Epstein-Barr virus DNA load kinetics analysis in allogeneic hematopoietic stem cell transplant recipients: Is it of any clinical usefulness?

Abstract Background There is a lack of clinical information regarding the usefulness of plasma Epstein-Barr virus (EBV) DNA load kinetics analyses in the management of EBV infections in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Namely, it remains unknown whether this type of analysis can help physicians to anticipate the development of high-level EBV DNAemia episodes requiring rituximab treatment or predict the risk of recurrent EBV DNAemia or post-transplant lymphoproliferative disorders (PTLDs). Study design Unicentric, retrospective, observational study including 142 consecutive patients undergoing T-cell replete allo-HSCT. The plasma EBV DNA load was mon…

Loss of a novel tumor suppressor gene locus at chromosome 8p is associated with leukemic mantle cell lymphoma

Abstract Patients with mantle cell lymphoma (MCL) may present with either nodal or leukemic disease. The molecular determinants underlying this different biologic behavior are not known. This study compared the pattern of genetic abnormalities in patients with nodal and leukemic phases of MCL using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) for specific gene loci. Although both leukemic and nodal MCL showed similar genomic patterns of losses (involving 6q, 11q22-q23, 13q14, and 17p13) and gains (affecting 3q and 8q), genomic loss of chromosome 8p occurred more frequently in patients with leukemic disease (79% versus 11%,P < .001). Subsequent…

Study of the Expression of Angiogenic Factors and Dopaminergic Receptors: Correlation with ZAP70, CD38 and the Mutational State in Chronic Lymphocytic Leukaemia (CLL).

Abstract The angiogenesis is a well known process implicate in the progression of CLL. In this disease has been described an increase of angiogenic and pro-angiogenic factors in serum and angiogenic receptors in B cells, mainly in advances stages. Recently had been known that the agonist of the dopaminergic receptor D2 can inhibit the tumour growth and a possible mechanism mediator is the internalization of VEGFR-2. The aim of this work had been to analyze the expression of the dopaminergic receptors (D1, D2, D3, D4 and D5), the angiogenic receptors and its correlation with the main biological factor implicated in the illness (ZAP-70, CD38 and the mutational status of IgVH/BCL-6). We had de…

Impact of different strategies of second-line stem cell harvest on the outcome of autologous transplantation in poor peripheral blood stem cell mobilizers.

The optimal approach to obtain an adequate graft for transplantation in patients with poor peripheral blood stem cell (PBSC) mobilization remains unclear. We retrospectively assessed the impact of different strategies of second-line stem cell harvest on the transplantation outcome of patients who failed PBSC mobilization in our institution. Such patients were distributed into three groups: those who proceeded to steady-state bone marrow (BM) collection (group A, n = 34); those who underwent second PBSC mobilization (group B, n = 41); those in whom no further harvesting was carried out (group C, n = 30). PBSC harvest yielded significantly more CD34+ cells than BM collection. Autologous trans…

Epidemiologic and Clinical Characteristics of Coronavirus and Bocavirus Respiratory Infections after Allogeneic Stem Cell Transplantation: A Prospective Single-Center Study

Highlights • Human coronavirus are common after allogeneic stem cell transplantation and can progress to LRTDs, and in some cases this leads to hospitalization and requires supportive care. • Human bocavirus are quite rare after allogeneic stem cell transplantation and are commonly detected in conjunction with other viral co-pathogens.

Treatment of B-CLL Cells with Bortezomib and Rituximab Reduces Cell Viability In Vitro..

