Publications by authors named "Laura Magnano"

53 Publications

Revised International Prognostic Index and genetic alterations are associated with early failure to R-CHOP in patients with diffuse large B-cell lymphoma.

Br J Haematol 2021 Oct 10. Epub 2021 Oct 10.

Department of Hematology, Hospital Clínic, Barcelona, Spain.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) cases have a poor outcome. Here we analysed clinico-biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12 months from diagnosis. In addition to clinical features, mutational status of 106 genes was studied by targeted next-generation sequencing in 111 cases, copy number alterations in 87, and gene expression profile (GEP) in 39. Ninety-seven cases (26%) were identified as EF and showed significantly shorter overall survival (OS). Patients with B symptoms, advanced stage, high levels of serum lactate dehydrogenase (LDH) or β2-microglobulin, low lymphocyte/monocyte ratio and higher Revised International Prognostic Index (R-IPI) scores, as well as those with BCL2 rearrangements more frequently showed EF, with R-IPI being the most important in logistic regression. Mutations in NOTCH2, gains in 5p15·33 (TERT), 12q13 (CDK2), 12q14·1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R-IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over-representation of gene sets related to extra-cellular matrix and tumour microenvironment.
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http://dx.doi.org/10.1111/bjh.17858DOI Listing
October 2021

Clinico-biological features and outcome of patients with splenic marginal zone lymphoma with histological transformation.

Br J Haematol 2021 Sep 14. Epub 2021 Sep 14.

Hematology Department and Hematopathology Section, Pathology Department, Hospital Clínic of Barcelona, Barcelona, Spain.

We describe 36 patients with splenic marginal zone lymphoma (SMZL) with transformation (SMZL-T), including 15 from a series of 84 patients with SMZL diagnosed at the Hospital Clinic of Barcelona (HCB) and 21 diagnosed with SMZL-T in other centres. In the HCB cohort, the cumulative incidence of transformation at 5 years was 15%. Predictors for transformation were cytopenias, hypoalbuminaemia, complex karyotype (CK) and both the Intergruppo Italiano Linfomi (ILL) and simplified Haemoglobin, Platelet count, lactate dehydrogenase (LDH) and extrahilar Lymphadenopathy (HPLL)/ABC scores (P < 0·05). The only independent predictor for transformation in multivariate analysis was CK [hazard ratio (HR) 4·025, P = 0·05]. Patients with SMZL-T had a significantly higher risk of death than the remainder (HR 3·89, P < 0·001). Of the 36 patients with SMZL-T, one developed Hodgkin lymphoma and 35 a diffuse large B-cell lymphoma, 71% with a non-germinal centre phenotype. The main features were B symptoms, lymphadenopathy, and high serum LDH. CK was observed in 12/22 (55%) SMZL-T and fluorescence in situ hybridisation detected abnormalities of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and/or BCL6 in six of 14 (43%). In all, 21 patients received immunochemotherapy, six chemotherapy, one radiotherapy and three splenectomy. The complete response (CR) rate was 61% and the median survival from transformation was 4·92 years. Predictors for a worse survival in multivariate analysis were high-risk International Prognostic Index (HR 5·294, P = 0·016) and lack of CR (HR 2·67, P < 0·001).
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http://dx.doi.org/10.1111/bjh.17815DOI Listing
September 2021

Primary refractory follicular lymphoma: a poor outcome entity with high risk of transformation to aggressive B cell lymphoma.

Eur J Cancer 2021 Sep 8;157:132-139. Epub 2021 Sep 8.

CHIMOMODepartment, University of Modena and Reggio Emilia, Modena, Italy.

Background: Primary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome.

Methods: Six thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation.

Findings: The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27-43), whilst it was 7.1% (95% CI: 6.0-8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0-4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28-39) for the PREF group, 57% (95% CI 54-61) in patients with PR, 51% (95% CI 43-58) in the SD group after first-line therapy and 63% (95% CI: 66-72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12-31), clearly diminished when compared with those patients with PREF who did not experience HT (38% [95% CI: 31-44]) (p-value = 0.001).

