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Chronic Lymphocytic Leukemia (CLL)

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Richter's Syndrome

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Shanafelt TD, Wang XV, Kay NE, et al.
Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.
N Engl J Med. 2019; 381(5):432-443 [PubMed] Related Publications
BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.
METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.
RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (
CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

Ioannidou A, Zachaki S, Daraki A, et al.
Paraoxonase 1 (PON1) Q192R and L55M Polymorphisms as Potential Predisposition Factors for Chronic Lymphocytic Leukemia.
Anticancer Res. 2019; 39(6):2861-2869 [PubMed] Related Publications
BACKGROUND/AIM: PON1 gene has an executive role in antioxidant defense, protecting cells from genotoxic factors. Q192R and L55M PON1 polymorphisms reduce catalytic activity of the encoded protein. These polymorphisms were studied in 300 chronic lymphocytic leukemia (CLL) patients and 106 healthy donors. They were also associated with patients' cytogenetic findings, to investigate their possible implication in CLL pathogenesis.
MATERIALS AND METHODS: SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Karyotypic analysis was also performed by chromosome G-banding analysis and fluorescence in situ hybridization.
RESULTS: Genotypic and allelic distribution of Q192R polymorphism showed a statistically significant higher frequency of mutant genotypes and mutant alleles in patients compared to controls. The same observation was noted in patients with abnormal karyotypes and those carrying abn14q32 and del(6q). A statistically increased frequency for the mutant allele was also revealed in patients with del(11q). On the contrary, L55M polymorphism showed a similar distribution between patients and controls.
CONCLUSION: Q192R polymorphism plays a role in CLL predisposition and the formation of specific chromosomal aberrations.

Michalová Z, Čoma M, Kičová M, et al.
Overexpression of Galectin-3 in Chronic Lymphocytic Leukemia Is Associated With 17p Deletion: A Short Report.
Anticancer Res. 2019; 39(6):2805-2810 [PubMed] Related Publications
BACKGROUND/AIM: Galectins belong to the family of galactose-binding proteins known to play an important role in the processes of cell proliferation, differentiation, migration and neoplastic progression. Herein, we studied the expression of galectin-3 (Gal-3) in chronic lymphocytic leukemia (CLL).
MATERIALS AND METHODS: The expression of Gal-3 was analyzed by means of multiparametric flow cytometry in normal and pathological B-cells from peripheral blood and bone marrow samples of 67 patients with CLL.
RESULTS: Pathological B-cells expressed significantly higher levels of cytoplasmic Gal-3 than normal B-cells. Moreover, overexpression of cytoplasmic Gal-3 was observed in the prognostically poorest subgroup of CLL patients, namely those with 17p deletion.
CONCLUSION: Our results indicate a possible role of galectin-3 in CLL pathophysiology and its potential value as a prognostic marker and therapeutic target.

Bogeljić Patekar M, Milunović V, Mišura Jakobac K, et al.
Acta Clin Croat. 2018; 57(3):542-553 [PubMed] Free Access to Full Article Related Publications
- The aim of this review is to present data on bendamustine, a non-cross resistant alkylating agent, alone or in combination for treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bendamustine is currently approved for rituximab-resistant indolent NHL and CLL in patients not fit for conventional chemotherapy. Recent studies have shown superiority of bendamustine combination with rituximab (B-R) in first line treatment of indolent NHLs and mantle cell lymphoma, suggesting a shift of the standard of care in this setting. B-R regimen has also shown efficacy in relapsed setting suggesting the possible treatment option for patients failing conventional chemotherapy. In rituximab-resistant NHL, the recent GADOLIN study exploring the addition of obinutuzumab to bendamustine has yielded impressive result changing the standard of care in this hard-to-treat population. Concerning CLL, despite inferiority to the standard of care in young fit patients, as defined in CLL10 study, B-R has yielded a more beneficial toxicity profile and its use in first line treatment should be decided individually. In relapsed setting, the addition of ibrutinib to B-R has shown superior results compared to B-R alone, possibly changing the paradigm of treatment of relapsed CLL. In conclusion, bendamustine as a single agent or in combinations has shown activity with acceptable toxic profile in the treatment of patients with indolent NHLs or CLL without del(17p) mutation.

