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COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus. Hybrid immunity in immunocompromised patients with CLL after SARS-CoV-2 infection followed by booster mRNA vaccination. COVID-19 vaccination: Evaluation of humoral and cellular immunity after the booster dose in chronic lymphocytic leukemia patients. [Extracted from the article]

Takezaki et al. analyzed the outcome of 57 patients with indolent lymphomas treated with Bendamustine plus Rituximab (BR) according to the number of cycles received, showing that patients who discontinued BR after four cycles had similar outcomes compared to patients who received five or six cycles. Considering the similarities but also the differences between indolent lymphomas and chronic lymphocytic leukemia (CLL), we enriched the results obtained with a cohort of CLL patients treated with BR starting from the experience of the Lazio region group on CLL. Out of 115 patients, 97 (84%) received 4–6 cycles of BR, while 18 (16%) received 1–3 cycles. The outcome of the group of patients who received at least 4 cycles was superior in terms of response rate (ORR 96% vs. ORR 83%, p = 0.041; CR 58% vs. CR 28%, p = 0.052 respectively) and PFS [median PFS 52.6 (40.3–64.9) versus 26.2 (19.3–33.0) months, p < 0.001]. The number of patients undergoing 4 cycles of BR (4‐cycles group) and 5–6 cycles (over‐4‐cycles group) was 9 and 88, respectively. Compared to analysis conducted by the Japanese group in indolent lymphomas, in CLL we did not observe any difference between the outcome of the 4‐cycles group and the over‐4‐cycles group in terms of ORR (89% vs. 97%, p = 0.268) and in survival [median PFS 40.8 (13.7–67.8) versus 52.6 (38.7–66.5) months, p = 0.117]. Moreover, we observed that patients who achieved a clinical CR showed overlapping outcomes with patients who received more than 4 cycles [CR vs. non‐CR median PFS not reached vs. 11.0 months; over‐4‐cycles group median PFS 52.6 months (40.3–64.9); p < 0.001]. Nowadays chemoimmunotherapy with BR is reserved to fit elderly CLL patients, and there are many chemo‐free treatment options available; therefore, discontinuation after 4 cycles may be permissible in patients who obtained a CR in order to limit toxicity as much as possible. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions: Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration. [ABSTRACT FROM AUTHOR]

Clonal haematopoiesis of indeterminate potential (CHIP) may predispose for the development of therapy‐related myeloid neoplasms (t‐MN). Using target next‐generation sequencing (t‐NGS) panels and digital droplet polymerase chain reactions (ddPCR), we studied the myeloid gene mutation profiles of patients with chronic lymphocytic leukaemia (CLL) who developed a t‐MN after treatment with chemo‐(immuno)therapy. Using NGS, we detected a total of 30 pathogenic/likely pathogenic (P/LP) variants in 10 of 13 patients with a t‐MN (77%, median number of variants for patient: 2, range 0–6). The prevalence of CHIP was then backtracked in paired samples taken at CLL diagnosis in eight of these patients. Six of them carried at least one CHIP‐variant at the time of t‐MN (median: 2, range: 1–5), and the same variants were present in the CLL sample in five cases. CHIP variants were present in 34 of 285 patients from a population‐based CLL cohort, which translates into a significantly higher prevalence of CHIP in patients with a CLL who developed a t‐MN, compared to the population‐based cohort (5/8, 62.5% vs. 34/285, 12%, p = 0.0001). Our data show that CHIP may be considered as a novel parameter affecting treatment algorithms in patients with CLL, and highlight the potential of using chemo‐free therapies in CHIP‐positive cases. [ABSTRACT FROM AUTHOR]

Objectives: To compare the capacity of ibrutinib (IB) and idelalisib‐rituximab (IDELA‐R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only. Methods: A real‐life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study. Results: At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA‐R vs IB HR = 0.5, 95% CI = 0.36‐0.71) although with some limitations due to the non‐randomized and retrospective nature of the study and to the lower number of patients in the IDELA‐R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA‐R (HR = 0.67, 95% CI = 0.45‐0.98, P =.04) independent of potential confounders. Conclusions: Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules. [ABSTRACT FROM AUTHOR]