Interpretation: Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis.
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http://dx.doi.org/10.1016/j.ejca.2021.08.005DOI Listing
September 2021

Prognostic ability of five clinical risk scores in follicular lymphoma: A single-center evaluation.

Hematol Oncol 2021 Sep 7. Epub 2021 Sep 7.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

With the intention of identifying follicular lymphoma (FL) patients at higher risk of progression, early relapse (POD24), histological transformation (HT) or death, multiple risk scores (RS) have been proposed. However, it has not yet been established whether any of them globally outperforms the others. We evaluated the clinical utility and statistical performance of the five most widely used clinical scores (IPI, ILI, FLIPI, FLIPI2, PRIMA-PI) in a single-center series of 414 grade 1-3A FL patients diagnosed in the rituximab era. Overall concordance (proportion of patients allocated to the same risk category by all five RS) was 24%. FLIPI and FLIPI2 were predictive of time to first treatment. All five scores were predictive of response, POD24, progression-free, and OS, while only FLIPI predicted HT. IPI identified a small subset (7%) of truly high-risk patients (10-year OS of 16%). In subgroup analyses, we showed that ILI is useful in the prognostication of limited-disease patients, and PRIMA-PI is an age-independent score that can identify a high-risk subset of older patients. Performance metrics were slightly better for IPI in terms of calibration (Harrell's c-index 0.73), without major differences among RS regarding other parameters. Although the incorporation of molecular and imaging data will continue to refine the stratification of FL patients, FLIPI remains the most powerful clinical prognostic index in the rituximab era, predicting the greatest number of endpoints.
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http://dx.doi.org/10.1002/hon.2922DOI Listing
September 2021

Balanced and unbalanced translocations in a multicentric series of 2843 patients with chronic lymphocytic leukemia.

Genes Chromosomes Cancer 2021 Aug 19. Epub 2021 Aug 19.

Hematopathology Section, Department of Pathology, Hospital Clinic, Barcelona, Spain.

Chromosomal translocations in chronic lymphocytic leukemia (CLL) are very rare, and therefore systematic analysis of large series of cases is needed to allow the identification of recurrent rearrangements, breakpoints involved, and target genes. The aims of the present study were to identify new translocations and their clinical impact and to establish their frequency in a large cohort of 2843 CLL patients. By conventional cytogenetics 250 translocations were identified in 215 (7.5%) patients, 186 (74%) were apparently balanced and 64 (26%) were unbalanced. All chromosomes were involved in translocations, except Y chromosome. The chromosomes more frequently translocated were in decreasing frequency chromosomes 14, 18, 13, 17, 1, 6, 2, 3, 8, and 11. Translocations were found in the karyotypes either as the unique chromosomal abnormality (27%), associated with another alteration (24%), or as a part of a complex karyotype (CK, 48%). A large proportion of rearranged breakpoints involved genes related to CLL such as IGH (14q32), RB1, MIR15A, MIR16-1 (13q14), BCL2 (18q21), IGL (22q11.2), TP53 (17p13), IRF4 (6p25-p23), ATM (11q22), and CDK6 (7q21). Overall, 76 novel CLL translocations were identified, including a recurrent t(8;11)(p21;q21-23). Whole-genome sequencing and/or copy-number microarray data of 24 cases with translocations confirmed all rearrangements, enabled refinement of 3 karyotypes and all breakpoints at gene level. The projected survival and time to first treatment significantly decreased linearly with the number of translocations. In summary, this study allowed to establish the frequency of translocations (7.5%) and to identify new translocations in a cohort of 2843 CLL patients.
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http://dx.doi.org/10.1002/gcc.22994DOI Listing
August 2021

Clinicobiological Characteristics and Outcomes of Patients with T-Cell Large Granular Lymphocytic Leukemia and Chronic Lymphoproliferative Disorder of Natural Killer Cells from a Single Institution.