Fischer K, Al-Sawaf O, Bahlo J, et al.
Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.
N Engl J Med. 2019; 380(23):2225-2236 [PubMed] Related Publications
BACKGROUND: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known.
METHODS: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated.
RESULTS: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with
CONCLUSIONS: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).

Birkinshaw RW, Gong JN, Luo CS, et al.
Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations.
Nat Commun. 2019; 10(1):2385 [PubMed] Free Access to Full Article Related Publications
Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.

Žigart N, Časar Z
A literature review of the patent publications on venetoclax - a selective Bcl-2 inhibitor: discovering the therapeutic potential of a novel chemotherapeutic agent.
Expert Opin Ther Pat. 2019; 29(7):487-496 [PubMed] Related Publications
INTRODUCTION: Studies presented in patents show that a novel chemotherapeutic agent, venetoclax, might be useful in additional therapeutic indications. Venetoclax is approved in America for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax selectively inhibits the B-cell lymphoma-2 (Bcl-2) protein, an anti-apoptotic protein that can be overexpressed in most B-cell lymphoid malignancies.
AREAS COVERED: This is a review of all the patents granted until November 2018, with venetoclax in the examples or claim section of the patent document. The patents include the synthesis, polymorphism, formulations,
EXPERT OPINION: The approved indications for treatment with venetoclax are limited but expanding rapidly. Studies suggest that venetoclax might be useful in several other therapeutic indications, mostly other hematological malignancies. Numerous studies use venetoclax in combinations with other therapeutic agents. Such combinational treatment shows promising results in additional indications as well as drug-resistant cancers. Venetoclax is an interesting new therapeutic involved in a variety of clinical research. Patent applications in recent years even include venetoclax in somewhat exotic fields such as type 1 diabetes, asthma, and Zika virus treatment.

Jain N, Keating M, Thompson P, et al.
Ibrutinib and Venetoclax for First-Line Treatment of CLL.
N Engl J Med. 2019; 380(22):2095-2103 [PubMed] Related Publications
BACKGROUND: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.
METHODS: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated
RESULTS: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated
CONCLUSIONS: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).

Sachanas S, Pangalis GA, Fink AM, et al.
Small Lymphocytic Lymphoma: Analysis of Two Cohorts Including Patients in Clinical Trials of the German Chronic Lymphocytic Leukemia Study Group (GCLLSG) or in "Real-Life" Outside of Clinical Trials.
Anticancer Res. 2019; 39(5):2591-2598 [PubMed] Related Publications
BACKGROUND: Only few studies have focused exclusively on patients with small lymphocytic lymphoma (SLL).
PATIENTS AND METHODS: In the present report, 103 SLL patients were analyzed from both, clinical trials of the German Chronic Lymphocytic Leukemia Study Group and Greek centers, and emphasis was placed on the therapeutic strategy. The impact of lymph node characteristics, such as the presence of proliferation centers (PCs) on response and survival was also assessed.
RESULTS: SLL patients included in clinical trials were treated mostly with fludarabine-based regimens while those in "real-life" were staged and treated mostly as patients with low-grade lymphomas. Our analysis showed a trend for better survival for patients with SLL without detectable PCs.
CONCLUSION: Patients with SLL outside of clinical trials are usually treated as cases of lymphoma. In addition, this analysis supports published data regarding the adverse prognostic value of the presence of PCs in lymphoid nodes in SLL.

Lavezzi SM, de Jong J, Neyens M, et al.
Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial.
Pharm Res. 2019; 36(7):93 [PubMed] Related Publications
INTRODUCTION: In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab.
METHODS: 578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling.
RESULTS: Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data.
CONCLUSIONS: BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments.
TRIAL REGISTRATION: This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090 .

