Reduced prognostic value of beta-2-microglobulin for time to first treatment in CLL patients with compromised kidney function.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and characterized by a highly heterogeneous clinical course. The CLL-IPI and the OCLL-1 scores are among the best validated tools to predict time-to-first-treatment. In both models, elevated beta-2-microglobulin plasma level (B2M) is an independent prognostic factor. Yet, B2M is commonly increased in patients with chronic kidney disease (CKD) per se and both models were not adjusted for CKD. We analyzed the clinical outcomes of 297 treatment-naive CLL patients between 2000 and 2022. B2M was more frequently elevated in CKD patients and lost prognostic significance at the threshold > 2.5 mg/L. Both CLL-IPI and OCLL-1 failed to facilitate prognostic segregation in CKD patients. 22.2% of CKD patients were assigned to a higher CLL-IPI risk group due to elevated B2M. Our results suggest that both models overestimate the risk for disease progression and need to be interpreted with caution in CKD patients.

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.

B cell receptor signaling proteins as biomarkers for progression of CLL requiring first-line therapy.

The molecular landscape of chronic lymphocytic leukemia (CLL) has been extensively characterized, and various potent prognostic biomarkers were discovered. The genetic composition of the B-cell receptor (BCR) immunoglobulin (IG) was shown to be especially powerful for discerning indolent from aggressive disease at diagnosis. Classification based on the IG heavy chain variable gene (IGHV) somatic hypermutation status is routinely applied. Additionally, BCR IGH stereotypy has been implicated to improve risk stratification, through characterization of subsets with consistent clinical profiles. Despite these advances, it remains challenging to predict when CLL progresses to requiring first-line therapy, thus emphasizing the need for further refinement of prognostic indicators. Signaling pathways downstream of the BCR are essential in CLL pathogenesis, and dysregulated components within these pathways impact disease progression. Considering not only genomics but the entirety of factors shaping BCR signaling activity, this review offers insights in the disease for better prognostic assessment of CLL.

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting.

Immunoglobulin heavy chain variable ( IGHV ) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p < 0.0001), and shorter OS (112 vs. 246 months, p < 0.0001) than the mutated CLL. IGHV3 was the most frequently used IGHV family (46%), followed by IGHV1 (30%) and IGHV4 (16%). IGHV5-51 and IGHV1-69 subfamilies were associated with poor prognosis, while IGHV4 and IGHV2 showed the best outcomes. The prevalence of CK was 15% and was significantly associated with U-CLL. In the multivariable analysis, IGHV2 gene usage and del13q were associated with longer TTFT, while VH1-02, +12, del11q, del17p, and U-CLL with shorter TTFT. Moreover, VH1-69 usage, del11q, del17p, and U-CLL were significantly associated with shorter OS. A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.

A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.

Serum soluble CD23 levels are an independent predictor of time to first treatment in chronic lymphocytic leukemia.

Serum soluble CD23 (sCD23) levels have been acknowledged as a prognostic factor in patients with chronic lymphocytic leukemia (CLL), but their potential relevance has not been analyzed in recent times. We retrospectively studied 338 CLL, small lymphocytic lymphoma, or CLL-type monoclonal B-cell lymphocytosis patients from a single institution, with available sCD23 levels at diagnosis. Baseline features and outcomes were compared between patients with sCD23 ≤/>1000 UI/L. The 140 patients (41%) who had sCD23 > 1000 UI/L showed adverse-risk clinical and biological characteristics. High sCD23 levels were predictive of a shorter time to first treatment (5-year probability of requiring treatment: 60 vs. 20%, p < 0.0001; hazard ratio (HR) = 1.72, p = 0.003 in a multivariable model also including the CLL International Prognostic Index and the absolute lymphocyte count), and a poorer 5-year overall survival (70 vs. 82%, p = 0.0009). These data suggest the potential of sCD23 to predict treatment-free survival and to shed light on mechanisms of activity and resistance to CD23-directed therapies.

Role of cytogenetic abnormalities detected by fluorescence in situ hybridization as a prognostic marker: Pathogenesis & clinical course in patients with B-chronic lymphocytic leukaemia.

