5 AEs. G‐mono‐, G‐bendamustine and G‐FC‐treated patients with unmutated immunoglobulin heavy chain trended towards shorter progression‐free survival. Achievement of minimal residual disease negativity was greatest in 1L patients treated with G‐FC. In this final analysis of the GREEN trial, the safety profile of G was consistent with current risk management strategies. Biomarker analyses supported efficacy in the specific subgroups. [ABSTRACT FROM AUTHOR]

Summary: Most patients with chronic lymphocytic leukaemia (CLL) are nowadays diagnosed without any symptoms and do not require therapy. A prognostic score identifying patients within this large group who are at high risk of disease progression would be highly beneficial. The recently published International Prognostic Score for Early asymptomatic patients (IPS‐E) uses combination of absolute lymphocyte count (ALC) >15 × 109/l, palpable lymphadenopathy, and unmutated immunoglobulin heavy‐chain variable‐region (IGHV) gene to predict the time to first‐line therapy (TTFT). Patients at low, intermediate, and high risk had estimated 5‐year TTFT of 8%, 28%, and 61%. We performed an external validation of the IPS‐E score using an unselected, consecutive group of 130 Binet A patients. The 5‐year TTFT was 11%, 36%, and 78% (C‐statistic 0·74). Furthermore, we propose an alternative system (AIPS‐E) using cytogenetic aberrations instead of palpable lymphadenopathy. This system yielded 5‐year TTFT of 14%, 40%, and 72%. These results were externally validated in 388 Binet A patients from five Czech centres; the 5‐year TTFT was 16%, 37%, and 80% (C‐statistic 0·74). In conclusion, we have successfully validated the IPS‐E score for patients with early stage CLL. In addition, we propose a modified scoring system, the AIPS‐E, combining IGHV, fluorescence in situ hybridisation, and ALC. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency of Del 13q14 in Chronic lymphocytic leukaemia, to compare its association with clinicpathologic features and to define the contribution of this abnormality to the prognosis. Study Design: Cross-sectional study. Place and Duration of Study: Department of Haematology, Armed Forces Institute of Pathology, Armed Forces Bone Marrow Transplant Centre and Oncology department, Combined Military Hospital Rawalpindi, from Apr 2017 to Jul 2018. Methodology: A total of 56 newly diagnosed cases of CLL were included in the study. Patients were diagnosed on the basis of National Cancer Institute Working Group guidelines for diagnosis of CLL. After detailed history and thorough clinical examination; complete blood counts, biochemical profile, bone marrow examination, immunophenotyping on bone marrow or peripheral blood samples were done and Interphase FISH studies on blood or bone marrow specimens for detection of Del 13q14 were performed. Clinico-pathological features of CLL patients with Del 13q14 were compared with other cytogenetic abnormalities. Results: The frequency of Trisomy 12 was found to be 37.5%. Most of CLL patients with Del 13q14 were aymptomatic and were diagnosed on routine workup. The WBC count and Absolute lymphocyte count was slightly lower in patients with Del13 q14 lower when compared with the CLL patients without 13q14 Deletion. Most of the patients with this aberration presented in early stage (Binet stage A) and this association of Del 13q14 with Binet stage was statistically significant (p<0.05). However, no association was found between 13q14 deletion and ZAP70 as all of our patients were negative for this marker. Many patients with Del 13q14 did not require chemotherapy at diagnosis and during follow up as compared to patients without del13q14, and this association was statistically significant (p<0.05). The study also showed that disease progression in patients with deletion 13q14 become significantly less as compared to patient without Del 13q14. Conclusions: The deletion of 13q14 influence clinical outcome of patients with CLL and was found to be associated with favourable prognosis. A determination of Del 13q14 should therefore be included in the investigations of the prognostic factors of B-cell chronic lymphocytic leukemia. This can prevent unwanted chemotherapy in these patients. [ABSTRACT FROM AUTHOR]