Pastore A, Gaiti F, Lu SX, et al.
Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL.
Nat Commun. 2019; 10(1):1874 [PubMed] Free Access to Full Article Related Publications
Cancer evolution is fueled by epigenetic as well as genetic diversity. In chronic lymphocytic leukemia (CLL), intra-tumoral DNA methylation (DNAme) heterogeneity empowers evolution. Here, to comprehensively study the epigenetic dimension of cancer evolution, we integrate DNAme analysis with histone modification mapping and single cell analyses of RNA expression and DNAme in 22 primary CLL and 13 healthy donor B lymphocyte samples. Our data reveal corrupted coherence across different layers of the CLL epigenome. This manifests in decreased mutual information across epigenetic modifications and gene expression attributed to cell-to-cell heterogeneity. Disrupted epigenetic-transcriptional coordination in CLL is also reflected in the dysregulation of the transcriptional output as a function of the combinatorial chromatin states, including incomplete Polycomb-mediated gene silencing. Notably, we observe unexpected co-mapping of typically mutually exclusive activating and repressing histone modifications, suggestive of intra-tumoral epigenetic diversity. Thus, CLL epigenetic diversification leads to decreased coordination across layers of epigenetic information, likely reflecting an admixture of cells with diverging cellular identities.

Hasan KM
Clinical Aspects, Immunophenotypic Analysis and Survival Rate of Chronic Lymphocytic Leukaemia Patients in Erbil City, Iraq.
Sultan Qaboos Univ Med J. 2018; 18(4):e461-e467 [PubMed] Free Access to Full Article Related Publications
Objectives: Chronic lymphocytic leukaemia (CLL) is characterised by an accumulation of clonal B cells in the blood, bone marrow and lymphatic tissue. This study aimed to evaluate the clinical and immunophenotypic characteristics and survival rate of CLL patients.
Methods: This retrospective study was conducted at the Nanakaly Hospital for Blood Diseases & Oncology in Erbil, Iraq, between January 2011 and December 2017. A total of 105 CLL patients were assessed to determine clinical presentation and staging, immunophenotype and survival rate.
Results: The median age of the patients was 65 years and 63.8% were male. The main clinical presentations were splenomegaly (64.8%), pallor (61.9%) and lymphadenopathy (60%). More than half of the patients presented at an advanced clinical stage according to the Rai and Binet staging systems (59.1% and 55.2%, respectively). All CLL cases expressed both cluster of differentiation (CD)19 and CD5, 67.6% had monoclonal kappa light chains and 21% expressed CD38. The five-year overall survival (OS) rate was 61.3%. The mean duration of five-year survival was 41.3 months (95% confidence interval: 36.4-46.3 months). There were no correlations between survival and sociodemographic, clinical or laboratory characteristics.
Conclusion: In comparison to the existing Western literature, Iraqi CLL patients more frequently presented with hepatosplenomegaly and at a more advanced clinical stage. In addition, the five-year OS rate was much lower.

Hamdy R, Elseginy SA, Ziedan NI, et al.
New Quinoline-Based Heterocycles as Anticancer Agents Targeting Bcl-2.
Molecules. 2019; 24(7) [PubMed] Free Access to Full Article Related Publications
The Bcl-2 protein has been studied as an anticancer drug target in recent years, due to its gatekeeper role in resisting programmed cancer cell death (apoptosis), and the design of BH3 domain mimetics has led to the clinical approval of Venetoclax (ABT-199) for the treatment of chronic lymphocytic leukaemia. In this work we extend our previous studies on the discovery of indole-based heterocycles as Bcl-2 inhibitors, to the identification of quinolin-4-yl based oxadiazole and triazole analogues. Target compounds were readily synthesized via a common aryl-substituted quinolin-4-carbonyl-