Previous studies investigated the efficacy and the safety of bendamustine (B) vs. chlorambucil (Chl) associated with rituximab (R) in fludarabine-ineligible patients with treated and untreated chronic lymphocytic leukemia (CLL). We conducted a retrospective multicenter study in the Lazio region to further evaluate and compare the efficacy and the toxicity of Chl-R and B-R regimen in CLL patients over the age of 65. We enrolled 192 untreated CLL patients: 111 treated with B-R and 81 with Chl-R. The overall response rates (ORR; 93.6% in B-R and 86.5% in Chl-R) were not statistically different between the two groups, such as progression-free survival (PFS), time to retreatment (TTR), and overall survival (OS). The B-R group showed a higher hematological (p = 0.007) and extra-hematological (p = 0.008) toxicity. When comparing the toxicities according to age, we noted that the extra-hematological toxicity was higher in patients over the age of 75 who were treated with B-R than those treated with Chl-R (p = 0.03). This retrospective study confirms the feasibility of B-R and Chl-R in elderly untreated CLL patients. Currently, patients who are over 75 and unfit are usually treated with Chl-R. This scheme allows achieving the same ORR, PFS, TTR, and OS when compared with B-R because of hematological and extra-hematological toxicities due to B, in which a greater dose reduction has been shown in comparison to Chl. [ABSTRACT FROM AUTHOR]

COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus. In our series, the majority of CLL patients on treatment (21/29) were receiving the BTK inhibitor ibrutinib, a drug that, by blocking the B cell receptor pathway in both normal and malignant B cells, may significantly impair the humoral response to vaccination. Among CLL patients, 29/46 were males, and, at the time of vaccination, 20/46 patients had an age >= 70 years. [Extracted from the article]

The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ~30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21-derived heavy chains (HCs) with IGLV3-21-derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21R110), we show that IGLV3-21R110-expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21*01 facilitates effective homotypic BCR-BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21*01-expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21R110-expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors. [ABSTRACT FROM AUTHOR]

Venetoclax in CLL patients who progress after B-cell Receptor inhibitor treatment: a retrospective multi-centre Italian experience The median duration of the first BCRi treatment was 14-5 months (range 1-59) in patients who received only one BCRi and 16 months (range 1-46) in patients who received two BCRi treatments. GLO:1XW/01oct19:bjh16123-fig-0001.jpg PHOTO (COLOR): Kaplan-Meier survival curves for patients stratified according to number of prior BCRi treatments or reason for discontinuation of BCRi treatment. [Extracted from the article]

The article offers information on clinical relevance of subclonal mutations and mutation types in NOTCH1 mutational status in chronic lymphocytic leukaemia. It mentions the role of NOTCH1 gene mutations in chronic lymphocytic leukaemia (CLL). It discusses the capacity of NOTCH1 mutations to predict both time to first treatment and overall survival.

Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in cancer and autoimmune disorders, as well. [ABSTRACT FROM AUTHOR]

The immunoglobulin heavy chain variable gene ( IGHV) mutational status has been recognized as an important predictor of prognosis in chronic lymphocytic leukaemia (CLL) since 1999. More recently, other features of the B-cell receptor, such as stereotypy, have been identified as capable of refining the prognostic potential of IGHV status in the clinical assessment of CLL patients. In this context, different genes belonging to the IGHV3 subgroup, the most frequently used subgroup in CLL, have been shown to denote disease subsets that either display a bad prognosis (i.e. IGHV3-21, IGHV3-23) or are associated with particularly good clinical outcomes, including a highly stable/indolent clinical course, even prone to spontaneous regression (i.e. IGHV3-72, IGHV3-30). The present review focuses on the molecular and biological features of CLL-expressing specific genes belonging to the IGHV3 subgroup that are known to mark disease subsets with completely different clinical courses, and may be possibly related to CLL pathogenesis via antigen and/or superantigen involvement. [ABSTRACT FROM AUTHOR]

There are no standard therapies for chronic lymphocytic leukemia (CLL)-associated immune thrombocytopenia (IT) so far. We report the results of therapy with single agent rituximab in 21 patients with CLL-associated IT. The mean age at CLL and IT diagnosis was 64 and 68 yr, respectively. IT developed at a mean time of 44 months from the diagnosis of CLL. In four cases, IT was diagnosed at the same time as CLL. For three patients, IT was considered fludarabine-related and two patients showed autoimmune hemolysis also. All patients but one received steroids as first-line treatment for IT. Some patients received intravenous high-dose Ig, vincristine, and Cytoxan also, without beneficial effect. After a mean time of 43 d from the diagnosis of IT, all patients were scheduled to receive rituximab at a dosage of 375 mg/mq/weekly. Eighteen (86%) patients completed the scheduled four cycles of rituximab. Irrelevant first infusion side effects were seen only in one patient. Twelve (57%) patients showed a complete response (CR), six (29%) patients a partial response (PR), and three (14%) patients did not respond. In responding patients, the mean duration of response was 21 months (4-49 months). At a mean follow-up of 28 months, 14 (66%) patients were still alive, 10 (48%) of them in CR and three (14%) in PR. This retrospective analysis prove that rituximab is an effective and well-tolerated alternative treatment for CLL-associated IT. [ABSTRACT FROM AUTHOR]