Cancers (Basel) 2021 Aug 2;13(15). Epub 2021 Aug 2.

Hematopathology Unit, Department of Pathology, Hospital Clínic, 08036 Barcelona, Spain.

T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of are involved in the pathogenesis of these entities. We describe the clinicobiological features, mutational status of , treatment and outcome of 131 patients. Neutropenia was the most frequent finding at diagnosis, followed by anemia. Concurrent hematological disorders were diagnosed in 37% of patients and autoimmune conditions and solid tumors in 17% and 15%, respectively. All patients who needed treatment belonged to the CD8CD57 group. Remarkably, patients included in the CD4 group had a higher association with solid tumors ( = 0.037). mutations were found in 17% of patients, mainly Y640F and D661Y mutations. Patients carrying mutations more frequently presented with anemia, neutropenia, high LDH, high large granular lymphocyte counts and need for treatment ( = 0.0037). Methotrexate was the most frequently used agent (72% of cases). The overall response rate to all treatments was 50%. The 10-year overall survival of this series was 78%, with no differences according to the mutational status of . We compared the survival of these patients with the general Spanish population and no differences were found, confirming the indolent nature of these hematological malignancies. Our study further extends findings documented by others on the clinical behavior of the disease and the impact of , and for the first time analyzes survival compared to a matched general Spanish population.
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http://dx.doi.org/10.3390/cancers13153900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345581PMC
August 2021

Defining an Ultra-Low Risk Group in Asymptomatic IgM Monoclonal Gammopathy.

Cancers (Basel) 2021 Apr 23;13(9). Epub 2021 Apr 23.

Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, 08036 Barcelona, Spain.

We analyzed 171 patients with asymptomatic IgM monoclonal gammopathies (64 with IgM monoclonal gammopathy of undetermined significance-MGUS and 107 with smoldering Waldenström macroglobulinemia - SWM) who had a bone marrow (BM) evaluation performed at diagnosis. Abnormal free-light chain ratio (53% vs. 31%) and mutation prevalence (66% vs. 30%) were higher in patients with SWM. No other differences were found among groups. With a median follow-up of 4.3 years, 14 patients progressed to Waldenström macroglobulinemia, 1 to amyloidosis, and 28 died without progression. The mutation was found in 53% of patients (available in 160 patients). Multivariate analysis showed that immunoparesis (subhazard ratio-SHR 10.2, 95% confidence interval-CI: 4.2-24.8; < 0.001) and BM lymphoplasmacytic infiltration ≥ 20% (SHR: 6, 95% CI: 1.6-22.1; = 0.007) were associated with higher risk of progression. We developed a risk model based on these two risk factors. In the absence of both variables, an ultra-low risk group was identified (SHR 0.1, 95% CI 0.02-0.5; = 0.004), with 3% and 6% of cumulative incidence of progression at 10 and 20 years, respectively. Bootstrap analysis confirmed the reproducibility of these results. This study finds immunoparesis and BM infiltration as biomarkers of progression as well as a low-risk group of progression in asymptomatic IgM monoclonal gammopathies.
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http://dx.doi.org/10.3390/cancers13092055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122982PMC
April 2021

The receptor of the colony-stimulating factor-1 (CSF-1R) is a novel prognostic factor and therapeutic target in follicular lymphoma.

Leukemia 2021 09 17;35(9):2635-2649. Epub 2021 Mar 17.

Department of Hematology-Oncology, IDIBAPS, Barcelona, Spain.

