Abstract 884: Tumor mutational load derived from recurrently mutated genes in chronic lymphocytic leukemia (CLL) predicts time-to-first treatment in high-count monoclonal B-cell lymphocytosis (HC MBL)

Abstract We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently patients with Rai stage 0 (P=0.008) and mutated IgVH (P=0.03). In contrast, peripheral blood lymphocytosis (P=0.06), serum β2-m (P=0.159), LDH (P=0.333) and percentage of ZAP-70-positive (P=0.242) or CD38-positive B-CLL cells (P=0.142) did not reflect circulating levels of BAFF. The relationship among various bio-pathological parameters, analyzed by the multiple correspondence analysis (MCA), showed two different clinico-biological profiles. The first, characterized by higher BAFF serum levels (i.e., > 336 ng/mL), presence of mutation in the IgVH, low percentage of CD38-positive B-CLL cells (< 30%) and low LDH was associated with a stable pattern of disease generally not requiring therapy. The second, defined by lower BAFF levels, absence of mutation in the IgVH, high percentage of CD38- positive B-CLL cells and high LDH was associated with a more progressive pattern of disease and a shorter TFT. After a median follow-up time of 35 months (range, 2–120 months) 26 (37.6%) out of 69 patients experienced a need for chemotherapy. Kaplan-Meier estimates of patientsTFT, plotted after searching the best cut-off for BAFF (i.e., 336 ng/mL), demonstrated that low BAFF concentration was associated with a shorter TFT (median TFT 36 months) while median was not reached by patients with BAFF levels higher than 336 ng/mL (P<0.0001). Along with lower serum levels of BAFF (Hazard Ratio [HR], 0.19; P<0.0001), the univariate Cox proportional hazard model identified absence of mutation in IgVH (HR, 0.17; P<0.0001), CD38-positivity (HR, 3.32; P=0.01) and lower platelet count (HR, 0.19; P=0.03) as predictor of shorter TFT. Finally, in multivariate analysis only mutational status of IgVH (HR, 0.25; P=0.007) and serum concentration of BAFF (HR, 034; P=0.04) affected significantly TFT. Our results indicate that in early B-cell CLL clinico-biological profile including among other parameters BAFF may provide a useful insight into the complex interrelationship of prognostic variables and semplify their interpretation. The possible presence of BAFF isoform in B-CLL could peraphs account for the unexpected correlation between low soluble BAFF levels and poor clinical outcome in patients with early disease.

Download Full-text

Incidence of chronic lymphocytic leukemia and high-count monoclonal B-cell lymphocytosis using the 2008 guidelines

Cancer ◽

10.1002/cncr.28690 ◽

2014 ◽

Vol 120 (13) ◽

pp. 2000-2005 ◽

Cited By ~ 22

Author(s):

Timothy G. Call ◽

Aaron D. Norman ◽

Curtis A. Hanson ◽

Sara J. Achenbach ◽

Neil E. Kay ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Lymphocytic Leukemia ◽

High Count

Download Full-text

Serum BAFF (B-CELL Activating Factor Of The TNF Family) predicts time to First Treatment in Early B-CELL Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v112.11.4158.4158 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4158-4158

Author(s):

Stefano Molica ◽

Gaetano Vitelli ◽

Giovanna Cutrona ◽

Giovanna Digiesi ◽

Rosanna Mirabelli ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Serum Concentration ◽