Introduction : In B-CLL, somatic mutation of IgVH genes defines a group of patients with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Our previous data suggested that BCL-6 mutations identify a subgroup of patients with high risk of progression despite the presence of mutated IgVH gene, but the clinical significance of this molecular alteration remains uncertain. New approaches are now being tested for the treatment of B-CLL. Proteasome inhibitor, Bortezomib (Btz), and monoclonal antibodies specific for surface antigens, Rituximab (Rtx), represent potential therapeutic strategy. Objetives : To study the effects of Btz and Rtx on viability of…

Prognostic Value of Radiomics Signature By Diagnostic 18F-FDG PET/CT Analysis in Aggressive Non-Hodgkin's Lymphoma

Abstract BACKGROUND Although the overall prognosis of patients with aggressive non-Hodgkin's lymphoma (NHL) has improved, nearly a third of patients will have refractory disease or relapse. Identification of these high-risk patients using traditional prognostic factors is limited. PET is the recommended imaging modality for the staging of FDG-avid lymphoma but the value of a comprehensive new imaging biomarkers analysis applied to PET for the prediction of patients outcome has still not been deeply investigated. New metrics estimating the overall tumor burden such as metabolic tumor volume (MTV) and those that may capture intratumoral biological heterogeneity such as total lesion glycolysis…

Umbilical cord blood transplantation in adults with advanced hodgkin's disease: high incidence of post-transplant lymphoproliferative disease

We report the outcome of 30 consecutive patients with Hodgkin disease (HD) who underwent single-unit UCBT. Most (90%) patients had failed previous autologous hematopoietic stem cell transplantation. The conditioning regimens were based on combinations of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin. The cumulative incidence (CI) of myeloid engraftment was 90% [95% confidence interval (C.I.), 74-98%] with a median of 18 d (range, 10-48). CI of acute graft-versus-host disease (GvHD) grades II-IV was 30% (95% C.I., 17-44%), while the incidence of chronic GVHD was 42% (95% C.I., 23-77%). The non-relapse mortality (NRM) at 100 d and 4 yr was 30% (95% C.I., 13-4…

A Time-to-Event Model for Acute Kidney Injury after Reduced-Intensity Conditioning Stem Cell Transplantation Using a Tacrolimus- and Sirolimus-based Graft-versus-Host Disease Prophylaxis.

There is a paucity of data evaluating acute kidney injury (AKI) incidence and its relationship with the tacrolimus-sirolimus (Tac-Sir) concentrations in the setting of reduced-intensity conditioning (RIC) after allogeneic stem cell transplantation (allo-HSCT). This multicenter retrospective study evaluated risk factors of AKI defined by 2 classification systems, Kidney Disease Improving Global Outcome (KDIGO) score and "Grade 0-3 staging," in 186 consecutive RIC allo-HSCT recipients with Tac-Sir as graft-versus-host disease prophylaxis. Conditioning regimens consisted of fludarabine and busulfan (n = 53); melphalan (n = 83); or a combination of thiotepa, fludarabine, and busulfan (n = 50). …

Peripheral T-cell lymphoma associated consecutively with hemophagocytic lymphohistiocytosis and hypereosinophilic syndrome

:  Both hemophagocytic lymphohistiocytosis and hypereosinophilic syndrome have been associated with hematologic neoplasms and are respectively related to an overproduction of the cytokines Thelper 1 (Th1) and Th2 by tumor cells or reactive cells. To our knowledge, this is the first time a case of a peripheral T-cell lymphoma consecutively associated with both paraneoplastic conditions has been reported. Importantly, in this case when the lymphoma exclusively involved the bone marrow, severe paraneoplastic systemic damage, a CD8+ suppressor/cytotoxic phenotype and a hypereosinophilia not related to high levels of interleukin (IL)-5 was found. Interestingly, progression of the lymphoma coinci…

Influence of different complement sources in apoptosis of B-CLL cells with rituximab

Abstract Introduction: Rituximab (Rtx) is an anti-CD20 monoclonal antibody that is clinically active in B-cell chronic lymphocytic leukemia (B-CLL). In vitro and in vivo data indicate that Rtx mediates its biologic effect through multiple mechanisms including apoptosis, complement dependent cytotoxicity (CDC), and antibody dependent cellular cytotoxicity (ADCC). Objetive: To study in vitro sensitivity to apoptosis by Rtx of isolated cells obtained from B-CLL patients Binet stage A, in the presence of complement from different sources and correlate with CD20 and CD59 molecules expression. Methods: PBMCs were isolated from peripheral blood samples by centrifugation on a Ficoll/Hypaque gradien…

Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome

To identify recurrent genomic changes in mantle cell lymphoma (MCL), we used high-resolution comparative genomic hybridization (CGH) to bacterial artificial chromosome (BAC) microarrays in 68 patients and 9 MCL-derived cell lines. Array CGH defined an MCL genomic signature distinct from other B-cell lymphomas, including deletions of 1p21 and 11q22.3-ATM gene with coincident 10p12-BMI1 gene amplification and 10p14 deletion, along with a previously unidentified loss within 9q21-q22. Specific genomic alterations were associated with different subgroups of disease. Notably, 11 patients with leukemic MCL showed a different genomic profile than nodal cases, including 8p21.3 deletion at tumor necr…

Ighv Mutational Status By Deep Next Generation Sequencing Refines Ighv Sanger Sequencing Classification in Patients with Chronic Lymphocytic Leukaemia

Introduction: Determination of the mutational status of rearranged immunoglobulin heavy chain variable (IgHV) genes in patients with Chronic Lymphocytic Leukaemia (CLL), is considered one of the most important prognostic factors: patients with unmutated IgHV (UM; ≥98% of identity to the germline) genes have a more aggressive disease course and develop more frequently unfavourable genetic deletions or mutations than patients with mutated IgHV (M; ≤98%). Mutational status, is currently determined by Sanger sequencing (Sseq) that allows the analysis of the major clone, however, international guidelines recommend caution in assigning mutational status in cases with "Borderline" IgHV identity (9…

Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) a…

Cryptic Insertions Of The Immunoglobulin Light Chain Enhancer Region Near CCND1 In T(11;14)-Negative Mantle Cell Lymphoma

Cyclin D1+ mantle cell lymphoma (MCL) is molecularly characterized by the t(11;14)(q13;q32) or rearrangements of CCND1 gene with the immunoglobulin (IG) light chains.1,2 Most MCL can be diagnosed based on the characteristic pathologic features and cyclin D1 expression without the need for demonstrating the genetic translocation. However, in cases with atypical morphologic or phenotypic features other B-cell neoplasms that sometimes also have cyclin D1 positivity may be in the differential diagnosis.1 In these situations the detection of the CCND1 rearrangements may assist in the diagnosis since most other lymphomas do not carry translocations of the gene.3-7 A subset of plasma cell myelomas…

Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia after treatment of breast cancer and hematological malignancies

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) is a malignancy occurring after exposure to chemotherapy and/or radiotherapy. Polymorphisms involved in chemotherapy/radiotherapy response genes could be related to an increased risk of developing this neoplasia. We have studied 11 polymorphisms in genes of drug detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair cross complementing protein (1)), Nijmegen breakage syndrome (1), excision repair cross-complementing rodent repair deficiency, complementation group (5) and X-ray repair cross complementing protein (3) and in the methy…

Cytomegalovirus‐specific T‐cell immunity and DNAemia in patients with chronic lymphocytic leukaemia undergoing treatment with ibrutinib

Proteomic Profile Study of Chronic Lymphocytic Leukemia-B Patients with IGVH and BCL6 Mutated or Unmutated Genes.

Abstract Introduction: Chronic lymphocytic leukemia B (CLL-B) is the most frequent chronic lymphoproliferative disorder in western countries. The majority of patients are diagnosed in incipient Binet stage A. Some prognostic factors have been identified, as mutations in the genes coding for immunoglobulin variable regions (IgVH). Complementary somatic mutations in the BCL6 gene have been observed in 25% of CLL-B patients, although its clinical relevance remains unclear. Objective: To identify molecular markers of different patient groups of lymphoproliferative disorder through analysis of their proteomic profiles. Material and Methods: 15 samples of peripheral blood lymphocytes B from Binet…

In the literature: February 2017

The hallmark of mantle cell lymphoma (MCL) is the t(11;14)(q13,q32) translocation, which leads to the juxtaposition of CCDN1 to the IgH promoter locus, resulting in cyclin D1 overexpression. However, studies from transgenic mouse show that additional secondary genetic events are required for oncogenic transformation. Epigenetic dysregulation is an important mechanism of oncogenesis and tumour progression, but there are only few genome-wide studies of DNA methylome in MCL and mainly focused on promoter regions. In an elegant article published in Cancer Cell , Queiros et al 1 studied the genome-wide methylation profiles of 82 MCL cases using microarray containing approximately 450 000 CPG sit…