Keywords: eosinophilia; chronic lymphocytic leukaemia; prognostic factors EN eosinophilia chronic lymphocytic leukaemia prognostic factors e81 e84 4 02/02/21 20210201 NES 210201 Blood eosinophilia may be an early sign of a haematological malignancy.1,2 Temporary eosinophilia occurs as an adverse event in chronic lymphocytic leukaemia (CLL) during fludarabine treatment,3 whereas persistent eosinophilia in CLL with a I TP53 i mutation may be a prognostic factor for variant Richter transformation.4 A dose-dependent association between eosinophil counts and the risk of CLL has been reported.5 Several prognostic factors have been established and the clinical staging systems6 have been superseded in the era of targeted treatment by molecular markers,7 but the predictive properties of eosinophilia at CLL diagnosis have not previously been analysed. Patients with a blood eosinophil count outside the normal range (<0-10 × 10 SP 9 sp /l or >0-50 × 10 SP 9 sp /l) had a significantly shorter TFS compared with patients with an eosinophil count within the normal range when adjusting for CLL-IPI variables and sex. [Extracted from the article]

Summary: Richter syndrome (RS) is an uncommon evolution of chronic lymphocytic leukaemia (CLL) with a dismal prognosis. Clinical‐biological features predicting outcome and best therapeutic approach for these patients remain to be established. In this study, 128 patients with RS, including 112 diffuse large B‐cell lymphoma (DLBCL)‐type RS, 15 Hodgkin lymphoma (HL)‐type RS, and one plasmablastic lymphoma, were identified in 11 centres of the Spanish CLL Study Group (GELLC). The median overall survival (OS) was 5·9 months for DLBCL‐type RS and 30·8 months for HL‐type RS. Eastern Cooperative Oncology Group Performance Status, haemoglobin level, platelet count, serum lactate dehydrogenase and β2‐microglobulin levels, tumour protein p53 (TP53) abnormalities in the CLL clone concomitant to RS, number of prior therapies, and clonal relationship between CLL and RS, were associated with OS in patients with DLBCL‐type RS. A platelet count of <100 × 109/l, prior CLL therapy (0 vs. ≥1), and presence of TP53 alterations maintained an independent prognostic impact in the multivariate analysis. Patients without any of these factors had a better clinical outcome, with a median OS of 75·3 months, while patients with one or two or more of these factors presented a median OS of 25·5 and 3 months, respectively. Although OS of patients with RS is generally poor, a proportion of patients achieved prolonged survival. Treatment of RS remains a medical need, and further therapeutic approaches with novel therapies are warranted. [ABSTRACT FROM AUTHOR]

Summary: In chronic lymphocytic leukaemia (CLL), caution is warranted regarding the clinical implications of immunoglobulin variable heavy chain region (IGHV) rearrangements with a 'borderline' (BL) percentage of mutations (i.e. 97–97·9% IGHV identity). We analysed the IGHV mutational status in 759 untreated CLL patients (cohort 1). BL‐CLL (n = 36, 5%) showed a time to first treatment (TFT) similar to that of M‐CLL (n = 338) and significantly longer than that of UM‐CLL (n = 385), despite the enrichment in subset #2 cases. In fact, CLLs belonging to subset #2 (n = 15/759, 2%) were significantly more frequent among BL‐CLLs (n = 5/36, 14%), with a brief TFT. TFT of BL‐CLL remained comparable to that of M‐CLL also considering the 327 CLL patients evaluated at diagnosis. These findings were then validated in an independent cohort 2 of 759 newly diagnosed CLL patients (BL‐CLL: n = 11, 1·4%) and in all newly diagnosed patients from cohorts 1 and 2 (n = 1 086, 84% stage A; BL‐CLL: n = 47, 4·3%). BL‐CLL at diagnosis showed a biological profile comparable to that of M‐CLL with a low frequency of unfavourable prognostic markers, except for a significant enrichment in subset #2. Our data suggest that the prognosis of BL‐CLL is good and similar to that of M‐CLL, with the exception of subset #2 cases. [ABSTRACT FROM AUTHOR]