Microenvironment contributes to follicular lymphoma (FL) pathogenesis and impacts survival with macrophages playing a controversial role. In the present study, using FL primary samples and HK follicular dendritic cells (FDC) to mimic the germinal center, together with mouse models, we have analyzed the three-way crosstalk of FL-FDC-macrophages and derived therapeutic opportunities. Ex vivo primary FL-FDC co-cultures (n = 19) and in vivo mouse co-xenografts demonstrated that FL-FDC crosstalk favors tumor growth and, via the secretion of CCL2 and CSF-1, promotes monocyte recruitment, differentiation, and polarization towards an M2-like protumoral phenotype. Moreover, FL-M2 co-cultures displayed enhanced angiogenesis, dissemination, and immunosuppression. Analysis of the CSF-1/CSF-1R pathway uncovered that CSF-1 was significantly higher in serum from grade 3A FL patients, and that high CSF-1R expression in FL biopsies correlated with grade 3A, reduced overall survival and risk of transformation. Furthermore, CSF-1R inhibition with pexidartinib (PLX3397) preferentially affected M2-macrophage viability and polarization program disrupting FL-M2 positive crosstalk. In vivo CSF1-R inhibition caused M2 reduction and repolarization towards M1 macrophages and antitumor effect cooperating with anti-CD20 rituximab. In summary, these results support the role of macrophages in FL pathogenesis and indicate that CSF-1R may be a relevant prognostic factor and a novel therapeutic target cooperating with anti-CD20 immunotherapy.
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http://dx.doi.org/10.1038/s41375-021-01201-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410584PMC
September 2021

Age and comorbidity are determining factors in the overall and relative survival of patients with follicular lymphoma.

Ann Hematol 2021 May 25;100(5):1231-1239. Epub 2021 Feb 25.

Department of Hematology, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain.

Frailty and concurrent medical conditions are crucial factors in the management of follicular lymphoma (FL). We evaluated the impact of age and comorbidity on survival, causes of death, histological transformation (HT), and second malignancies (SM) in a large single-center series of grade 1-3A FL. We studied 414 patients diagnosed in the rituximab era, categorized into three age groups (≤60, 61-70, >70 years) and two comorbidity groups (Charlson Comorbidity Index, CCI, 0-1 and ≥2). Despite a similar cumulative incidence of relapse, older and comorbid patients had a lower 10-year overall survival (OS, 88, 65, and 41% for patients ≤60 years, 61-70 years, and >70 years, P<0.0001; and 76 vs. 51% for CCI 0-1 and ≥2, P<0.0001). In a multivariate analysis for OS, comorbidity retained its prognostic impact (HR=2.5, P=0.0003). The proportion of patients dying due to FL was higher among those ≤60 years (74%) and those with a CCI 0-1 (67%). Furthermore, 10-year excess mortality (survival reduction) was more prominent for patients >70 years (30%) and those with a CCI ≥2 (32%). Patients with a CCI ≥2 also had a higher incidence of SM. These data encourage a comprehensive pre-treatment evaluation and a tailored therapeutic approach for all FL patients.
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http://dx.doi.org/10.1007/s00277-021-04470-7DOI Listing
May 2021

Baseline correlations and prognostic impact of serum monoclonal proteins in follicular lymphoma.

Br J Haematol 2021 04 16;193(2):299-306. Epub 2020 Nov 16.

Department of Haematology, Hospital Clínic de Barcelona, Barcelona, Spain.

The presence of a serum monoclonal component has been associated with poor outcomes in some lymphomas. However, data in follicular lymphoma (FL) are scarce. We studied 311 FL patients diagnosed at a single institution, for whom information on serum immunofixation electrophoresis (sIFE) at diagnosis was available. Baseline characteristics and outcomes were compared between patients with a positive (+sIFE) and a negative sIFE (-sIFE). sIFE was positive in 82 patients (26%). Baseline features were comparable between both groups, except for an older age and higher proportion of elevated β -microglobulin levels in the +sIFE group. With a median follow-up of 4.6 years, a +sIFE was associated with a higher risk of early relapse (POD24, 27% vs. 15%, P = 0·02), shorter progression-free survival (PFS; 42% vs. 52% at 5 years, P = 0·008), and shorter overall survival (OS; 59% vs. 77% at 10 years, P = 0·046). In patients >60 years, a +sIFE was an independent predictor of OS [hazard ratio (HR) = 2·4, 95% confidence interval (CI): 1·2-5·0; P = 0·02]. Approximately one quarter of patients with FL has a +sIFE at diagnosis, which is a predictor of poor outcome. These findings encourage further investigation of its relationship with B-cell biology and the tumour microenvironment.
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http://dx.doi.org/10.1111/bjh.17138DOI Listing
April 2021