Korycka-Wolowiec A, Wolowiec D, Kubiak-Mlonka A, Robak T
Venetoclax in the treatment of chronic lymphocytic leukemia.
Expert Opin Drug Metab Toxicol. 2019; 15(5):353-366 [PubMed] Related Publications
INTRODUCTION: Venetoclax, an antagonist of BCL-2 protein plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). It has been approved by the FDA for the treatment of relapsed/refractory CLL with del17p, and by the EMA for patients with del17p/TP53 mutation who have failed a BCR inhibitor, or in patients without those aberrations who have failed previous therapy, regardless of their genetic/molecular profile. Venetoclax in combination with rituximab has been also approved for the treatment of CLL after at least 1 prior therapy, regardless of del17p. Areas covered: This article reviews the chemical structure, mechanisms of action, pharmacokinetic, and the clinical applications of venetoclax in monotherapy and in combined treatment of CLL. Publications dated 2010 through March 2019 were obtained from the MEDLINE database. The proceedings of the American Society of Hematology held during the last five years were also included. Expert opinion: Venetoclax shows high efficacy, a favorable toxicity profile, and a high rate of minimal residual disease negativity, which is thought to have an impact on overall survival. It is efficient in patients with del17p/TP53 mutations, the incidence of which increases during clonal CLL evolution, and after the failure of BCR pathway inhibitors.

Alsagaby SA
Transcriptomics-based validation of the relatedness of heterogeneous nuclear ribonucleoproteins to chronic lymphocytic leukemia as potential biomarkers of the disease aggressiveness.
Saudi Med J. 2019; 40(4):328-338 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To use independent transcriptomics data sets of cancer patients with prognostic information from public repositories to validate the relevance of our previously described chronic lymphocytic leukemia (CLL)-related proteins at the level of transcription (mRNA) to the prognosis of CLL.  Methods: This is a validation study that was conducted at Majmaah University, Kingdom of Saudi Arabia between January-2017 and July-2018. Two independent data sets of CLL transcriptomics from Gene Expression Omnibus (GEO) with time-to-first treatment (TTFT) data (GSE39671; 130 patients) and information about overall survival (OS) (GSE22762; 107 patients) were used for the validation analyses. To further investigate the relatedness of a transcript of interest to other neoplasms, 6 independent data sets of cancer transcriptomics with prognostic information (1865 patients) from the cancer genomics atlas (TCGA) were used. Pathway-enrichment analyses were conducted using Reactome; and correlation analyses of gene expression were performed using Pearson score. Results: Nine of the CLL-related proteins exhibited transcript expression that predicted TTFT and 7 of the CLL-related proteins showed mRNA levels that predicted OS in CLL patients (p≤0.05). Of these transcripts, 8 were different types of heterogeneous nuclear ribonucleoproteins (HNRNPs); and 2 (HNRNPUL2 and HIST1C1H) retained prognostic significance in the 2 independent data sets. Furthermore, genes that enriched CLL-related pathways (p≤0.05; false discovery rate [FDR] ≤0.05) were found to correlate with the expression of HNRNPUL2 (Pearson score: ≥0.50; p lessthan 0.00001). Finally, increased expression of HNRNPUL2 was indicative of poor prognosis of various types of cancer other than CLL (p less than 0.05). Conclusion: The cognate transcripts of 14 of our CLL-related proteins significantly predicted CLL prognosis.

Alsagaby SA, Alhumaydhi FA
Proteomics insights into the pathology and prognosis of chronic lymphocytic leukemia.
Saudi Med J. 2019; 40(4):317-327 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) is an incurable malignant disease of B-lymphocytes characterized by drastically heterogeneous clinical courses. Proteomics is an advanced approach that allows a global profiling of protein expression, providing a valuable chance for the discovery of disease-related proteins. In the last 2 decades, several proteomics studies were conducted on CLL to identify aberrant protein expression underpinning the malignant transformation and progression of the disease. Overall, these studies provided insights into the pathology and prognosis of CLL and reveal protein candidates with the potential to serve as biomarkers and/or therapeutic targets of the tumor. The major findings reported in these studies are discussed here.

Basabaeen AA, Abdelgader EA, Babekir EA, et al.
Clinical presentation and hematological profile among young and old chronic lymphocytic leukemia patients in Sudan.
BMC Res Notes. 2019; 12(1):202 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To assess the clinical presentation and hematological profile among young (≤ 55 years) and old (> 55 years) chronic lymphocytic leukemia patients in Sudan.
RESULT: In the present cross-sectional descriptive study, out of 110 cases studied, among them 31 (28.2%) were young (≤ 55 years) patients with mean age 48 years, and 79 (71.8%) were elder patients (> 55 years) with mean age 66 years, the overall mean age was 62.97 ± 12.06 with range (22-85 years), and 79 (71.8%) were males and 31 (28.2%) were females (M:F = 2.6:1) (P = 0.000). (7.3%) were asymptomatic, 61 (55.5%) presented with nonspecific complains. Generalized lymphadenopathy was seen in 52 (47.27%) with elder predominance (P = 0.03). Splenomegaly, hepatomegaly, thrombocytopenia and anemia were seen in 54 (49.1%), 14 (12.7%), 43 (39.1%) and 38 (34.5%) of patients respectively with male predominance. 54 (49.1%) and 42 (38.18%) of patients presented at Rai high risk and Binet C stages respectively with nearly same age and sex distribution. CLL in Sudan is a disease of elders, same as seen in literature, with high male to female ratio. In general hematological parameters means were noted to be distributed equally according to age and sex groups. Majority of patients were presented with nonspecific symptoms and nearly half of patients presented at late stages as reported in most developing countries.

Bilous N, Abramenko I, Chumak A, et al.
Analysis of LPL gene expression in patients with chronic lymphocytic leukemia.
Exp Oncol. 2019; 41(1):39-45 [PubMed] Related Publications
AIM: The IGHV mutational status is one of the most important markers for chronic lymphocytic leukemia (CLL) prognostication. Lipoprotein lipase (LPL) gene expression was found to correlate with IGHV status and was suggested as its surrogate marker. Recent data reported that LPL expression might be influenced by pivotal signalling pathways in CLL. This study aimed to assess LPL gene expression in relation to key immunogenetic and molecular markers of CLL, including IGHV mutational status, B-cell receptor (BCR) stereotypy, TP53, NOTCH1, and SF3B1 gene mutations. Materials and Methods: Expression of LPL mRNA was measured in peripheral blood mononuclear cells of 73 CLL patients by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). IGHV, NOTCH1, TP53, and SF3B1 gene mutation analysis was performed by PCR amplification and direct sequencing.
RESULTS: 44 of 73 (60%) CLL cases were categorized as LPL-positive based on the cut-off value established by ROC (receiver operating characteristic) curve analysis. LPL expression was significantly associated with IGHV mutation status (r = 0.684; p < 0.0001) and tended to correlate with presence of NOTCH1 gene mutations (p = 0.113). BCR stereotyped cases showed higher LPL expression values in comparison to unstereotyped cases in the LPL-positive group of patients (p = 0.041). LPL expression was associated with a shorter overall survival in the entire СLL group (median 107 vs 143, p = 0.048) as well as in Binet A patients, albeit with borderline significance (median 139 vs not reached, p = 0.086).
CONCLUSION: LPL expression was found to be closely correlated with IGHV gene mutational status and overall survival, proving LPL as prognostic marker in CLL. Our results also indicate a possible relationship between aberrant expression of LPL and BCR- and NOTCH1-dependent signalling pathways.

Savovic T, Prior JO, Nicod-Lalonde M, et al.
First experience of durable cytoreduction in chronic lymphoid leukemia with
Med Oncol. 2019; 36(5):41 [PubMed] Related Publications
This is the first described case of effective and durable cytoreduction after PRRT with