Summary: Chronic lymphocytic leukaemia (CLL) patients often have abnormal expansions of CD4+ and CD8+ T cells and this can be associated with progressive disease. To characterise the key T‐cell populations involved in this phenomenon, we used flow cytometry and 11 phenotypic markers to study 74 CLL patients and 14 controls. T cells of CLL patients were more phenotypically complex than those of healthy controls with significant increases in the frequencies of CD4 and CD8 memory T cells expressing exhaustion‐, activation‐ and senescence‐associated markers. Multivariate analysis of 111 different T‐cell subsets showed that high frequencies of four subsets (three CD8 and one CD4) were associated with shorter progression‐free survival. The most significant association was with CD4+HLA‐DR+PD‐1+ T cells, and patients could be stratified into high‐ and low‐risk groups based on the frequency of these T cells. The expansion of this CD4+ subset could not be accounted for by age, cytomegalovirus infection or increases in Treg cells. Overall, these results highlight two relatively simple biomarkers, percentage CD8+ and percentage CD4+PD‐1+HLA‐DR+ T cells, which can be used to risk‐stratify CLL patients, independent of other tumour‐associated markers. They also provide further evidence for the pivotal role of T cells in modulating the pathology of CLL. [ABSTRACT FROM AUTHOR]

Summary: Chronic lymphocytic leukaemia (CLL) is characterized by expression of CD5 on clonal B cells, and is partly driven by activated B‐cell receptor (BCR) signalling. While CD5 is known to be a negative regulator of BCR signalling, it is unknown if variability in CD5 expression exists among patients and whether CLL cell CD5 expression affects CLL clinical outcomes. We assessed the extent to which CD5 expression is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated CD5 expression from 1275 blood samples, established prognostic markers and time to event data from 423 CLL patients followed at the Duke University and Durham VA Medical Centers. CD5 median fluorescence intensity (MFI) was largely stable over time in individual patients, but ranged between 0·5 and 760 in the entire cohort. Lower CD5 MFI was significantly associated with a shorter time to first therapy. CD5 MFI, combined with established clinical and molecular prognostic markers, significantly improved risk‐stratification. CD5 may affect disease outcomes by suppressing signalling through the BCR. Thus, a strategy to modulate CLL cell CD5 expression or function could be a therapeutic approach in CLL. [ABSTRACT FROM AUTHOR]

The article focuses on the results of a study which concludes that CD52 induces minimal residual disease-negativity in the bone marrow of poor-prognosis chronic lymphocytic leukaemia patients but is associated with opportunistic infections. It mentions the dual targeting of Bruton tyrosine kinase and trial of combination of ibrutinib and alemtuzumab.

Summary: Complex karyotype (CK) is a negative prognostic factor in chronic lymphocytic leukaemia (CLL). However, CK is a heterogeneous cytogenetic category. Unbalanced rearrangements were present in 73·3% of 90 CLL patients with CK (i.e. ≥3 chromosome aberrations in the same clone), and were associated with a shorter overall survival (P = 0·025) and a shorter time to first treatment (P = 0·043) by multivariate analysis. Patients with unbalanced rearrangements presented a distinct mRNA expression profile. In conclusion, CLL patients with unbalanced rearrangements might represent a subset of very high‐risk CLL patients with distinct clinical and biological characteristics. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukaemia (CLL) is a clonal B lymphocyte malignancy with a highly heterogeneous course. Some patients remain asymptomatic and do not require treatment for many years, while patients with aggressive forms of the disease require therapy soon after diagnosis. Recently, evidence has been growing about the important role of methylations in natural evolution as well as in the development of various diseases including cancer. Whole genome sequencing has revealed that in CLL, similarly to other malignancies, aberrant methylations arise in the early phases of the disease. CLL patients have diverse methylation profiles and the methylation status of certain loci correlates with disease aggressiveness. In this brief report, we focus on methylation changes and their role in CLL prognosis.. [ABSTRACT FROM AUTHOR]

This study explored the relative efficacy of ibrutinib versus previous standard-of-care treatments in relapsed/refractory patients with chronic lymphocytic leukaemia (CLL), using multivariate regression modelling to adjust for baseline prognostic factors. Individual patient data were collected from an observational Stockholm cohort of consecutive patients (n = 144) diagnosed with CLL between 2002 and 2013 who had received at least second-line treatment. Data were compared with results of the RESONATE clinical trial. A multivariate Cox proportional hazards regression model was used which estimated the hazard ratio (HR) of ibrutinib versus previous standard of care. The adjusted HR of ibrutinib versus the previous standard-of-care cohort was 0.15 (p < 0.0001) for progression-free survival (PFS) and 0.36 (p < 0.0001) for overall survival (OS). A similar difference was observed also when patients treated late in the period (2012-) were compared separately. Multivariate analysis showed that later line of therapy, male gender, older age and poor performance status were significant independent risk factors for worse PFS and OS. Our results suggest that PFS and OS with ibrutinib in the RESONATE study were significantly longer than with previous standard-of-care regimens used in second or later lines in routine healthcare. The approach used, which must be interpreted with caution, compares patient-level data from a clinical trial with outcomes observed in a daily clinical practice and may complement results from randomised trials or provide preliminary wider comparative information until phase 3 data exist. [ABSTRACT FROM AUTHOR]

