Safety profile of first-line targeted therapies in elderly and/or comorbid chronic lymphocytic leukaemia patients (unfit subpopulation). A systematic review and network meta-analysis.

This systematic literature review (CRD42023393903) and a Bayesian network meta-analysis (NMA) aimed to assess the relative safety profile of first-line targeted therapies (acalabrutinib, ibrutinib, obinutuzumab, ofatumumab, pirtobrutinib, ublituximab, umbralisib, venetoclax, zanubrutinib) in chronic lymphocytic leukaemia (CLL) patients with advanced age and/or comorbidities. The NMA revealed that zanubrutinib was the safest treatment option in terms of the overall safety profile (e.g., serious adverse events [AEs] grade 1-5), followed by venetoclax-obinutuzumab, which showed an advantage in terms of AEs grade 1-5. The use of Bruton's tyrosine kinase inhibitor (BTKi) monotherapy was more favourable in terms of the risk of haematological AEs, but chemoimmunotherapy showed advantages in terms of cardiovascular, gastrointestinal, and infectious AEs. The risk of secondary cancers was similar between treatments. In conclusion, targeted therapies are associated with variable and clinically relevant AEs. The therapies appear to be safer when used as monotherapy rather than in combination with immunological agents in naïve CLL patients with advanced age and/or comorbidities.

A retrospective observational study of ibrutinib in chronic lymphocytic leukaemia in a real-life setting in France using the national claims database (OSIRIS).

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase inhibitor indicated for the first-line treatment and relapse of chronic lymphocytic leukaemia (CLL), Waldenström's macroglobulinemia (WM) and mantle cell lymphoma (MCL). This study aimed to describe the characteristics of CLL patients treated with ibrutinib and its effectiveness, safety, and treatment pattern in real life. METHODS: All patients covered by the general health scheme (approximately 80% of the French population) with a first ibrutinib dispensation from August 1, 2017 (date of reimbursement in France) to December 31, 2020, were identified in the French National Health Insurance database (SNDS). An algorithm was developed to identify the disease (CLL, MCL or WM) for which ibrutinib was prescribed. This article focused on CLL patients. The time to next treatment (TTNT) was plotted using Kaplan‒Meier curves. RESULTS: During this period, 6,083 patients initiated ibrutinib, among whom 2,771 (45.6%) patients had CLL (mean age of 74 years; 61% of men). At ibrutinib initiation, 46.6% of patients had a cardiovascular comorbidity. Most patients (91.7%) were not hospitalized during the exposure period for one of the cardiovascular or bleeding events studied. Hospitalizations were more frequent in patients with a cardiovascular comorbidity (5.9% versus 11.0%, p-value < 0.0001) and aged over 70 (5.9% versus 9.4%, p-value < 0.0001). The median TTNT was not reached. CONCLUSION: This is one of the largest cohorts of ibrutinib-treated patients in the world. The profile of CLL patients treated with ibrutinib was in accordance with the marketing authorization and reimbursement. This study confirmed effectiveness and safety data.

Australians with chronic lymphocytic leukaemia continue to have high rates of second primary malignancies in the modern era.

Population-based studies have demonstrated a high risk of second cancers, especially of the skin, among patients with chronic lymphocytic leukaemia (CLL). We describe age-standardised incidence ratios (SIRs) of second primary malignancies (SPM) in Australian patients with relapsed/refractory CLL treated with at least two lines of therapy, including ibrutinib. From December 2014 to November 2017, 156 patients were identified from 13 sites enrolled in the Australasian Lymphoma and Related Diseases Registry, and 111 had follow-up data on rates of SPM. At 38.4 months from ibrutinib therapy commencement, 25% experienced any SPM. SIR for melanoma and all cancers (excluding nonmelanomatous skin cancers) were 15.8 (95% confidence interval (CI): 7.0-35.3) and 4.6 (95% CI: 3.1-6.9) respectively. These data highlight the importance of primary preventive interventions and surveillance, particularly as survival from CLL continues to improve.

Unmutated IGHV at diagnosis in patients with early stage CLL independently predicts for shorter follow-up time to first treatment (TTFT).

The mutational status of the IGHV gene is routinely assessed in patients with chronic lymphocytic leukaemia (CLL), since it is both prognostic of clinical outcome and predictive of response to treatment. This study evaluates the IGHV mutational status, assessed in newly diagnosed CLL patients, as a stand-alone predictor of time to first treatment (TTFT). We analysed the data of 236 CLL patients, diagnosed at our centre between January 2004 and September 2020, with a minimum follow-up period of 3.0 years, Binet A-B and Rai 0-II stages. IGHV was unmutated in 38.1 % and mutated in 61.9 % of cases. The univariate analysis showed a statistically significant difference (p < 0.001) in TTFT based on unmutated (85.2 % at 14 years, 95 % CI = 63.3-94.5 %) or mutated (41.3 % at 14 years, 95 % CI = 29.5-51.8 %) and the need for treatment at 1, 3 and 5 years was of 20.0 % vs 4.1 % (p < 0.001), 42.7 % vs 11.4 % (p < 0.001) and 55.8 % vs 20.0 % (p < 0.001) in unmutated and mutated IGHV patients, respectively. Multivariate analysis confirmed that unmutated IGHV status negatively affects TTFT (p < 0.001), in addition to high-risk genomic aberration (p = 0.025), Rai stage I (p = 0.007) and II (p-value < 0.001). The difference in TTFT based on unmutated or mutated IGHV status remains statistically significant also when considering the subgroups by the genomic aberrations and Rai stages. Our findings suggest that, with the single analysis of the IGHV mutational status at CLL diagnosis, along with clinical and laboratory data, and without karyotype and TP53 data, clinicians will have prognostic and predictive indications for the first clinical treatment and appropriate follow-up of patients.

Prognostic impact of chronic lymphocytic leukemia comorbidity index in a young population: a real-world evidence study of a national gulf region cohort.

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.

A decade of chronic lymphocytic leukaemia therapy in Germany: Real-world treatment patterns and outcomes (2010-2022).

Pharmacotherapy options for chronic lymphocytic leukaemia (CLL) have expanded significantly in recent years. These options include chemotherapy, chemoimmunotherapy and signalling pathway inhibitors. A notable shift in the treatment landscape began with the widespread adoption of ibrutinib in 2016. This analysis of claims data focuses on understanding how the use of novel therapies has evolved in clinical practice over the past decade in Germany. Anonymized claims data (2010-2022) from German statutory health insurance was used, covering patient demographics, treatments, and prescriptions. The study population included patients with two confirmed CLL diagnoses. Treatment patterns were analysed, and survival outcomes were compared using time-to-event analyses. In the analysed cohort of 2983 incident CLL patients, 1041 started first-line therapy between 2011 and 2022, with a median duration of 18 months from diagnosis to the first prescription. Chemoimmunotherapy, the predominant 1L therapy until 2019, decreased significantly, while targeted therapy usage increased from 3% in 2015 to 77% in 2022. Targeted therapies became dominant in patients receiving treatment for relapsed or refractory disease after 2016. Median treatment durations were: 122 days for chemo, 176 days for chemo-immuno, and 373 days for targeted therapy. The overall survival for patients diagnosed in or after 2016 was significantly better (hazard ratio 0.56, 95% confidence interval, 0.44-0.69)). The adoption of targeted therapies like ibrutinib and venetoclax has transformed CLL treatment in Germany, leading to improved patient outcomes. Additionally, we demonstrate successful adherence to evolving clinical guidelines.

A Rare Case of an Elderly Male with Progression to Chronic Myeloid Leukaemia Secondary to Chronic Lymphocytic Leukaemia.

Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder characterised by an accumulation of monoclonal B lymphocytes, with an increased risk of secondary cancers. The coexistence of CLL and chronic myeloid leukaemia (CML) is a rare phenomenon, with three main types being classified: CML preceding CLL, CLL preceding CML and simultaneous occurrence. The coexistence of these chronic leukaemias poses a complex clinical challenge, with the underlying mechanisms of their association remaining enigmatic. Here, we present a report of an elderly male with a long history of CLL, who was subsequently diagnosed with secondary CML. LEARNING POINTS: The development of chronic myeloid leukaemia (CML) subsequent to chronic lymphocytic leukaemia (CLL) is an uncommon occurrence, challenging conventional expectations of disease evolution in chronic leukaemia.Extensive and appropriate testing is necessary to promptly identify secondary CML in CLL patients.Targeted therapy with dasatinib, a tyrosine kinase inhibitor, may demonstrate efficacy in reducing leukocytosis and BCR-ABL1 levels in patients with coexisting CLL and CML.

Integrative NGS testing reveals clonal dynamics of adverse genomic defects contributing to a natural progression in treatment-naïve CLL patients.

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.

Invasive fungal infection incidence and risk factors in patients receiving ibrutinib in real-life settings: A nationwide population-based cohort study.

BACKGROUND: Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce. OBJECTIVES: This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings. METHODS: We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients ≥18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors. RESULTS: Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]). CONCLUSIONS: In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups.

Novel identification of t(14;18)(q32;q21)/IGH::MALT1 in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a clonal B-cell malignancy and remains a chronic disease despite improvements in clinical outcomes since the use of targeted therapies. Both clinical and biological parameters are important for determining prognosis. Unlike other mature B-cell lymphomas, translocations involving the immunoglobulin heavy chain (IGH) locus are uncommon in CLL. There have been few case reports of CLL harbouring t(14;18)/IGH::BCL2 and t(14;19)/IGH::BCL3. Here we describe the first two cases of patients with CLL with documented t(14;18)(q32;q21)/IGH::MALT1. Both cases in this report were associated with lower-risk biological parameters. Thus, FISH testing for MALT1 in cases with unknown IGH translocation partners in the setting of CLL should be implemented in clinical practice to better define such cases.

Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

Biological, prognostic, and therapeutic impact of the epigenome in CLL.

Chronic lymphocytic leukemia (CLL) is characterized by widespread alterations in the genetic and epigenetic landscapes which seem to underlie the variable clinical manifestations observed in patients. Over the last decade, epigenomic studies have described the whole-genome maps of DNA methylation and chromatin features of CLL and normal B cells, identifying distinct epigenetic mechanisms operating in tumoral cells. DNA methylation analyses have identified that the CLL methylome contains imprints of the cell of origin, as well as of the proliferative history of the tumor cells, with both being strong independent prognostic predictors. Moreover, single-cell analysis revealed a higher degree of DNA methylation noise in CLL cells, which associates with transcriptional plasticity and disease aggressiveness. Integrative analysis of chromatin has uncovered chromatin signatures, as well as regulatory regions specifically active in each CLL subtype or in Richter transformed samples. Unique transcription factor (TF) binding motifs are overrepresented on those regions, suggesting that altered TF networks operate from disease initiation to progression as nongenetic factors mediating the oncogenic transcriptional profiles. Multiomics analysis has identified that response to treatment is modulated by an epigenetic imprint, and that treatments affect chromatin through the activity of particular set of TFs. Additionally, the epigenome is an axis of therapeutic vulnerability in CLL, as it can be targeted by inhibitors of histone modifying enzymes, that have shown promising preclinical results. Altogether, this review aims at summarizing the major findings derived from published literature to distill how altered epigenomic mechanisms contribute to CLL origin, evolution, clinical behavior, and response to treatment.

Richter's transformation: Transforming the clinical landscape.

Richter transformation (RT) represents an aggressive histological transformation from chronic lymphocytic leukaemia, most often to a large B cell lymphoma. It is characterised by chemo-resistance and subsequent short survival. Drug development has struggled over recent years in light of the aggressive kinetics of the disease, lack of pivotal registrational trials and relative rarity of the phenomenon. In this review we will highlight the diagnostic and therapeutic challenges of managing patients with RT as well as taking a look to the future therapeutic landscape. Highly active therapies developed across B cell malignancies are starting to impact this field, with T-cell activation therapies (CAR-T, bispecific antibodies), antibody-drug conjugates, and novel small molecule inhibitor combinations (e.g. BTKi-BCL2i) being actively studied. We will highlight the data supporting these developments and look to the studies to come to provide hope for patients suffering from this devastating disease.

Untargeted metabolomics identifies metabolic dysregulation of sphingolipids associated with aggressive chronic lymphocytic leukaemia and poor survival.

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.

Synthesis and Pro-Apoptotic Effects of Nitrovinylanthracenes and Related Compounds in Chronic Lymphocytic Leukaemia (CLL) and Burkitt's Lymphoma (BL).

Chronic lymphocytic leukaemia (CLL) is a malignancy of the immune B lymphocyte cells and is the most common leukaemia diagnosed in developed countries. In this paper, we report the synthesis and antiproliferative effects of a series of (E)-9-(2-nitrovinyl)anthracenes and related nitrostyrene compounds in CLL cell lines and also in Burkitt's lymphoma (BL) cell lines, a rare form of non-Hodgkin's immune B-cell lymphoma. The nitrostyrene scaffold was identified as a lead structure for the development of effective compounds targeting BL and CLL. The series of structurally diverse nitrostyrenes was synthesised via Henry-Knoevenagel condensation reactions. Single-crystal X-ray analysis confirmed the structure of (E)-9-chloro-10-(2-nitrobut-1-en-1-yl)anthracene (19f) and the related 4-(anthracen-9-yl)-1H-1,2,3-triazole (30a). The (E)-9-(2-nitrovinyl)anthracenes 19a, 19g and 19i-19m were found to elicit potent antiproliferative effects in both BL cell lines EBV-MUTU-1 (chemosensitive) and EBV+ DG-75 (chemoresistant) with >90% inhibition at 10 µM. Selected (E)-9-(2-nitrovinyl)anthracenes demonstrated potent antiproliferative activity in CLL cell lines, with IC50 values of 0.17 µM (HG-3) and 1.3 µM (PGA-1) for compound 19g. The pro-apoptotic effects of the most potent compounds 19a, 19g, 19i, 19l and 19m were demonstrated in both CLL cell lines HG-3 and PGA-1. The (E)-nitrostyrene and (E)-9-(2-nitrovinyl)anthracene series of compounds offer potential for further development as novel chemotherapeutics for CLL.

Case report: Successful treatment of refractory immune thrombocytopenia in chronic lymphocytic leukaemia with venetoclax monotherapy.

In chronic lymphocytic leukaemia (CLL), immune dysregulation is common and can manifest as immune thrombocytopenia (ITP). Corticosteroids are the mainstay for front-line management of CLL-associated ITP. Therapy refractoriness represents a clinical challenge and is an indication to commence CLL-directed treatment, historically with anti-CD20 antibody-based chemoimmunotherapy. There is a small but growing body of evidence supporting the use of Bruton's tyrosine kinase (BTK) inhibitors in this setting, but not the B-cell lymphoma-2 inhibitor, venetoclax. Here, we describe two cases of refractory ITP in patients with CLL who successfully achieved and sustained complete remission with fixed-duration venetoclax monotherapy. Responses were rapid and durable and not explained by the concomitant use of an anti-CD20 antibody. This supports a dual role for single-agent venetoclax in managing active CLL and associated ITP as an alternative to BTK inhibitors and anti-CD20 monoclonals.

Australian data on the utilisation and duration on treatment of ibrutinib with a proton pump inhibitor in patients with relapsed or refractory chronic lymphocytic leukaemia.

In Australia, over half of patients with relapsed/refractory chronic lymphocytic leukaemia treated with ibrutinib use concomitant proton pump inhibitors (PPIs). High gastric pH reduces the bioavailability of some Bruton tyrosine kinase inhibitors. There was no difference in duration on ibrutinib with or without concomitant PPI (unadjusted P = 0.61; adjusted hazard ratio: 1.23, 95% confidence interval: 0.75-2.02, P = 0.411). PPI use does not affect ibrutinib treatment persistence.