Helbig G, Spałek A, Wieczorkiewicz-Kabut A, et al.
Allogeneic transplantation for high-risk chronic lymphocytic leukemia-a summary of a 16-year experience.
Ann Hematol. 2019; 98(6):1477-1483 [PubMed] Free Access to Full Article Related Publications
In the pathway inhibitor era, the number of allogeneic stem cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL) continues to decrease and this approach should be offered only after careful risk-benefit assessment. Nevertheless, ASCT still remains only curative therapeutic modality for CLL, especially in countries with limited access to novel agents. Thirty patients with CLL at median age of 42 years at diagnosis (range 29-64) underwent ASCT between years 2002 and 2018. Thirteen patients were transplanted in complete remission (CR), ten patients achieved partial response (PR), and seven had stable disease. The median time from diagnosis to transplant was 4 years (range 0.5-12). Twenty-three patients received HLA-matched related donor stem cell grafts, and seven patients received either matched unrelated donor or HLA-mismatched grafts. Reduced intensity conditioning (RIC) and myeloablative regimen (MAC) were used in 24 and 6 patients, respectively. Mortality to day + 100 after transplant was 16% (8% for RIC only). Acute and chronic graft versus host disease (GVHD) developed in 40% and 63% of patients, respectively. Fifteen patients relapsed or progressed after transplant. Thirteen patients (43%) are alive at last follow-up and 10 (77%) remain in clinical CR. Median follow-up for survivors was 6.8 years (range 0.4-15.2). Three-year progression-free and overall survivals were 56% and 60%, respectively. These outcomes were better for patients who received RIC conditioning: 64% and 72%, respectively. CR at transplant was found to have favorable impact on post-allograft survival. RIC should be preferred over MAC. ASCT may remain a valuable option for some CLL patients.

Bright SA, Byrne AJ, Vandenberghe E, et al.
Selected nitrostyrene compounds demonstrate potent activity in chronic lymphocytic leukaemia cells, including those with poor prognostic markers.
Oncol Rep. 2019; 41(5):3127-3136 [PubMed] Related Publications
The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG‑3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro‑apoptotic effects of the compounds were found to be reactive oxygen species and caspase‑dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3‑kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co‑cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.

Bowen T, Silver SA, Sila C
Rapidly Progressive Intracranial Vasculopathy in Graft Versus Host Disease.
J Stroke Cerebrovasc Dis. 2019; 28(6):e73-e74 [PubMed] Related Publications
After allogenic hematopoietic stem cell transplantation, cerebrovascular complications are uncommon, occurring in approximately 2%, and typically due to coagulopathy or infection. Graft versus host disease has been rarely reported to affect the central nervous system but these cases typically describe leukoencephalopathy, encephalitis, or perivascular infiltrates or vasculitis with subcortical ischemia or hemorrhage. We report a previously undescribed noninflammatory vasculopathy causing multifocal intracranial arterial occlusions and cerebral infarctions in a man following allogenic hematopoietic stem cell transplantation for chronic lymphocytic leukemia, which we propose to be a central nervous system manifestation of graft versus host disease.

Daniele G, L'Abbate A, Turchiano A, et al.
1q23.1 homozygous deletion and downregulation of Fc receptor-like family genes confer poor prognosis in chronic lymphocytic leukemia.
Clin Exp Med. 2019; 19(2):261-267 [PubMed] Related Publications
The identification of chromosome 1 translocations and deletions is a rare and poorly investigated event in chronic lymphocytic leukemia (CLL). Nevertheless, the identification of novel additional molecular alterations is of great interest, opening to new prognostic and therapeutic strategies for such heterogeneous hematological disease. We here describe a patient affected by CLL with a mutated IGHV status, showing a balanced t(1;3)(q23.1;q21.3) translocation and a der(18)t(1;18)(q24.2;p11.32), accompanying the recurrent 13q14 heterozygous deletion in all analyzed cells at onset. By combining whole-genome sequencing, SNP array, RNA sequencing, and FISH analyses, we defined a 1q23.1 biallelic minimally deleted region flanking translocations breakpoints at both derivative chromosome 1 homologues. The deletion resulted in the downregulation of the Fc receptor-like family genes FCRL1, FCRL2, and FCRL3 and in the lack of expression of FCRL5, observed by RT-qPCR. The mutational status of TP53, NOTCH1, SF3B1, MYD88, FBXW7, and XPO1 was investigated by targeted next-generation sequencing, detecting a frameshift deletion within NOTCH1 (c.7544_7545delCT). We hypothesize a loss of tumor suppressor function for FCRL genes, cooperating with NOTCH1 mutation and 13q14 genomic loss in our patient, both conferring a negative prognosis, independently from the known biological prognostic factors of CLL.