Serum monoclonal component in chronic lymphocytic leukemia: baseline correlations and prognostic impact.

Haematologica 2021 06 1;106(6):1754-1757. Epub 2021 Jun 1.

Department of Hematology, Hospital Clínic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid.

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http://dx.doi.org/10.3324/haematol.2020.263228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168485PMC
June 2021

Mutational Landscape and Tumor Burden Assessed by Cell-free DNA in Diffuse Large B-Cell Lymphoma in a Population-Based Study.

Clin Cancer Res 2021 01 29;27(2):513-521. Epub 2020 Oct 29.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

Purpose: We analyzed the utility of cell-free DNA (cfDNA) in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with diffuse large B-cell lymphoma (DLBCL).

Experimental Design: A total of 100 patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed, paraffin-embedded samples and volumetric PET/CT were assessed when available.

Results: Appropriate cfDNA to perform the analyses was obtained in 79 of 100 cases. At least one mutation could be detected in 69 of 79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% confidence interval, 56.2-78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of circulating tumor DNA (ctDNA) significantly correlated with clinical parameters related to tumor burden (elevated lactate dehydrogenase and β2-microglobulin serum levels, advanced stage, and high-risk International Prognostic Index) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (>2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%; < 0.004), shorter progression-free survival (65% vs. 85%; = 0.038), and overall survival (73% vs. 100%; = 0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses.

Conclusions: In a population-based prospective DLBCL series, cfDNA resulted as an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2558DOI Listing
January 2021

Violence against pregnant women in the experience of the rape centre of Turin: Clinical and forensic evaluation.

J Forensic Leg Med 2020 Nov 14;76:102071. Epub 2020 Oct 14.

Department of Health Sciences, University of Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy. Electronic address:

Pregnant women can be victims of violence: as a matter of fact, far from being a protective factor, pregnancy can trigger or worsen episodes of abuse. Studies conducted by the WHO highlight that its incidence fluctuates between 1% and 28%. Therefore violence during pregnancy is endemic all over the world and involves all social strata. We analysed 113 medical records concerning pregnant women (average age 27.9 ± 6.0 years, 80 foreigners), who turned to the Centro Soccorso Violenza Sessuale, one of the two Italian Rape Centre, in Turin between January 1st, 2005 and December 31st, 2017. Fifty-three women were visited in the first trimester, 41 in the second, and 16 in the third, while 3 during the puerperium. The current partner was accused to be the abuser by the 84.4% of the Italian women and by the 69.2% of the foreigners. Sixty-eight women suffered multiple forms of violence, while 98 suffered only physical violence, and 3 reported only sexual abuse. According to 20 women, violent episodes increased during pregnancy. The clinical history of these women was characterized by some recurrent physical symptoms, such as pelvic pain, abdominal pain, facial pain and headache and 54 women presented injuries (abrasions and ecchymosis). Our results confirm that violence in pregnancy is a social and public health problem. Therefore it is important that the health personnel should be prepared not only to care for women seeking help, but above all its better preparation could also identify victims of violence, which do not report abuse.
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http://dx.doi.org/10.1016/j.jflm.2020.102071DOI Listing
November 2020

A low lymphocyte-to-monocyte ratio is an independent predictor of poorer survival and higher risk of histological transformation in follicular lymphoma.

