Estella Matutes

Familial chronic lymphocytic leukaemia: a survey and review of published studies.

B‐cell chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia. To gain insight into the role of inherited factors in the disease, we have conducted a survey of the family histories of 268 CLL patients and have reviewed published familial cases and epidemiological studies. The results of our survey and published studies strongly support the hypothesis that a subset of the disease can be ascribed to a genetic predisposition. The most likely genetic model for inherited predisposition appears to be dominantly acting genes with pleiotropic effects because in many families CLL appears to be associated with other lymphoproliferative disorders.

Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing

Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL. Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03). Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively. Clin Cancer Res; 21(18); 4174–83. ©2015 AACR.

Hairy cell leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

T. Robak1, E. Matutes2, D. Catovsky3, P. L. Zinzani4 & C. Buske5, on behalf of the ESMO Guidelines Committee* Department of Hematology, Medical University of Lodz, Lodz, Poland; Haematopathology Unit, Hospital Clinic, Barcelona University, Barcelona, Spain; Haemato-Oncology Research Unit, The Institute of Cancer Research, Sutton, Surrey, UK; Seràgnoli Institute of Hematology, University of Bologna, Bologna, Italy; Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital, Ulm, Germany

T-cell prolymphocytic leukaemia: Antigen receptor gene rearrangement and a novel mode of MTCP1 B1 activation

T‐cell prolymphocytic leukaemia (T‐PLL) is a sporadic, mature T‐cell disorder in which there is usually an aberrant T‐cell receptor alpha (TCRA) rearrangement that activates the TCL1 or MTCP1‐B1 oncogenes. As mutations of the Ataxia Telangiectasia (A‐T) gene, ATM, are frequent in T‐PLL and as ATM seems to act as a tumour suppressor through a mechanism involving V(D)J recombination, we examined V(D)J recombination in T‐PLL. Using Southern blotting and the polymerase chain reaction, two of 60 TCRG coding joints were abnormal. In all cases, both TCRD alleles were deleted, IGH was germline, and patterns of TCRB and TCRA rearrangement were normal. However, in a case harbouring t(X;7)(q28;q35), we identified TCRB segment Jβ2·7 juxtaposed to MTCP1 exon 1. This is the first time that TCRB has been implicated in MTCP1 B1 activation. The structure of the breakpoint supports a model in which translocation activates a cryptic MTCP1 promoter. This analysis of V(D)J recombination is consistent with it being a variable that is independent of ATM in T‐PLL.

Splenic marginal zone lymphoma: disease features and management

Splenic marginal zone lymphoma (SMZL) is a lymphoma recognized as a distinct entity in the WHO classification of the lymphoid tumors. SMZL probably results from the expansion of a marginal zone B-cell driven by persistent antigen stimulation. SMZL is clinically and biologically heterogeneous. The SMZL Working Group has published guidelines for the diagnosis, workup and treatment of SMZL. There are no standard criteria to initiate treatment. A policy of watch and wait in asymptomatic patients is recommended. In symptomatic patients, data from retrospective studies suggest that rituximab with or without chemotherapy is the best strategy for SMZL. It is uncertain which is the optimal type of chemotherapy and whether patients may benefit from splenectomy prior chemoimmunotherapy. In the future, we may see progress with agents targeting known molecular lesions in SMZL.

Risk of developing chronic lymphocytic leukemia is influenced by HLA-A class I variation

Although chronic lymphocytic leukemia (CLL) is characterized by a strong familial risk, the genetic basis of inherited susceptibility to CLL is largely unknown. The increased risk of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) in relatives of CLL patients suggests a common etiology to B-cell lymphoproliferative disorders (LPDs) through HLA variation.1 Moreover, as B-cell proliferation is part of an adaptive immune response, which can be initiated by major histocompatibility complex (MHC)-restricted T-cell activation, a possible influence of HLA on CLL pathogenesis is plausible.

The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry

The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry

Higher expression levels of activation-induced cytidine deaminase distinguish hairy cell leukemia from hairy cell leukemia-variant and splenic marginal zone lymphoma

Higher expression levels of activation-induced cytidine deaminase distinguish hairy cell leukemia from hairy cell leukemia-variant and splenic marginal zone lymphoma

Large granular lymphocytic leukemia. Current diagnostic and therapeutic approaches and novel treatment options

ABSTRACT Introduction: Large granular lymphocytic leukemia (LGLL) is a low grade lymphoproliferative disorder characterized by the clonal proliferation of large granular lymphocytes (LGL) and recognised by the WHO. The diagnosis and management of these patients is challenging due to the limited information from prospective studies. Guidelines for front-line therapy have not been established. The prognosis is favourable with median overall survivals greater than 10 years. Areas covered: This manuscript is a review of the clinical features, diagnosis, pathogenesis and, in particular, the various available therapeutic options for this rare lymphoid leukemia. A systematic literature search using electronic PubMed database has been carried out. Expert commentary: A watch and wait strategy without therapeutic intervention is recommended in asymptomatic patients. The immunomodulators methotrexate, cyclophosphamide and cyclosporin are the most commonly used drugs in the routine practice with responses ranging from 50 to 65% and without evidence of cross-resistance among them. Purine analogs such as 2´deoxycoformycin and fludarabine alone or in combination may be indicated in patients with bulky and/or widespread disease. Trials using monoclonal antibodies such as Alemtuzumab and agents targeting the disrupted JAK/STAT pathway in LGLL such as JAK-3 inhibitors are promising particularly in a relapse setting.