A fraction of chronic lymphocytic leukemia (CLL) carries highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable ( IGHV) genes and heavy-chain complementarity-determining region-3 (HCDR3), often associated with a restricted selection of IG(K/L)V light chains. We analyzed the features of CLL expressing homologous HCDR3 in a cohort of 264 Ukrainian patients by merging them with a recently published reference series of 1426 cases. This approach allowed us to identify 96/264 (36%) cases as expressing homologous HCDR3, subdivided into 47 subsets. Among these, 27 apparently novel subsets were identified, although most of them were composed of two sequences per subset (‘potential subsets’). CLL cases belonging to several stereotyped subsets showed HCDR3 homologies with various autoreactive clones. Our analysis identified molecular and clinical features of a Ukrainian cohort of patients with CLL. [ABSTRACT FROM AUTHOR]

A letter to the editor discussing prognostic marker in chronic lymphocytic leukaemia is presented.

In chronic lymphocytic leukemia (CLL), inhibition of spontaneous apoptosis determines a worse prognosis and increasing evidences show that disease progression relies also upon cycling CLL cells. We investigated bcl-2, as measure of apoptosis, and CD71, as measure of proliferation, by flow cytometry in 265 patients with CLL. Combining bcl-2 with CD71 values, we defined three subgroups: (1) bcl2 − CD71−; (2) bcl2 + CD71+; and (3) bcl2 + CD71− or bcl2− CD71+. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70+ ( p < 0.00001) and in patients with bcl2 + CD71+ ( p < 0.00001 and p = 0.02). The patients with discordant in bcl2 + CD71− and bcl2− CD71+ showed an intermediate outcome. Noteworthy, patients with bcl2 + CD71+ showed a shorter PFS within ZAP-70 negative subgroup ( p = 0.00009). In multivariate analysis of PFS, age ( p = 0.005), beta-2 microglobulin (B2-M) ( p = 0.003), bcl-2 ( p = 0.004), CD49d ( p = 0.001), and ZAP-70 ( p < 0.001) resulted to be significant prognostic factors. The independent prognostic significance of B2-M ( p = 0.009) and bcl-2 ( p = 0.03) was confirmed within ZAP-70 negative patients. Bcl-2 and CD71 can be considered as interesting progression indicators, which should be validated in an independent cohort of patients, to take timely therapeutic decisions in CLL. [ABSTRACT FROM AUTHOR]

Background: ZAP-70 is an independent negative prognostic marker in chronic lymphocytic leukemia (CLL). Usually, its expression is investigated by flow cytometric protocols in which the percentage of ZAP-70 positive CLL cells is determined in respect to isotypic control (ISO-method) or residual ZAP-70 positive T cells (T-method). These methods, however, beside suffering of an inherent subjectivity in their application, may give discordant results in some cases. The aim of this study was to assess the prognostic significance of these methods in comparison with another in which ZAP-70 expression was evaluated as a Mean-Fluorescence-Intensity Ratio between gated T and CLL cells (T/B Ratio-method). Methods: Cytometric files relative to ZAP-70 determination according to the three readouts were retrospectively reviewed on a cohort of 173 patients (test set), all with complete clinical and biological prognostic assessment and time-to-treatment (TTT) available. Findings were then validated in an independent cohort of 341 cases from a different institution (validation set). Results: The optimal prognostic cut-offs for ZAP-70 expression were selected at 11% (ISO-method) or 20% of positive cells (T-method), as well as at 3.0 (T/B Ratio-method) in the test set; these cut-offs yielded 66, 60 and 73 ZAP-70+ cases, respectively. Univariate analyses resulted in a better separation of ZAP-70+ vs. ZAP-70- CLL patients utilizing the T/B Ratio, compared to T- or ISO-methods. In multivariate analyses which included the major clinical and biological prognostic markers for CLL, the prognostic impact of ZAP-70 appeared stronger when the T/B-Ratio method was applied. These findings were confirmed in the validation set, in which ZAP-70 expression, evaluated by the T- (cut-off = 20%) or T/B Ratio- (cut-off = 3.0) methods, yielded 180 or 127 ZAP-70+ cases, respectively. ZAP-70+ patients according to the T/B Ratio-method had shorter TTT, both if compared to ZAP-70- CLL, and to cases classified ZAP-70+ by the T-method only. Conclusions: We suggest to evaluate ZAP-70 expression in routine settings using the T/B Ratio-method, given the operator and laboratory independent feature of this approach. We propose the 3.0 T/B Ratio value as optimal cutoff to discriminate ZAP-70+ (T/B Ratio less than 3.0) from ZAP-70- (T/B Ratio more/equal than 3.0) cases. [ABSTRACT FROM AUTHOR]