B Cell ◽

Serum Levels ◽

Lymphocytic Leukemia ◽

B Cell Activating Factor ◽

Mutational Status ◽

Time To First Treatment ◽

The Impact ◽

Cell Chronic Lymphocytic Leukemia

Abstract We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70− and CD38− expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 125 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently females (P=0.01), patients with Rai stage 0 (P=0.03), mutated IgVH disease (P=0.008) and low ZAP-70 expression (P=0.04). In contrast, age (P=0.35), peripheral blood lymphocytosis (PBL)(P=0.09), hemoglobin (Hb) level (P=0.64), platelet (PLT) count (P=0.12), serum β2-m (P=0.49), LDH (P=0.85) and percentage of CD38-positive B-CLL cells (P=0.63) did not reflect circulating levels of BAFF. We used an optimal cut-point search to determine how to best split soluble BAFF data. Maximally selected log-rank statistics plots identified a BAFF serum concentration of 311 ng/mL as the best cut-off (P<0.0001). Accordingly, patients who had BAFF levels higher than 311 ng/mL experienced a longer TFT (median 108 months) in comparison to patients whose BAFF levels were lower than 311 ng/mL (median 30 months; P<0.0001). Along with serum concentration of BAFF, the univariate Cox proportional hazard model identified Rai substage I–II (P=0.003), lower PLT count (P=0.04), higher PBL count (P=0.01), increased LDH (P=0.01), ZAP-70 expression > 20% (P=0.02) and absence of mutation of IgVH (P<0.0001) as predictor of shorter TFT. In multivariate analysis only soluble BAFF (Hazard ratio [HR], 6.13; CI 95%, 2.31–16.25) and mutational status of IgVH, (HR= 2.99; CI 95% 1.33–6.76, P=0.008) maintained their discriminating power. The effects of BAFF on TFT were masked by mutational status of IgVH in patients with unmutated IgVH. However, serum levels of BAFF and mutational status of IgVH had a joint effect on TFT in patients with mutated IgVH which translates into a segregation of patients with mutated IgVH in two groups with different TFT according to BAFF levels (HR= 8.9; P<0.0001). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, BAFF along with mutational status of IgVH can be adequately used to predict clinical behaviour of patients with low biological risk.

Download Full-text

Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification

Blood ◽

10.1182/blood-2015-02-585059 ◽

2015 ◽

Vol 126 (4) ◽

pp. 454-462 ◽

Cited By ~ 96

Author(s):

Paolo Strati ◽

Tait D. Shanafelt

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Risk Stratification ◽

B Cell ◽

Cell Count ◽

Early Stage ◽

Lymphocytic Leukemia ◽

High Count ◽

Genetic Characteristics ◽

Increased Risk ◽

Risk Of Progression

Abstract Monoclonal B lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 × 109/L B-cells and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukemia (CLL). MBL can be categorized as either low count or high count based on whether the B-cell count is above or below 0.5 × 109/L. Low-count MBL can be detected in ∼5% of adults over the age of 40 years when assessed using standard-sensitivity flow cytometry assays. A number of biological and genetic characteristics distinguish low-count from high-count MBL. Whereas low-count MBL rarely progresses to CLL, high-count MBL progresses to CLL requiring therapy at a rate of 1% to 2% per year. High-count MBL is distinguished from Rai 0 CLL based on whether the B-cell count is above or below 5 × 109/L. Although individuals with both high-count MBL and CLL Rai stage 0 are at increased risk of infections and second cancers, the risk of progression requiring treatment and the potential to shorten life expectancy are greater for CLL. This review highlights challenging questions regarding the classification, risk stratification, management, and supportive care of patients with MBL and CLL.

Download Full-text

Developmental DNA Methylation Subtype Predicts Progression to Treatment and Survival in High-Count Monoclonal B Lymphocytosis

Blood ◽

10.1182/blood-2019-123564 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3022-3022

Author(s):

Brian Giacopelli ◽

Kari G. Chaffee ◽

Yue-zhong Wu ◽

John C. Byrd ◽

Tait D. Shanafelt ◽

...

Keyword(s):