Objective To evaluate the prognostic significance of oxidative stress ( OS) and antioxidant defence status measurement in patients with chronic lymphocytic leukaemia ( CLL). Methods d- ROMs test and BAP test were evaluated at diagnosis of 165 patients with CLL and correlated with clinical-biological features and prognosis. Results An increased oxidative damage (d- ROMs test) and a reduced antioxidant potential ( BAP test) were found in CLL patients than normal controls ( P<.0001). CLL patients with higher d- ROMs values had higher number of circulating white blood cells and lymphocytes, and higher values of β2-microglobulin. Higher d- ROMs values were found in female ( P=.0003), in patients with unmutated Ig VH ( P=.04), unfavourable cytogenetics ( P=.002) and more advanced clinical stage ( P=.002). Higher BAP test values were found in patients expressing CD49d ( P=.01) and with more advanced clinical stage ( P=.004). At a median follow-up of 48 months, CLL patients with d- ROMs ≥418 CARR U were found to have a shorter time to first treatment ( TFT) ( P=.0002), and a reduced survival ( P=.006) than others. CLL patients with BAP test values ≥2155 μmol/L had a shorter TFT ( P=.008) and a shorter survival ( P=.003). Conclusions OS can affect CLL patients by concomitantly increasing reactive oxygen metabolites production and decreasing antioxidant defences. [ABSTRACT FROM AUTHOR]

The article discusses the impact of functionally relevant germline CD5 variants on the prognosis of chronic lymphocytic leukaemia (CLL). CD5 variants were found to have influenced the natural behavior of CLL cell biology and its outcome. CD5 signalling was also considered a relevant factor for the production of B1a cell autocrine growth factor interleukin 10.

Background Major infections (MIs), secondary cancers (SCs) and autoimmune diseases (ADs) are the most common and relevant complications in patients with chronic lymphocytic leukaemia. Methods We performed a single-centre retrospective study to investigate the prevalence of the above quoted complications, the association with most important prognostic markers and their impact on survival (n = 795). Results Almost one out of three patients experienced at least one complication and only 0.9% of the cohort developed all three complications. One hundred and twenty (20%) subjects developed SC, 98 MI (12%) and 80 AD (10%); these complications seem to occur in a mutually exclusive manner. By Kaplan–Meier analysis we estimated that after 20 years from the diagnosis SC, MI and AD occurred in 48%, 42% and 29% of patients, respectively. Furthermore, we showed that some clinical and biological markers are skewed among patients with different complications and that subjects with MI and SC had a worse prognosis than those with AD and all other patients (p < 0.0001). Conclusions This study reveals the existence of different clinical subsets of chronic lymphocytic leukaemia patients characterised by an increased and different risk for developing specifically MI, SC and AD. [ABSTRACT FROM AUTHOR]

The presence of chromosomal gains other than trisomy 12 in chronic lymphocytic leukaemia ( CLL) is unusual. However, some patients may show gains on several chromosomes simultaneously suggesting a hyperdiploid karyotype. Objective The objective of this study was to analyse by FISH the frequency and prognostic impact of hyperdiploidy in CLL. Method A review of 1359 consecutive cases diagnosed with CLL referred for FISH analysis to a unique institution was carried out. Hyperdiploidy was considered when a gain of at least three of the five FISH probes used was observed. Results Seven cases (0.51%) with hyperdiploidy were found, confirming that it is a rare event in this disease. Although most patients presented with early Binet stages at diagnosis, six of seven (86%) shortly progressed. The median of time to the first therapy ( TTFT) and overall survival ( OS) for the patients with hyperdiploidy were short (1.4 months and 20 months, respectively). Moreover, comparing them with a control group of patients (non-hyperdiploid) with completed follow-up data, TTFT and OS of the patients with hyperdiploidy were significantly shorter than the control group. Conclusion The presence of hyperdiploidy is uncommon and probably associated with poor prognostic markers in CLL. [ABSTRACT FROM AUTHOR]

The canonical Wnt pathway, dependent on β-catenin-controlled transcription, is the most explored Wnt pathway, known to drive the malignant transformation of multiple cell types. Several reports have suggested that this pathway also participates in chronic lymphocytic leukaemia ( CLL) pathogenesis. To get a better insight into the role of the Wnt/β-catenin pathway in CLL we analysed in detail the expression of the most overexpressed Wnt ligand, encoded by the WNT3 gene, in a well-defined cohort of 137 CLL patients. Our analysis demonstrated that (i) untreated patients with more aggressive disease (with a notable exception of patients with 11q deletion) express less WNT3, (ii) WNT3 declines with disease progression in a significant proportion of patients and (iii) low WNT3 was identified as a strong independent marker indicating shorter treatment-free survival in CLL patients with IGHV mutation. Interestingly, CLL-related lymphoid cell lines, but not stromal cells, failed to respond to the ligand-induced activation of the Wnt/β-catenin pathway. This opens the possibility that CLL cells use Wnt-3 to communicate with the cells in the microenvironment. We thus propose that the Wnt/β-catenin pathway plays a more complex role in CLL pathogenesis than previously anticipated. [ABSTRACT FROM AUTHOR]

Introduction. Chronic lymphocytic leukaemia is a disease with heterogeneous clinical course and outcome. Some patients have a progressive course of the disease and require therapy immediately after the diagnosis, while others have a stable form without the need for treatment. Recently, two new biological markers, the expression of CD38 antigen and ZAP-70 have shown independent significance in the prognosis in CLL patients. Objective. The aim of our study was to evaluate the clinical value of CD38 antigen and ZAP-70 expression as predictors of the disease progression and to analyze the correlation of these markers with other B-CLL prognostic markers. Methods. We assessed the expression of CD38 antigens by flow cytometry on peripheral blood samples and the expression of ZAP-70 by immunohistochemistry on formalin-fixed bone marrow (BM) biopsies in 40 newly diagnosed B-CLL patients. Disease progression was defined by the period elapsed from diagnosis to the time to first treatment (TFT). Results. Expression of CD38 antigen correlated positively with ZAP-70 expression (Pearson, r=0.476; p=0.002). Also, correlation analysis results showed that a positive expression of CD38 and ZAP-70 statistically significantly correlated with unfavourable classical prognostic parameters, such as advanced Binet stage C, diffuse BM infiltration, increased lactate-dehydrogenase and beta-2 microglobulin serum levels. Patients with positive expression of CD38 antigen and ZAP-70 had a shorter TFT (log rank, 0.003 vs. 0.049). Conclusion. Both new biological markers were shown to have an exceptional significance in the prediction of prognosis in CLL patients.

Evans syndrome (ES) is defined by the combination (either simultaneous or sequential) of immune thrombocytopenia (ITP) and autoimmune haemolytic anaemia (AIHA). When related to secondary conditions, ES may arise in patients with chronic lymphocytic leukaemia (CLL), which is frequently associated to autoimmune cytopenias (AIC). We analysed 25 patients with ES secondary to CLL, which were identified from a large series of consecutive patients with CLL, diagnosed and followed up in two institutions. They represented 2.9 % of the whole series. Thirteen patients presented with concurrent ITP and AIHA (simultaneous ES), while others developed the two AIC sequentially. Occurrence of ES was associated with unfavourable biological prognostic factors like ZAP-70 expression, unmutated immunoglobulin heavy chain variable region gene status, 17-p13 deletion and TP53 gene mutations. Of note, the majority of patients with ES (66 %) had stereotyped B cell receptor configuration. Most patients had short-lasting remissions and required second-line treatments to control the autoimmune manifestations of ES. Patients with ES were associated with inferior survival compared to patients not developing AIC, especially when ES developed early in the course of CLL, although the reduced survival was not confirmed by multivariate analysis. In conclusion, ES secondary to CLL is a difficult-to-treat complication, characterised by adverse biological features and clinical outcome. [ABSTRACT FROM AUTHOR]

This study revisited the Dohner prognostic hierarchy in a cohort of 1585 well-documented patients with chronic lymphocytic leukaemia. The duration of both time to first treatment ( TTFT) and overall survival ( OS) were significantly longer than observed previously, and this is at least partly due to improved therapeutic options. Deletion 13q remains the most favourable prognostic group with median TTFT and OS from fluorescence in situ hybridization ( FISH) testing of 72 months and >12 years, respectively. Deletion 11q had the poorest median TTFT (22 months) and 17p deletion the poorest median OS (5 years). The percentages of abnormal nuclei were significantly associated with differential TTFT for the trisomy 12, 13q and 17p deletion cohorts but not for the 11q deletion cohort. From the date of the first FISH study, patients with >85% 13q deletion nuclei had a notably shorter TTFT (24 months). Patients with ≤20% 17p deletion nuclei had longer median TTFT and OS from the date of the first FISH study (44 months and 11 years), and were more likely to be IGHV mutated. [ABSTRACT FROM AUTHOR]

IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia ( CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment ( TTFT) among Stage A patients and in overall survival ( OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial. Cox Regression analyses in the Stage A cohort revealed that a model which incorporated <97%, 97-98·99% and ≥99% identity as subgroups, was a better predictor of TTFT in CLL than using the 98% cut-off. Multivariate analysis selected the three mutational subgroups as independent predictors of TTFT in Stage A patients, and of OS in the diagnostic cohort. This study highlights that cases with 97% identity should not be considered to have the same prognosis as other cases with mutated IGHV genes defined as <98% identity to germline. [ABSTRACT FROM AUTHOR]

We investigated CD49d (also termed ITGA4) expression and its biological and clinical correlations in 415 patients with chronic lymphocytic leukaemia. CD49d expression was stable over the course of the disease. A high expression of CD49d (>30%) was found in 142/415 (34%) patients and was associated with progressive disease (advanced clinical stage, high serum lactate dehydrogenase or β2-microglobulin levels; all p < 0·05) and aggressive disease biology (increased ZAP70 or CD38, unmutated IGHV, trisomy 12, mutations of NOTCH1 and SF3B1; all P < 0·05). A higher CD49d expression was also associated with a lower blood lymphocyte count and a higher number of lymphoid areas involved by the disease. Patients with high CD49d expression were treated more frequently (55% vs. 27%; P < 0·001) and earlier (median time to treatment [TTT] 65·4 months vs. not reached; P < 0·001) than those with low CD49d expression. However, no significant differences in response rates were observed. In the subgroup of patients with mutated IGHV, high CD49d expression was predictive of a shorter TTT while other markers, such as ZAP70 and CD38, were not. In conclusion, in this study CD49d expression correlated with high-risk CLL biomarkers and proved to be useful for separating patients with mutated IGHV into two different prognostic groups. [ABSTRACT FROM AUTHOR]

The significance of rarer cytogenetic abnormalities in chronic lymphocytic leukaemia ( CLL) remains controversial. We performed fluorescence in situ hybridization ( FISH) prior to initial therapy on 618 CLL patients seen at our centre between 2005 and 2012. With a median follow-up of 5·6 years, we found that 55 patients harbouring 14q32 rearrangements without t(14;18) had a shorter time to first treatment ( TTFT) (median 26 months, P = 0·03) than patients with t(14;18) (median not reached). Patients with mono- or bi-allelic del(13q) as a sole abnormality had a similarly long TTFT (median not reached). Those patients who harboured 3 or more FISH abnormalities without del(17p) had a short TTFT (4·6 months), comparable to patients with del(17p) (8 months); however, the overall survival for patients with 3 or more FISH abnormalities was longer than for patients with del(17p) with 0 or 1 additional abnormalities (median not reached vs. 54 months). FISH cytogenetics remains a useful genetic tool in the clinic, even in the era of next generation sequencing and, as such, our data provide valuable new insights for counselling patients. [ABSTRACT FROM AUTHOR]