Afacan-Öztürk HB, Falay M, Albayrak M, et al.
CD81 Expression in the Differential Diagnosis of Chronic Lymphocytic Leukemia.
Clin Lab. 2019; 65(3) [PubMed] Related Publications
BACKGROUND: Immunophenotyping has a central role in CLL. However, CLL is a very heterogenous disease, both morphologically and immunophenotypically; thus, its diagnosis may prove a challenge. We investigated CD81 ex-pression in the differential diagnosis of CLL and MCL.
METHODS: We retrospectively examined CD81 expression with 8 color Multiparameter Flow cytometry devices in 101 CLL and 19 MCL cases.
RESULTS: We found negative CD81 expression in CLL cases whereas it was positive in MCL cases.
CONCLUSIONS: Our results suggest that CD81 may be a valuable marker for the differential diagnosis of CLL. We are of the opinion that it should be definitely included in the diagnostic algorithm for CLL.

Ahmadvand M, Eskandari M, Khakpour G, et al.
Identification of MiR-125a as a Novel Plasma Diagnostic Biomarker for Chronic Lymphoblastic Leukemia.
Clin Lab. 2019; 65(3) [PubMed] Related Publications
Background: Chronic lymphocytic leukemia (CLL) is a type of malignancy in which the bone marrow makes too many lymphocytes. MicroRNAs (miRNAs) are endogenous short (~22-nucleotides) non-protein-coding regulatory RNA molecules with key roles in cellular and molecular processes linked to different cancers including CLL. Re-cently, some investigations have demonstrated that miR-125a downregulation is correlated with the expression of P53, NRG1 and ERBB2. Methods: In this study, samples including 38 patients with CLL and 25 healthy individuals were collected. We used quantitative real-time PCR (qRT-PCR) to assess the expression of miR-125a in plasma of the CLL patients in comparison with healthy controls. Moreover, we used the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis on miR-125a targets in the DAVID database in order to investigate the potential role of miR-125a in cancer pathways. MiR-125a exerted a variety of roles in the cancer pathway via downregulating target genes including ERBB2. Results: The expression of miR-125a dramatically decreased (~2-fold) in the patients with CLL compared with the healthy controls (p = 0.03). Furthermore, overexpression of miR-125a was associated with different CLL staging and B symptoms (all at p < 0.05). The KEGG pathway enrichment analysis demonstrated the eight statistically related KEGG signaling pathways with miR-125a targetome. Conclusions: The results suggested that the miR-125a expression level could be a novel potential biomarker for CLL prognosis.

Bolger GT, Licollari A, Bagshaw R, et al.
Intense Uptake of Liposomal Curcumin by Multiple Myeloma Cell Lines: Comparison to Normal Lymphocytes, Red Blood Cells and Chronic Lymphocytic Leukemia Cells.
Anticancer Res. 2019; 39(3):1161-1168 [PubMed] Related Publications
BACKGROUND/AIM: Curcumin is being widely investigated for its anticancer properties and several studies in the literature suggest that curcumin is distributed to a higher degree in cancer cells compared to normal cells. The goal of this study was to investigate the disposition of curcumin in the form of Lipocurc™ in multiple myeloma (MM)-causing plasma cell lines and B-lymphocytes from healthy individuals and compare the uptake to previously published data for red blood cells (RBCs), peripheral blood mononuclear cells (PBMCs) from healthy individuals and PBMCs from patients with chronic lymphocytic leukemia (CLL-cells).
MATERIALS AND METHODS: Two MM-producing cell lines were studied: RPMI-8266, an IgG lambda cell line, and NCL-H929, an IgA kappa line. The distribution of liposomal curcumin and its metabolism to the major stable metabolite tetrahydrocurcumin (THC) were measured in vitro in the cell lines and B-lymphocytes. The cells were incubated in plasma protein-supplemented media with liposomal curcumin (Lipocurc™) for 15 min at 37°C and the levels of curcumin and THC in cells and medium were determined by liquid chromatography tandem mass spectrometry.
RESULTS: Extremely intense uptake was seen in both MM lines compared to that in B-lymphocytes and previously published data in RBCs, PBMCs and CLL cells. The levels of curcumin in RPMI-8266 and NCI-H929 cells were 14,225±847 and 12,723±500 pg/10
CONCLUSION: The extremely intense uptake of curcumin (as Lipocurc™) in both MM lines further suggests that Lipocurc™ should be investigated in the treatment of patients with this disease.