Genomic Abnormalities Acquired in the Blastic Transformation of Splenic Marginal Zone B-cell Lymphoma

Among 20 cases of typical splenic marginal zone lymphoma (SMZL), two cases had blastic transformation. The genetic mechanisms underlying the morphologic transformation were investigated by comparing genetic changes in initial and blastic phases. A complex karyotype including trisomy of 3q and genomic gain of 17q22-q24 was seen in both cases at diagnosis. However, the extra copy of 3q was lost during the transformation process in both tumors. Additionally, the Karpas 1718 cell line, which was derived from a patient with transformed SMZL and carried a trisomy of 3q, also evidenced the spontaneous loss of the extra 3q during the culturing process. Other acquired abnormalities observed exclusiv…

CAR-T therapy in solid transplant recipients with post-transplant lymphoproliferative disease: case report and literature review

Patients with postransplant lymphoproliferative disease (PTLD) who are refractory to rituximab-based regimens have extremely poor prognosis. Data is lacking in the setting of solid organ transplantation (SOT)-related PTLD treated with chimeric antigen receptor T-cell (CAR-T) therapy. Moreover, limited information is available on the influence of concomitant immunosuppressive drugs on CAR-T function. Here, we describe the clinical outcome in one PTLD patient and propose a strategy for tailoring immunosuppressive treatment and organ monitoring in patients with kidney allografts after CAR-T infusion. This report also reviews the limited published data in the setting of SOT-related PTLD treated…

Glofitamab (Glofit) in Combination with Polatuzumab Vedotin (Pola): Phase Ib/II Preliminary Data Support Manageable Safety and Encouraging Efficacy in Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Abstract Background: Glofit is a novel, CD20xCD3 T-cell-engaging bispecific antibody that provides monovalent binding to CD3 on T cells and bivalent binding to CD20 on B cells. As monotherapy, Glofit has shown promising response rates with manageable safety in R/R B-cell non-Hodgkin lymphoma (B-NHL) patients (pts; [Carlo-Stella et al. EHA 2021]). Because of their distinct and complementary mechanism of action, there is a rationale for combining Glofit with the anti-CD79b-targeted antibody-drug conjugate, Pola. NP39488 (NCT03533283) is a Phase Ib/II, open-label, multicenter, dose-escalation (DE) and expansion study evaluating Glofit + Pola or atezolizumab in R/R B-NHL pts (Hutchings et al. A…

Detection of Immunoglobulin Heavy Chain Gene Clonality By High-Throughput Sequencing for Minimal Residual Disease Monitoring in Chronic Lymphocytic Leukaemia

Introduction: The negative minimal residual disease (MRD) after treatment has been recently accepted as endpoint for Chronic Lymphocytic Leukaemia (CLL) clinical trials. Conventionally, MRD can be detected by using multi-color Flow Cytometry (FC) with high sensitivity. Determination of the clonal immunoglobulin gene rearrangement can be a useful monitoring marker in a broad range of B-cell lymphoproliferative neoplasms. Moreover, the mutational status of immunoglobulin heavy chain variable (IgHV) rearrangement is considered one of the most important prognostic factors in CLL. Therefore, the identification of the IgHV rearrangement can be a useful marker both at diagnostic and as monitoring …

Brentuximab Vedotin Plus ESHAP (BRESHAP) Versus ESHAP As Salvage Strategy for Patients with Primary Refractory or Relapsed Classical Hodgkin's Lymphoma. Preliminary Results from the Breselibet Prospective Clinical Trial

Abstract Introduction. Patients with relapsed/refractory classical Hodgkin's lymphoma (RRHL) still represent a therapeutic challenge. Consolidation with autologous stem cell transplantation (auto-HCT) is the standard of care in this setting. The achievement of a metabolic complete remission (mCR) with salvage chemotherapy (CT) improves long-term outcome after auto-HCT. The introduction of new drugs has significantly changed the landscape of RRHL. Our cooperative group (GELTAMO) has already demonstrated that brentuximab vedotin (BV) + ESHAP (BRESHAP, García-Sanz R et al, Ann Oncol 2019) is able to achieve a mCR rate of 70% before auto-HCT in patients with RRHL. Nevertheless, the superiority …