Leuk Lymphoma 2021 01 19;62(1):104-111. Epub 2020 Sep 19.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

The lymphocyte-to-monocyte ratio (LMR) is a prognostic factor in different neoplasms, but its potential importance in follicular lymphoma (FL) is not well defined. We studied 384 FL patients for which the LMR was available at diagnosis. Baseline features and outcomes were compared between patients with an LMR ≤/>2.5. The 76 patients (20%) who had an LMR ≤2.5 were older and had a higher tumor burden. A low LMR was predictive of a lower 10-y progression-free survival (32 vs. 55%,  = .001) and overall survival (35 vs. 78%,  < .0001; HR = 2.3,  = .003 in a 6-element multivariable model). A low LMR was also an independent risk factor for histological transformation (11 vs. 6% at 10 years,  = .01). Likewise, patients with a low LMR had a higher rate of second malignancies. The potential utility of this widely available parameter and its contribution to well-established prognostic scores need to be explored in independent, prospective series.
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http://dx.doi.org/10.1080/10428194.2020.1821010DOI Listing
January 2021

PI3Kδ inhibition reshapes follicular lymphoma-immune microenvironment cross talk and unleashes the activity of venetoclax.

Blood Adv 2020 09;4(17):4217-4231

Department of Hematology-Oncology, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.

Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition, biomarkers of response, and potential combinatorial therapies in FL remain to be established. Using ex vivo cocultures of FL patient biopsies and follicular dendritic cells (FDCs) to mimic the germinal center (n = 42), we uncovered that PI3Kδ inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation, and transendothelial migration in a subset of FL samples, defining an 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases was its interference with the CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B-T-cell synapses, leading to an inefficient cross talk between FL cells and the supportive T-follicular helper cells (TFH). Moreover, idelalisib downmodulates the chemokine CCL22, hampering the recruitment of TFH and immunosupressive T-regulatory cells to the FL niche, leading to a less supportive and tolerogenic immune microenvironment. Finally, using BH3 profiling, we uncovered that FL-FDC and FL-macrophage cocultures augment tumor addiction to BCL-XL and MCL-1 or BFL-1, respectively, limiting the cytotoxic activity of the BCL-2 inhibitor venetoclax. Idelalisib restored FL dependence on BCL-2 and venetoclax activity. In summary, idelalisib exhibits a patient-dependent activity toward angiogenesis and lymphoma dissemination. In all FL cases, idelalisib exerts a general reshaping of the FL immune microenvironment and restores dependence on BCL-2, predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3Kδ inhibitors and venetoclax in clinical trials.
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http://dx.doi.org/10.1182/bloodadvances.2020001584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479943PMC
September 2020

High serum levels of IL-2R, IL-6, and TNF-α are associated with higher tumor burden and poorer outcome of follicular lymphoma patients in the rituximab era.

Leuk Res 2020 07 19;94:106371. Epub 2020 May 19.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain. Electronic address:

The clinical behavior of FL patients is heterogeneous. The levels of sIL-2R have been correlated with tumor burden and outcome in FL. However, the impact of IL-6 and TNF-α in this disease is unclear. We studied 253 patients diagnosed with grade 1-3a FL between 2002 and 2018, with available information on serum levels of sIL-2R, IL-6, and TNF-α at diagnosis. Patients with cytokine levels above the cutoff had features of a higher tumor burden and higher-risk disease. Levels of any of the studied cytokines above the cutoff and a higher number of cytokines above the cutoff impacted on a shorter PFS and OS. TNF-α levels were an independent predictor of a poorer PFS. No differences were observed in the risk of histological transformation or second malignancies. The determination of cytokine levels in FL patients is feasible in clinical practice, and elevated levels are associated with a higher tumor burden and poorer survival.
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http://dx.doi.org/10.1016/j.leukres.2020.106371DOI Listing
July 2020

Patterns of change in treatment, response, and outcome in patients with follicular lymphoma over the last four decades: a single-center experience.