Dna Methylation ◽

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Research Funding ◽

Data Safety Monitoring Board ◽

Lymphocytic Leukemia ◽

State University ◽

High Count ◽

University Patents

Monoclonal B cell lymphocytosis (MBL) has been shown to be the precursor condition that precedes overt diagnosis of chronic lymphocytic leukemia (CLL). Whereas CLL is classified with greater than or equal to 5 × 109/L B lymphocytes in the peripheral blood, MBL is a clonal expansion of B-cells below this threshold. MBL can be further divided into high- or low-count based on whether the B-cell count is above or below 0.5 × 109/L. Approximately 10% of the population over 40 is estimated to have MBL, increasing to >50% over the age of 90. While low-count MBL is unlikely to progress, 1-2% of high-count (HC) MBL individuals progress to CLL requiring therapy per year. It is debatable if all patients with detectable MBL should be classified as an entity requiring monitoring by a hematologist, especially for low-count MBL. In addition, the diagnosis of leukemia is distressing to patients; therefore, it is important to identify HC MBL patients that are more likely to progress to disease requiring treatment and thus should be monitored more closely. As the majority of MBL cases phenotypically resemble CLL, established prognostic markers including recurrent chromosomal aberrations, beta-2 microglobulin levels, and the mutational status of the Immunoglobulin heavy-chain variable region locus (IGHV) have been shown to predict time to treatment (TTT) and overall survival (OS) in a large retrospective study of MBL1. CLL patients can also be divided into three distinct epigenetic subtypes that reflect progressive DNA methylation changes that occurs during B cell development. These 'epitypes' termed low-programmed (LP), intermediate-programmed (IP), and high-programmed (HP) independently predict clinical outcomes irrespective of disease stage and treatment2. LP-CLL patients follow a generally unfavorable clinical course compared to the more indolent HP-CLL patients, while IP CLL patients display an intermediate outcome. Here we sought to determine if epitype forecasts progression to CLL and eventual clinical outcome for individuals with MBL. We analyzed 66 individuals diagnosed with HC MBL at the Mayo Clinic with a median follow-up of 6.3 years. Developmental epitype was determined using our novel Methylation-iPLEX technique that interrogates 34 CpGs and assigns epitype using a random forest model2. Seventy-seven percent of the MBL cases were assigned to one of the three epitypes: 42.4% HP, 19.7% IP, and 15.2% LP. The residual 23% remained unclassified due to ambiguous (low confidence) epigenetic patterns or insufficient purity (Figure 1A). The overall proportion of HP and IP epitypes in MBL were significantly greater than proportions observed in CLL cohorts (P<0.01). Epitypes remained stable over time as 20/21 cases for which we obtained a high-confidence epitype classification at multiple time points remained unchanged. Epitype significantly predicted MBL individuals progressing to treatment (P=0.001) with LP individuals progressing in a median of 5.6 years (P=0.049 and P=0.0002 versus IP and HP, respectively); median was not reached in HP or IP (Figure 1B). Epitype also predicted overall survival (OS) in MBL (P=0.04), with LP individuals having a significantly shorter OS (median of 11 years versus not reached in IP and HP; P=0.056 and P=0.048 versus IP and HP, respectively). In this study we evaluated a cohort of 66 HC MBL cases and determined that classification using developmental DNA methylation epitypes can be employed in HC MBL to aid in risk stratification. HC MBL patients classified as LP are more likely to progress to requiring treatment and have a significantly reduced OS. The epigenetic classification may help clinicians decide how closely and frequently a HC MBL individual needs to be monitored. Figure 1: (A) Breakdown of the epigenetic subtype assigned to 66 HC MBL samples. (B) Kaplan-Meier analysis of time to treatment and (C) overall survival of MBL patients separated by epitype. 1. Parikh, S. A. et al. Outcomes of a large cohort of individuals with clinically ascertained high-count monoclonal B-cell lymphocytosis. Haematologica103, e237-e240 (2018). 2. Giacopelli, B. et al. Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia. Blood blood.2019000490 (2019). doi:10.1182/blood.2019000490 Disclosures Byrd: Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding. Shanafelt:Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Merck: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Glaxo-SmithKline: Research Funding; Abbvie: Research Funding; Cephalon: Research Funding; Celgene: Research Funding. Parikh:Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding. Kay:Agios: Other: DSMB; MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board.