A fraction of chronic lymphocytic leukaemia (CLL) cases carry highly homologous B-cell receptors (BCR), i.e. characterized by non-random combinations of immunoglobulin heavy-chain variable ( IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), often associated with a restricted selection of IGVK/L light chains. Such ‘stereotyped’ BCR occur more frequently in CLL with unmutated (UM) than mutated (M) IGHV genes. We analysed 1426 IG rearrangements (from 1398 CLL cases) by a clustering driven by HCDR3 similarities. Molecular findings were correlated to time-to-treatment (TTT) and presence of known prognosticators. Sixty-nine clusters (319 IG-rearrangements, 22·4%) with stereotyped BCR were identified. Among 30 confirmed clusters (≥3 IG-rearrangements/cluster), we found 14 novel clusters, of which 11 had M IG rearrangements (M clusters) and predominantly (8/11) used IGHV3 subgroup genes. Recurrent cluster-biased amino acid changes were found throughout IGHV sequences of these ‘M clusters’. Regarding clinical outcome: (i) UM CLL from the IGHV1-2/1-3/1-18/1-46/7-4-1/IGKV1-39 cluster had poorer prognosis than UM/M cases, or UM cases using the same IGHV genes but not in clusters; (ii) M CLL from the IGHV3-21/IGLV3-21 cluster had TTT similar to UM CLL, and shorter than M CLL expressing IGHV3-21 but not in cluster. Altogether, our analysis identified additional molecular and clinical features for CLL expressing stereotyped BCR. [ABSTRACT FROM AUTHOR]

Major advances have been made in our understanding of the biology and opportunities for treatment of chronic lymphocytic leukemia in recent times. Newer treatment regimens incorporating purine nucleoside analogs have increased the rate of successful remission induction in chronic lymphocytic leukemia patients. Moreover, recent combination chemoimmunotherapy regimens have produced more frequent complete molecular remissions, and early evidence seems to suggest that this could result in prolonged duration of responses, although this association remains to be clearly demonstrated. This review will summarize recent advances in the biology and the management of chronic lymphocytic leukemia, including prognostic factors, pointing mainly on combination chemotherapy based on nucleoside analogs and monoclonal antibodies. In our opinion, in the future a significant improvement of clinical benefits in chronic lymphocytic leukemia will be obtained through the administration of cocktails of monoclonal antibodies combined with chemotherapy in different modalities. [ABSTRACT FROM AUTHOR]

Studies of gene expression profiling have been successfully used for the identification of molecules to be employed as potential prognosticators. In analogy with gene expression profiling, we have recently proposed a novel method to identify the immunophenotypic signature of B-cell chronic lymphocytic leukemia subsets with different prognosis, named surface-antigen expression profiling. According to this approach, surface marker expression data can be analysed by data mining tools identical to those employed in gene expression profiling studies, including unsupervised and supervised algorithms, with the aim of identifying the immunophenotypic signature of B-cell chronic lymphocytic leukemia subsets with different prognosis. Here we provide an overview of the overall strategy employed for the development of such an "outcome class-predictor" based on surfaceantigen expression signatures. In addition, we will also discuss how to transfer the obtained information into the routine clinical practice by providing a flow-chart indicating how to select the most relevant antigens and build-up a prognostic scoring system by weighing each antigen according to its predictive power. Although referred to B-cell chronic lymphocytic leukemia, the methodology discussed here can be also useful in the study of diseases other than B-cell chronic lymphocytic leukemia, when the purpose is to identify novel prognostic determinants. [ABSTRACT FROM AUTHOR]

