Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, "(S+Rc) to Rnc IGHV mutation ratio". When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.

• Keywords
• CLL, chronic lymphocytic leukemia, immunoglobulin variable domain, prognosis, somatic mutations,
• Publication type
• Journal Article MeSH

The paradigm of first-line treatment of chronic lymphocytic leukaemia (CLL) is currently undergoing a radical change. On the basis of several randomised phase III trials showing prolongation of progression-free survival, chemoimmunotherapy is being replaced by treatment based on novel, orally available targeted inhibitors such as Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib or bcl-2 inhibitor venetoclax. However, the use of these agents may be associated with other disadvantages. First, with the exception of one trial in younger/fit patients, no studies have so far demonstrated benefit regarding the ultimate endpoint of overall survival. Second, oral inhibitors are extremely expensive and thus currently unavailable due to the absence of reimbursement in some countries. Third, treatment with ibrutinib and acalabrutinib necessitates long-term administration until progression; this may be associated with accumulation of late side effects, problems with patient compliance, and selection of resistant clones. Therefore, the identification of a subset of patients who could benefit from chemoimmunotherapy would be ideal. Current data suggest that patients with the mutated variable region of the immunoglobulin heavy chain (IGHV) achieve fairly durable remissions, especially when treated with fludarabine, cyclophosphamide, and rituximab (FCR) regimen. This review discusses current options for treatment-naïve patients with CLL.

• Keywords
• acalabrutinib, chemoimmunotherapy, chronic lymphocytic leukaemia, direct inhibitors, ibrutinib, obinutuzumab, prognosis, rituximab, venetoclax,
• Publication type
• Journal Article MeSH
• Review MeSH

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   pathology   therapy   MeSH
• Clinical Trials as Topic statistics & numerical data   MeSH
• Combined Modality Therapy MeSH
• Humans MeSH
• Survival Rate MeSH
• Mutation * MeSH
• Biomarkers, Tumor genetics   MeSH
• Follow-Up Studies MeSH
• Nomograms * MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers, Tumor MeSH

UNLABELLED: In this review, we discuss the intricate roles of the Wnt signalling network in the development and progression of mature B-cell-derived haematological malignancies, with a focus on chronic lymphocytic leukaemia (CLL) and related B-cell lymphomas. We review the current literature and highlight the differences between the β-catenin-dependent and -independent branches of Wnt signalling. Special attention is paid to the role of the non-canonical Wnt/planar cell polarity (PCP) pathway, mediated by the Wnt-5-receptor tyrosine kinase-like orphan receptor (ROR1)-Dishevelled signalling axis in CLL. This is mainly because the Wnt/PCP co-receptor ROR1 was found to be overexpressed in CLL and the Wnt/PCP pathway contributes to numerous aspects of CLL pathogenesis. We also discuss the possibilities of therapeutically targeting the Wnt signalling pathways as an approach to disrupt the crucial interaction between malignant cells and their micro-environment. We also advocate the need for research in this direction for other lymphomas, namely, diffuse large B-cell lymphoma, Hodgkin lymphoma, mantle cell lymphoma, Burkitt lymphoma and follicular lymphoma where the Wnt signalling pathway probably plays a similar role. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.

• MeSH
• Lymphoma, B-Cell diagnosis   metabolism   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell diagnosis   metabolism   MeSH
• Humans MeSH
• Wnt Signaling Pathway * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH