Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be ...relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations TP53abs), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.
•Complex karyotype defined by the presence of ≥3 chromosomal abnormalities should not be axiomatically considered unfavorable in CLL.•High cytogenetic complexity with ≥5 chromosomal aberrations emerges as prognostically adverse, independently of other biomarkers.
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is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of
mutations are largely unexplored. Furthermore, little is known about the prognostic impact of
...mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in
-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition,
-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that
mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons
mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years,
<0.001) similar to cases harboring
mutations (median progression-free survival: 2.6 years,
<0.0001).
mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6,
=0.004) in multivariate analysis adjusted for
mutation, 17p deletion and
mutation status. If validated,
mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.
The Notch pathway plays a key role in several processes, including stem-cell self-renewal, proliferation, and cell differentiation. Several studies identified recurrent mutations in hematological ...malignancies making Notch one of the most desirable targets in leukemia and lymphoma. The Notch signaling mediates resistance to therapy and controls cancer stem cells supporting the development of on-target therapeutic strategies to improve patients' outcome. In this brief review, we outline the therapeutic potential of targeting Notch pathway in T-cell acute jlymphoblastic leukemia, chronic lymphocytic leukemia, and mantle cell lymphoma.
Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural ...abnormalities) or high-CK (CK with ≥5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter real-life retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, and TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q- /TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (P<0.0001). We herein demonstrate that CK landscape at CLL diagnosis allows the risk of RS transformation to be refined and we recapitulated clinico-biological variables into a prognostic model.
The identification of patients at high risk of herpes zoster (HZ) requiring a prevention strategy with antiviral prophylaxis and anti-HZ vaccine is a clinically relevant issue in patients with ...immunological impairment. Absence of trials comparing vaccination to pharmacological prophylaxis or defining their sequential use makes the optimal prevention strategy uncertain. This article presents the results of group discussion among an ad hoc constituted panel of experts aimed to review the literature regarding antiviral prophylaxis and vaccine efficacy and safety in populations with malignant and non-malignant hematological diseases, and submitted to hematopoietic stem cell transplantation. The panel used the consensus methodology and proposed solutions for prevention strategy producing advice for the management of the most relevant unmet clinical needs. Such a comprehensive overview aims to support at the practice of HZ pharmacological and vaccine prevention and informing the design and the need of implementation of new studies in the field.
Summary
In a series of 349 patients with chronic lymphocytic leukaemia (CLL), we found lower levels of signalling lymphocytic activation molecule family member 1 (SLAMF1) expression in cases with ...highly complex karyotypes, as defined by the presence of five or more chromosomal abnormalities (CK5; P < 0·001) and with major chromosomal structural abnormalities (P < 0·001). SLAMF1 downregulation was significantly associated with advanced Binet Stage (P = 0·001), CD38 positivity (P < 0·001), high β2‐microglobulin levels (P < 0·001), immunoglobulin heavy chain variable region gene (IGHV) unmutated status (P < 0·001), 11q deletion (P < 0·001), tumour protein p53 (TP53) disruption (P = 0·011) and higher risk CLL International Prognostic Index categories (P < 0·001). Multivariate analysis showed that downregulated SLAMF1 levels had independent negative prognostic impact on time‐to‐first treatment (P < 0·001) and overall survival (P < 0·001).
Treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) has dramatically improved thanks to the development of mechanism-driven agents including drugs that inhibit kinases in the ...BCR pathway or BCL2. The treating physician has now the opportunity to decide i) which patient can be still offered chemoimmunotherapy as salvage treatment, ii) which patient at relapse is a candidate to receiving, continuous treatment with ibrutinib, idelalisib and rituximab or venetoclax and iii) which patient may benefit from a fixed-duration treatment using the BCL2 antagonist venetoclax in association with rituximab. Ibrutinib is the most actively investigated drug in R/R CLL and data at a 7-year follow-up were reported, showing durable efficacy and favorable efficacy profile. The patients with cardiac disease, hypertension, and anticoagulant therapy are not ideal candidates for continuous therapy with this agent. Idelalisib and rituximab were tested in patients with unfavorable characteristics including cytopenias. The short follow-up and treatment-emergent adverse events limit its role to patients unlikely to get a benefit with other agents. Venetoclax and rituximab is the only effective chemo-free approach for the treatment of R/R with a fixed duration (up to 24 months) schedule capable of inducing deep responses in the majority of cases with a reassuring safety profile. While a deep knowledge of the growing body of scientific evidence is required to inform and guide the appropriate treatment choice and management, physicians cannot disregard the growing problem of sustainability.
Bruton tyrosine kinase inhibitors (BTKi) and the BCL2 inhibitor venetoclax, with or without the anti-CD20 monoclonal antibody Obinutuzumab, represent the preferred options for the first-line therapy ...of CLL because they are more effective and may improve quality of life. However, patient inclusion criteria are heterogeneous across trials designed for older patients, and the identification of CLL-specific parameters identifying unfit patients at risk of developing drug-specific adverse events is required to guide treatment choice. Due to inclusion/exclusion criteria in trials, higher discontinuation rates with BTKi were reported in real-world studies, and registry analyses provided useful information on factors predicting earlier discontinuation in a real-world setting. Though targeted agents were shown to be cost-effective treatments in high-income countries, the out-of-pocket expenses may limit accessibility to these drugs, and the overall expenditure for new drugs in CLL is projected to increase substantially, posing an issue for sustainability. This being said, the choice of a finite-duration treatment based on venetoclax-containing regimens or treatment until progression with BTKi is today possible in high-income countries, and the therapy choice drivers are represented by coexisting medical conditions rather than age, patient expectations, logistics, and sustainability.