Cases of B-cell chronic lymphocytic leukaemia (B-CLL) with mutated (M) IgVH genes have a better prognosis than unmutated (UM) cases. We analysed the IgVH mutational status of B-CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B-CLLs, 124 cases were examined for IgVH gene per cent mutations and skewing of replacement/silent mutations in the framework/ complementarity-determining regions as evidence of antigen-driven selection; this identified three B-CLL subsets: significantly mutated (sM), with evidence of antigen-driven selection, not significantly mutated (nsM) and UM, without such evidence and IgVH gene per cent mutations above or below the 2% cut-off. sM B-CLL patients had longer survival within the good prognosis subgroup that had more than 2% mutations of IgVH genes. sM, nsM and UM B-CLL were also characterized for the biased usage of IgVH families, intraclonal IgVH gene diversification, preference of mutations to target-specific nucleotides or hotspots, and for the expression of enzymes involved in SHM (translesion DNA polymerase ζ and η and activation-induced cytidine deaminase). These findings indicate the activation of a canonical SHM process in nsM and sM B-CLLs and underscore the role of the antigen in defining the specific clinical and biological features of B-CLL. [ABSTRACT FROM AUTHOR]

Simple Summary: Ibrutinib demonstrated superior efficacy compared to chemoimmunotherapy in patients with chronic lymphocytic leukemia. However, adverse events are a frequent reason for treatment discontinuation. This study was aimed to evaluate the incidence, risk factors, and prognostic impact of infections in a large series of patients with chronic lymphocytic leukemia who received an ibrutinib-based therapy. Approximately one-third of patients developed pneumonia or a severe infection with an overall rate of 15.3% infections per 100 person-year. Patients who experienced a severe infection in the year before starting ibrutinib, those with chronic obstructive pulmonary disease, and those heavily pretreated showed greater vulnerability to infection. A scoring system based on these factors identified patients with a two- to threefold increase in the rate of infections. Infections showed an unfavorable impact in terms of treatment discontinuation and inferior survival. Our results demonstrate that infections are a relevant reason for treatment failure in patients treated with ibrutinib. Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This observational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections—PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments—identified patients with a two- to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib. [ABSTRACT FROM AUTHOR]

The article offers information about a study conducted to identify the suitable genes associated with resistance of p53wt chronic lymphocytic leukemia (CLL) cells to the in-vitro Nutlin-3 effects. It mentions that no treatment is required for patients with B-cell (CLL) but in other cases the disease requires treatment by alkylating agents, purine analogs, monoclonal antibodies. The result of the study led to the identification of murine double minute 2 (MDM2) protein as a gene.

Focuses on a study concerning the potential capability of the Sysmex NE-8000 to detect and characterize the acute of chronic form of lymphatic and myeloid leukaemias. Data on the combination of scattergram 3 and histogram type 5.

The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations, chromosomal abnormalities, and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples, and by using both a training-validation and a time-dependent design, four CLL subgroups were hierarchically classified: i) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival:29%); ii) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival:37%); iii) low-risk, harboring +12 or a normal genetics (10-year survival:57%); iv) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared to FISH karyotype (p<0.0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1 and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions. [ABSTRACT FROM AUTHOR]

Abstract: Studies of gene expression profiling have been successfully used for the identification of molecules to be employed as potential prognosticators. In analogy with gene expression profiling, we have previously proposed an original method to identify the immunophenotypic signature of chronic lymphocytic leukemia (CLL) subsets with different prognosis, named surface-antigen expression profiling. According to this method, expression data for surface markers can be successfully analyzed by data mining tools identical to those employed in gene expression profiling studies, including unsupervised and supervised algorithms, with the aim to identify the immunophenotypic signature of CLL subsets with different prognosis. By employing an identical approach for investigating the reactivity of a wide panel of monoclonal antibodies provided by the “Ninth International Workshop on Leukocyte Differentiation Antigens”, we were able to identify some of them (i.e. TCL1, CCR7, FCRL2, FCRL3, and CD150) as additional potential markers with prognostic relevance in CLL. These suggestions need to be confirmed: (i) in a new set of clinically characterized CLL cases; (ii) in combination with other prognostic markers in the context of comprehensive scoring systems for clinical outcome prediction. [Copyright &y& Elsevier]