Pituitary macroadenoma apoplexy as a rare complication of Bruton tyrosine kinase inhibitor in chronic lymphoid leukaemia.

BACKGROUND: Pituitary apoplexy is a neurosurgical emergency and is a known yet rare complication of pituitary macroadenoma. Patients typically present with visual field defects, headache and altered sensorium. There are multiple risk factors for this complication and a thorough drug history is essential to exclude iatrogenic causes of disease. We present an extremely rare case of newly diagnosed pituitary insufficiency unveiled by ibrutinib therapy (a Bruton tyrosine kinase inhibitor). Furthermore, after initial withdrawal of ibrutinib because of the erroneous diagnosis of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), its re-administration led to the development of classical pituitary apoplexy 4 months after treatment was restarted. CASE PRESENTATION: A male patient in his 60s with a background of chronic lymphocytic leukaemia (CLL) on ibrutinib and venetoclax presents with acute confusion and deranged electrolytes. He is found to be hyponatraemic and is diagnosed with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and treated with fluid restriction. He represents again 3 weeks later with hyponatraemia and further investigations reveal pituitary insufficiency and macroadenoma. He was restarted on ibrutinib and venetoclax at the time of discharge. Four months later, he presents with sudden retro-orbital headache associated with vomiting. Clinical findings include cranial nerve III, IV and XI palsy. Humphrey's visual field examination revealed a left visual field index (VFI) of only 1% while the right was 64% with temporal hemianopia. Both pupils were mid-dilated and poorly reactive to light. MRI pituitary with contrast showed features of pituitary apoplexy and optic nerve compression. He was urgently referred to the neurosurgical team and underwent an emergency trans-sphenoidal hypophysectomy with circumferential excision of the macroadenoma. Post-operative recovery was uneventful with marked improvement in vision bilaterally. The patient was restarted on ibrutinib and venetoclax 2 weeks post-operatively. Approximately 1 year post-treatment, he remains in radiological, clinical and biochemical remission from CLL and all medications have been withdrawn. CONCLUSIONS: This is a unique and rare case of pituitary macroadenoma apoplexy following the commencement of ibrutinib for CLL. Central nervous system haemorrhage is a rare side effect of ibrutinib due to its platelet dysfunction effects. A thorough assessment is required to assess the risks and benefits of using ibrutinib in patients with pituitary macroadenoma to avoid serious complications.

Empirical Study on Exploring the Role of CD180 and MD-1 Prognostic Indicators for the Chronic Lymphocytic Leukaemia (CLL) Disease.

&lt;b&gt;Background and Objective:&lt;/b&gt; Chronic Lymphocytic Leukaemia (CLL) is a frequent type of leukaemia disease. This study was focused on investigating the role of prognostic indicators, such as CD180 and MD-1 for Chronic Lymphocytic Leukaemia (CLL) pathogenesis because they involve cell signalling and proliferation. &lt;b&gt;Materials and Methods:&lt;/b&gt; A total of 12 normal controls and 52 patients were taken to determine the expressions of CD180 and MD-1 with different variations in comparison with the IgVH (Immunoglobulin Heavy Chain variable region gene) mutational status, FISH (fluorescence &lt;i&gt;in situ&lt;/i&gt; hybridization) and Rai staging. &lt;b&gt;Results:&lt;/b&gt; The quantitative data findings were evident that CD180 and MD-1 expressions showed insignificant differences among CLL patients at the protein level based on SPSS results. On the contrary, they resulted in significant differences for subgroups of established biomarkers like Rai staging (stages 0, I, II and III), FISH (13q and non-13q deletions) and IgVH (mutated and unmutated). &lt;b&gt;Conclusion:&lt;/b&gt; The CD180 and MD-1 have been used as prognostic indicators to evaluate the outcomes relevant to the cell cycle and survival rate of CLL cells.