BACKGROUND & OBJECTIVES: B-cell chronic lymphocytic leukaemia (B-CLL) is one of the most common forms of adult leukaemia, with a highly variable clinical course. Specific chromosomal and genetic aberrations are used clinically to predict prognosis, independent from conventional clinical markers. Molecular cytogenetic methods such as fluorescence in situ hybridization (FISH) detect aberrations in up to 80 per cent B-CLL patients. This study was conducted to score the frequencies of recurrent aberrations, i.e., del(13q14), trisomy 12, del(11q22), del(17p13), del(6q21) and IgH (immunoglobulin heavy chain) translocations and to understand their role in prognostication and risk stratification. METHODS: FISH studies were performed on bone marrow aspirate or peripheral blood of 280 patients using commercially available disease-specific probe set. The data were correlated with clinical and haematological parameters such as low haemoglobin, splenomegaly and lymphadenopathy. RESULTS: Chromosomal aberrations were detected in 79 per cent of patients, with del(13q14) (57%) as the most common cytogenetic aberration, followed by trisomy 12 (27%), del(11q22) (22%), t(14q32) (19%), del(17p13) (18%) and del(6q21) (9%). Single or in coexistence with other aberration del(13q14) had a favourable outcome in comparison to del(11q22), t(14q32), del(17p13) and del(6q21) which were associated with advanced stages of the disease. Trisomy 12 had a variable clinical course. INTERPRETATION & CONCLUSIONS: FISH was found to be a sensitive and efficient technique in detecting the prevalence of recurrent cytogenetic abnormalities. Each of these aberrations is an important independent predictor of disease progression and survival which aids in designing risk-adapted treatment strategies for better disease management.

Extracellular vesicles and their associated miRNAs as potential prognostic biomarkers in chronic lymphocytic leukemia.

PURPOSE OF REVIEW: Many prognostic and predictive biomarkers have been proposed for chronic lymphocytic leukaemia (CLL). Here, we aim to discuss the evidence showing a prognostic potential for extracellular vesicles (EV) and their associated microRNAs (miRNAs). RECENT FINDINGS: EV are produced by several cells in the body as a physiological event; however, there is evidence suggesting that an elevated EV concentration is present in the circulation of CLL patients. Moreover, some studies have associated EV concentration with advanced Rai stage and unmutated CLL while others have demonstrated its potential as an independent prognostic factor for TTFT and OS. Finally, some studies have shown that CLL EV shared some dysregulated microRNAs with CLL cells and plasma. On the other hand, it was found that CLL EV has a distinctive microRNA expression profile. Until now, EV-associated miR-155 is the most studied miRNA. Despite methodological diversity and limitations in study design, unanimity in CLL EV concentration behaviour and miRNA content has been found.

Comparative assessment of prognostic models in chronic lymphocytic leukemia: evaluation in Indian cohort.

Prognostic indices combining several clinical and laboratory parameters have been proposed for prognostication in chronic lymphocytic leukemia (CLL). Recently, international consortium on CLL proposed an international prognostic index (CLL-IPI) integrating clinical, molecular, and genetic parameters. The present study was designed to evaluate the reproducibility of CLL-IPI in Indian CLL cohort. The prognostic ability of CLL-IPI in terms of overall survival (OS) and time to first treatment (TTFT) was investigated in treatment-naive CLL patients and also compared with other existing prognostic scores. For assigning scores, clinical and laboratory details were obtained from medical records, and IGHV gene mutation status, ß2-microglobulin levels, and copy number variations were determined using c-DNA, ELISA, and multiplex ligation-dependent probe amplification (MLPA), respectively. The scores were generated as per the weighted grades assigned to each variable involved in score categorization. The predictive value of prognostic models was assessed and compared using Harrell's C-index and Akaike's information criterion (AIC). Stratification of patients according to CLL-IPI yielded significant differences in terms of OS and TTFT (p < 0.001). Comparative assessment of scores for OS suggested better performance of CLL-IPI (C = 0.64, AIC = 740) followed by Barcelona-Brno (C = 0.61, AIC = 754) and MDACC score (C = 0.59, AIC = 759). Comparison of predictive value of prognostic scores for TTFT illustrated better performance of CLL-IPI (C = 0.72, AIC = 726) followed by Barcelona-Brno (C = 0.68, AIC = 743), modified GCLLSG (C = 0.66, AIC = 744), and O-CLL1 index (C = 0.55, AIC = 773). The results suggest better performance of CLL-IPI in terms of both OS and TTFT as compared to other available scores in our cohort.

The prognostic role of HBV infection in chronic lymphocytic leukemia.

