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Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavy-chain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361−0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation ≥7% (HR: 0.291, 95% CI: 0.137−0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers. [ABSTRACT FROM AUTHOR]

Introduction: Molecular alterations leading progression of asymptomatic CLL-like high-count monoclonal B lymphocytosis (hiMBL) to chronic lymphocytic leukemia (CLL) remain poorly understood. Recently, genome-wide association studies have found 6p21.3, where the human leukocyte antigen (HLA) system is coded, to be a susceptibility risk region for CLL. Previous studies have produced discrepant results regarding the association between HLA and CLL development and outcome, but no studies have been performed on hiMBL. Aims: We evaluated the role of HLA class I (-A, -B and -C) and class II (-DRB1 and -DQB1) in hiMBL/CLL susceptibility, hiMBL progression to CLL, and treatment requirement in a large series of 263 patients diagnosed in our center with hiMBL (n = 156) or Binet A CLL (n = 107). Results: No consistent association between HLA specificities and hiMBL or CLL susceptibility was found. With a median follow-up of 7.7 years, 48/156 hiMBLs (33%) evolved to asymptomatic CLLs, while 16 hiMBLs (10%) and 44 CLLs (41%) required treatment. No HLA specificities were found to be significantly associated with hiMBL progression or treatment in the whole cohort. However, within antigen-experienced immunoglobulin heavy-chain (IGHV)-mutated hiMBLs, which represents the highest proportion of hiMBL cases (81%), the presence of HLA-DQB1*03 showed a trend to a higher risk of progression to CLL (60% vs. 26%, P = 0.062). Moreover, HLA-DQB1*02 specificity was associated with a lesser requirement for 15-year treatment (10% vs. 36%, P = 0.012). Conclusion: In conclusion, our results suggest a role for HLA in IGHV-mutated hiMBL prognosis, and are consistent with the growing evidence of the influence of 6p21 on predisposition to CLL. Larger non-biased series are required to enable definitive conclusions to be drawn. [ABSTRACT FROM AUTHOR]

Background and Objectives Minimal residual disease ( MRD) assessment by PCR in multiple myeloma ( MM) has several shortcomings, including the lack of a suitable target. Kappa deleting element ( KDE) rearrangements occur in virtually all Ig-lambda B-cell malignancies and in 1/3 of Ig-kappa are not affected by somatic hypermutation and, as in ALL, could be used as PCR targets. Methods We have first investigated the incidence, gene segment usage, and CDR3 composition of IGK- KDE rearrangements in 96 untreated myeloma patients. Second, we tested 16 KDE gene rearrangements as molecular targets for MRD assessment by RQ- PCR using a germline reverse primer and a germline Taqman probe in combination with allele-specific oligonucleotides ( ASO) as forward primers. Results Monoclonal KDE rearrangements were amplified in 45% (43/96) of cases, monoallelic in 2/3 of them (29 cases), and biallellic in the remaining 14 cases. Overall, 88% of cases were successfully sequenced, KDE being equally frequently rearranged with VK and with intron- Recombination signal sequence (RSS). Median numbers of inserted and deleted nucleotides in the junctional region were one and five, respectively. Conclusions Using KDE rearrangements as additional PCR target for MRD assessment in MM improves the applicability of these studies in 9% of cases overall and in 20% of lambda cases. Its use in the latter subset could represent a significant advance. [ABSTRACT FROM AUTHOR]

Barrena S, Almeida J, García-Macias M D C, López A, Rasillo A, Sayagués J M, Rivas R A, Gutiérrez M L, Ciudad J, Flores T, Balanzategui A, Caballero M D & Orfao A (2011) Histopathology , 906-918 To establish the utility of flow cytometry (FCM) for screening and diagnosis of B cell non-Hodgkin lymphoma (B-NHL) from lymphoid tissue samples obtained by fine-needle aspiration (FNA). We compared prospectively FCM versus cytology/histology analysis of FNA samples for the diagnostic screening and further World Health Organization (WHO) subclassification of B-NHL. FCM and cytology showed a high degree of agreement (93%); however, diagnosis of reactive processes (RP), B-NHL and T-NHL by FCM showed higher sensitivity than cytology (92-100% versus 64-94%, respectively), without false positive NHL cases. The antibody combination used did not allow a positive diagnosis of Hodgkin lymphoma as distinct from a RP. A high concordance rate was found between FCM and histopathology (74%) in subtyping B-NHL. In this regard, mantle-cell lymphoma and chronic lymphocytic leukaemia/small lymphocytic lymphoma showed the highest degree of agreement (100% concordant rates). In turn, FCM showed higher sensitivity/specificity in classifying follicular lymphoma (FL) and large B cell lymphomas, while the opposite occurred for marginal-zone and lymphoplasmacytic lymphomas. FCM enhances the diagnostic ability of FNA cytology, playing a crucial role in a rapid and accurate differential diagnosis between RP, B-NHL and T-NHL. In addition, immunophenotyping of FNA samples contributes to a more precise subclassification of B-NHL when combined with histopathology and genetic/molecular data. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1 "01 (29% vs 19.5%, P = .0008, Pc = .0104) and a lower frequency of HLA-C"03 (6.4% vs 17.9%, P < .0005, Pc = .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P= .019) and 5-year overall (71 %vs 92%, P= .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect. [ABSTRACT FROM AUTHOR]