Epidemiological Characterization and Determination of TP53 and IGHV Mutational Status of a Large Series of Previously-Untreated Chronic Lymphocytic Leukemia (CLL) Patients in Spain: The Epicll Study

Abstract Introduction: Among the genetic lesions described in chronic lymphocytic leukemia (CLL), TP53 and IGHV mutational status are well-established prognostic biomarkers. While mutations resulting in dysregulation of TP53 are associated with chemo-resistance, mutated IGHV (IGHV-M) identifies a good prognosis and unmutated (IGHV-UM) is associated with an aggressive clinical outcome. Thus, molecular assessment of TP53 and IGHV mutational status is recommended to make treatment decisions. Moreover, 30% of CLL patients have a highly homologous complementarity-determining region 3 (CDR3), allowing their classification in subsets based on the stereotypical B-cell receptor immunoglobulins (BcR …

Sirolimus exposure and the occurrence of cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation

Sirolimus appears to protect against cytomegalovirus (CMV) in organ transplant recipients. The effect of this drug in allogeneic hematopoietic stem cell transplantation recipients remains unexplored. By means of multivariate continuous-time Markov model analyses, we identified 3 independent covariates that significantly impacted the risk of CMV DNAemia: recipient/donor CMV serostatus, tacrolimus exposure, and sirolimus exposure. CMV-seropositive recipients with CMV-seronegative donors had a significantly higher probability of having detectable CMV DNAemia. Increasing the tacrolimus trough concentration from 0 to 16 ng/mL increased the probability of patients having detectable CMV DNAemia by…

Splenic Marginal Zone Lymphoma Shows a Distinct Pattern of DNA Copy Number Aberrations That Correlates with Tumor Characteristics and Predicts Disease Outcome.

Abstract Splenic marginal zone lymphoma (SMZL) is an indolent B cell malignancy whose diagnosis is based on lymphocyte morphology, immunophenotype and marrow and/or splenic histology. Unlike other lymphomas, there is not a common chromosomal translocation specific for SMZL, and genetic prognostic factors are poorly defined. To investigate the pattern of genomic aberrations in SMZL, we applied comparative genomic hybridization to BAC microarrays (array CGH) to a well characterized series of 75 SMZL specimens. We applied two different 1 Mb-resolution BAC arrays: UCSF HumArray 3.2 and a novel array CGH platform developed at Univ. of Salamanca. These arrays allowed us to detect DNA copy number …

Liquid Biopsy and Lymphoma Monitoring in Clinical Practice

Abstract INTRODUCTION Lymphomas represent the fourth most frequent type of cancer, 90% of them arising from B cell lymphocytes. Despite their high prevalence, around 40% remain incurable because of refractoriness to current chemoimmunotherapy or disease relapse after obtaining response (Li et al., 2018; Meng et al., 2020). The cell of origin is a B lymphocyte with a unique B cell receptor (BCR). The BCR is an immunoglobulin composed of two heavy chains (IgH) and two light chains (IgL) whose genes have multiple coding segments that through rearrangement first and further somatic hypermutation in the germinal center, generate a unique sequence that could be used to monitor the treatment respo…

Analysis of chronic lymphotic leukemia transcriptomic profile: differences between molecular subgroups

B cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with a variable clinical course. Patients with unmutated IgV(H) gene show a shorter progression-free and overall survival than patients with immunoglobulin heavy chain variable regions (IgV(H)) gene mutated. In addition, BCL6 mutations identify a subgroup of patients with high risk of progression. Gene expression was analysed in 36 early-stage patients using high-density microarrays. Around 150 genes differentially expressed were found according to IgV(H) mutations, whereas no difference was found according to BCL6 mutations. Functional profiling methods allowed us to distinguish KEGG and gene ontology terms showing…