PURPOSE: We attempt to assess the impact of hepatis-B virus (HBV) status on the prognosis of chronic lymphocytic leukemia (CLL) using a Chinese case cohort. METHODS: Five hundred and one consecutive newly diagnosed subjects with CLL were enrolled in this case cohort. HBV infection was defined as hepatitis B surface antigen (HBsAg) positive or hepatitis-B core antibody (HBcAb) positive. Univariate and stepwise multivariate Cox regression analyses were used to screen the prognostic risk factors associated with the end point of time-to-treatment (TTT) or overall survival (OS). Bootstrap re-sampling method was used to evaluate the model's internal validity. The discriminative ability of the models was evaluated using time-dependent receiver-operator characteristic (ROC) curves and corresponding areas under the curve (AUC). RESULTS: One hundred and twenty-one subjects (24%) among 501 patients were HBV positive. HBV infection was an independent predictor for the prognosis of TTT (HR = 1.37; 95% CI 1.04-1.80) or OS (HR =2.85; 95% CI 1.80-4.52). The AUCs for HBV infection were 0.62 (95% CI 0.58-0.66) for TTT and 0.69 (95% CI 0.66-0.72) for OS, respectively. When we combined HBV infection with the traditional clinical and biological factors, significant improvements for model's discrimination were observed for TTT [AUC: 0.81 (95% CI: 0.77-0.85) vs. 0.78 (95% CI: 0.74-0.82), P < 0.001] and OS [AUC: 0.81 (95% CI 0.76-0.86) vs. 0.76 (95% CI 0.71-0.82), P < 0.001). Further bootstrap re-sampling method revealed good internal consistence for the final optimal models (Average AUC: 0.78 for TTT and 0.79 for OS based on 1000 bootstraps). CONCLUSIONS: Our results indicated that HBV infection should be served as an important risk predictor for prognosis of CLL (TTT and OS).

In chronic lymphocytic leukaemia with complex karyotype, major structural abnormalities identify a subset of patients with inferior outcome and distinct biological characteristics.

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.

Cryptochrome-1 Gene Expression is a Reliable Prognostic Indicator in Egyptian Patients with Chronic Lymphocytic Leukemia: A Prospective Cohort Study

Objective: Traditional prognostic factors have proved insufficient to account for heterogeneity in the clinical behavior of chronic lymphocytic leukemia (CLL). Cryptochrome-1 (CRY-1) is a circadian clock gene essential in maintaining the circadian rhythm and regulating cell proliferation. We evaluated CRY-1 gene expression in CLL and addressed its putative role as a prognostic indicator for the clinical course of CLL. Materials and Methods: A total of 100 CLL patients at diagnosis were studied for CRY-1 gene expression by real-time reverse-transcription polymerase chain reaction and were followed for assessment of time to first treatment (TFT). Results: CRY-1 was expressed in 94% of the CLL patients at diagnosis. The median CRY-1 relative gene expression level (0.006) stratified patients into high and low expression groups. Forty of 100 (40%) CLL patients showed high CRY-1, 54/100 (54%) showed low CRY-1, and 6/100 (6%) had undetectable CRY-1 gene expression. High CRY-1 gene expression was concordant with CD38+, Zap-70+, and double CD38+Zap-70+ expression; unfavorable/intermediate cytogenetics; unmutated immunoglobulin heavy-chain variable-region gene; and diffuse marrow infiltration. The high CRY-1 gene expression patient group exhibited shorter TFT than the patients with low CRY-1 gene expression. A Cox proportional hazard regression model identified CRY-1 gene expression to be independently predictive for TFT. Conclusion: CRY-1 is differentially expressed among CLL patients, stratifying them into low-risk and high-risk groups. CRY-1 gene expression could constitute a reliable prognostic indicator for CLL progression, complementing the role of standard well-established prognostic factors. CRY-1 gene expression could be employed as a prognostic indicator for disease progression during the initial prognostic work-up and follow-up for CLL patients.

A study for proposal of use of regulatory T cells as a prognostic marker and establishing an optimal threshold level for their expression in chronic lymphocytic leukemia.

Although regulatory T cells (Tregs) have been extensively studied in chronic lymphocytic leukemia, there is no uniform guideline or consensus regarding their use as a prognostic marker. This study describes the methodology used to develop an optimal threshold level for Tregs in these patients. Treg levels were assessed in the peripheral blood of 130 patients and 150 controls. Treg frequencies were linked to established prognostic markers as well as overall survival and time to first treatment. The cut-offs for Treg positivity were assessed by receiver operating characteristic (ROC) analysis. A cut-off of 5.7% for Treg cell percentage and of 35 cells/µL for absolute Treg cell count were determined as optimal in patients with CLL along with a median Treg percentage of 15.5% used to separate patients with low- and high-risk disease. The experiments presented here will possibly aid in the use of Treg frequencies as a potential prognostic marker in CLL.