Elavarasi A, Dash D, Warrier AR, Jain D
Leptomeningeal leukaemia misdiagnosed as tubercular meningitis.
BMJ Case Rep. 2019; 12(3) [PubMed] Related Publications
Chronic meningitis is a common syndrome with multiple aetiological causes. It can be associated with visionproblems as well as multifocal involvement of the central nervous system. Often it presents with constitutional symptoms as well. The intervention commonly practised in a tropical country like India is starting antitubercular therapy with corticosteroids. This practice though may be correct in a majority of situations, may lead to diagnostic delay and may be fatal.

Patrussi L, Capitani N, Baldari CT
Abnormalities in chemokine receptor recycling in chronic lymphocytic leukemia.
Cell Mol Life Sci. 2019; 76(16):3249-3261 [PubMed] Related Publications
In addition to their modulation through de novo expression and degradation, surface levels of chemokine receptors are tuned by their ligand-dependent recycling to the plasma membrane, which ensures that engaged receptors become rapidly available for further rounds of signaling. Dysregulation of this process contributes to the pathogenesis of chronic lymphocytic leukemia (CLL) by enhancing surface expression of chemokine receptors, thereby favoring leukemic cell accumulation in the protective niche of lymphoid organs. In this review, we summarize our current understanding of the process of chemokine receptor recycling, focusing on the impact of its dysregulation in CLL.

Munakata W, Ando K, Hatake K, et al.
Phase I study of tirabrutinib (ONO-4059/GS-4059) in patients with relapsed or refractory B-cell malignancies in Japan.
Cancer Sci. 2019; 110(5):1686-1694 [PubMed] Free Access to Full Article Related Publications
We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and predictive biomarkers of tirabrutinib, a second-generation, enhanced-selectivity Bruton's tyrosine kinase inhibitor in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-cell NHL) and chronic lymphocytic leukemia (CLL). This was an open-label, multicenter, phase I study. Seventeen patients (male N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once daily [N = 3], 320 mg once daily [N = 3], 480 mg once daily [N = 4] and 300 mg twice daily [N = 7]); 4 patients had continued tirabrutinib administration as of 4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) was the dose-limiting toxicity for 300 mg twice daily. Common adverse events (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥PR) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 1-4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B-cell NHL/CLL.

Böttcher S
Flow Cytometric MRD Detection in Selected Mature B-Cell Malignancies.
Methods Mol Biol. 2019; 1956:157-197 [PubMed] Related Publications
The quantification of submicroscopic minimal residual disease (MRD) after therapy proved to have independent prognostic significance in many mature B-cell malignancies. With the advent of routine benchtop cytometers capable of simultaneously analyzing ≥4 colors and with improved standardization, flow cytometry has become the method of choice for MRD assessments in some lymphoma entities. Herein we describe general aspects of flow cytometric standardization. Chronic lymphocytic leukemia and multiple myeloma (MM) are used as examples to explain the technical standardization of flow cytometry for MRD detection according to EuroFlow strategies. MRD data acquisition and detailed analysis using a newly developed approach (so-called next generation flow, NGF) in MM is a particular focus of this chapter.

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