Download Full-text

Understanding Monoclonal B Cell Lymphocytosis: An Interplay of Genetic and Microenvironmental Factors

Frontiers in Oncology ◽

10.3389/fonc.2021.769612 ◽

2021 ◽

Vol 11 ◽

Author(s):

Chrysi Galigalidou ◽

Laura Zaragoza-Infante ◽

Anastasia Iatrou ◽

Anastasia Chatzidimitriou ◽

Kostas Stamatopoulos ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Disease Onset ◽

Gene Mutations ◽

Lymphocytic Leukemia ◽

High Count ◽

Microenvironmental Factors ◽

Genomic Aberrations ◽

The Relationship ◽

Malignant Condition

The term monoclonal B-cell lymphocytosis (MBL) describes the presence of a clonal B cell population with a count of less than 5 × 109/L and no symptoms or signs of disease. Based on the B cell count, MBL is further classified into 2 distinct subtypes: ‘low-count’ and ‘high-count’ MBL. High-count MBL shares a series of biological and clinical features with chronic lymphocytic leukemia (CLL), at least of the indolent type, and evolves to CLL requiring treatment at a rate of 1-2% per year, whereas ‘low-count’ MBL seems to be distinct, likely representing an immunological rather than a pre-malignant condition. That notwithstanding, both subtypes of MBL can carry ‘CLL-specific’ genomic aberrations such as cytogenetic abnormalities and gene mutations, yet to a much lesser extent compared to CLL. These findings suggest that such aberrations are mostly relevant for disease progression rather than disease onset, indirectly pointing to microenvironmental drive as a key contributor to the emergence of MBL. Understanding microenvironmental interactions is therefore anticipated to elucidate MBL ontogeny and, most importantly, the relationship between MBL and CLL.

Download Full-text

Serum CD26 (Dipeptidyl Peptidase IV, DPP IV) compared with Immunoglobulin Heavy-Chain Mutation Status, ZAP-70 and CD38 as a Predictor of Time to First Treatment in Early B-CELL Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v112.11.4187.4187 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4187-4187 ◽

Cited By ~ 1

Author(s):

Stefano Molica ◽

Gaetano Vitelli ◽

Giovanna Cutrona ◽

Rosanna Mirabelli ◽

Giovanna Digiesi ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Serum Concentration ◽

B Cell ◽

Heavy Chain ◽

Serum Levels ◽

Dipeptidyl Peptidase Iv ◽

Lymphocytic Leukemia ◽

Dpp Iv ◽

Mutational Status ◽

Time To First Treatment

Abstract We analyzed the correlation between well-established biological parameters of prognostic relevance in B-chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of CD26 (dipeptidyl peptidase IV, DPP IV) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-CLL patients. By using a commercial ELISA (Human DPPIV/CD26 Quantikine R D Systems, USA) we found that circulating levels of CD26 did not reflect Rai sub-stages (P=0.52), β2-microglobulin (P=0.68), LDH (P=0.06), mutational status of IgVH (P=0.28), ZAP-70 (P=0.52) and CD38 (P=0.48). We used an optimal cut-point search to determine how to best split soluble CD26 data. Maximally selected logrank statistics plots identified a CD26 serum concentration of 371 ng/mL as the best cut-off. Accordingly, patients who had CD26 levels higher than 371 ng/mL experienced a shorter TFT (median 40 months) in comparison to patients whose CD26 levels were lower than 371 ng/mL (median 120 months; P=0.003). The univariate Cox proportional hazard model identified higher serum concentration of CD26 and absence of mutation in IgVH as predictor of shorter TFT. Again in multivariate analysis all these parameters maintained their discriminating power: mutational status of IgVH (HR= 0.23; CI 95% 0.10−0.51, P<0.0001), soluble CD26 (HR= 0.38; CI 95% 0.17−0.85, P=0.02). The effects of CD26 on TFT were masked by mutational status of IgVH in patients with unmutated IgVH. In contrast, serum levels of CD26 and mutational status of IgVH had a joint effect on TFT in patients with mutated IgVH which translates into a segregation of patients with mutated IgVH in two sub-groups with different TFT according to CD26 levels (HR= 0.18; CI 95% 0.05−0.60, P=0.005). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble CD26 may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, CD26 along with mutational status of IgVH can be adequately used to predict clinical behaviour of patients with low biological risk.

Download Full-text