Blood Cancer J 2020 03 5;10(3):31. Epub 2020 Mar 5.

Department of Hematology, Hospital Clínic, Barcelona, Spain.

Although the introduction of immunotherapy has improved outcomes for follicular lymphoma (FL) patients, histological transformation (HT) and early relapse still confer a poor prognosis. We sought to describe the patterns of change in treatment, response, and outcome of FL patients at our institution over the last four decades. Seven hundred and twenty-seven patients (389 F/338 M; median age, 57 years) consecutively diagnosed with grade 1-3a FL between 1980 and 2017, categorized into four decades according to the time of diagnosis, constituted the study population. Clinical characteristics, treatment, response, absolute and relative survival, HT, second malignancies (SM), and causes of death were assessed. Median OS for the entire cohort was 17.6 years. From decade 1 to 4, there was an increase in the complete response rate (48 to 70%), progression-free survival (40 to 56% at 5 years), OS (77 to 86% at 5 years), and relative survival ratio (0.83 to 0.94 at 5 years), with no significant differences in the risk of HT or SM. Lymphoma remained the most common cause of death in all four decades. These findings illustrate the overall improvement in outcome for FL patients, but support the need for further research into risk stratification and management.
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http://dx.doi.org/10.1038/s41408-020-0299-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058022PMC
March 2020

Positive predictive value of CD200 positivity in the differential diagnosis of chronic lymphocytic leukemia.

Cytometry B Clin Cytom 2020 09 6;98(5):441-448. Epub 2019 Nov 6.

Clinical Laboratory ICS-Metropolitana Nord, Core-hematology Department, Hospital Germans Trias i Pujol, Badalona, Spain.

Background: The role of CD200 in the differential diagnosis of chronic lymphocytic leukemia (CLL) and classical mantle cell lymphoma (MCL) is well established. Its role in the differential diagnosis of CLL and other lymphoproliferative disorders (LPD) is less clear, in particular its positive predictive value (PPV).

Materials And Methods: We conducted a systematic review of the use of CD200 in the differential diagnosis of CLL, MCL, and other predominantly leukemic, typically CD103-negative LPD. With the results, we then derived a curve to determine the PPV based on the prevalence of the disorders included in the differential diagnosis.

Results: Of 43 publications screened, 27 were included in the systematic review (5,764 patients). The median CD200 positivity rate in all studies and the percentage of CD200-positive (pooled) patients was 100% and 95% (3,061/3,208) in CLL, 4 and 8% (86/1112) in MCL and 56 and 62% (425/689) in other LPD.

Conclusion: CD200 is suboptimal for the differential diagnosis of CLL and disorders other than nodal MCL.
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http://dx.doi.org/10.1002/cyto.b.21849DOI Listing
September 2020

Minimal residual disease - ready for prime time in follicular lymphoma?

Br J Haematol 2020 01 31;188(2):205-206. Epub 2019 Jul 31.

Department of Hematology, Hospital Clínic, Barcelona, Spain.

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http://dx.doi.org/10.1111/bjh.16119DOI Listing
January 2020

Quantitative PCR Is Faster, More Objective, and More Reliable Than Immunohistochemistry for the Diagnosis of Cytomegalovirus Gastrointestinal Disease in Allogeneic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 11 17;25(11):2281-2286. Epub 2019 Jul 17.

Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Institut Josep Carreras, Campus Clínic, Barcelona, Spain.

Diagnosis of gastrointestinal (GI) cytomegalovirus (CMV) disease relies on the presence of GI symptoms and detection of CMV, mainly by immunohistochemistry (IHC), in GI biopsy specimens. Thus, in a symptomatic patient, a positive CMV-IHC result is accepted as a diagnosis of CMV disease. However, a positive CMV-PCR in GI tissue is considered "possible" CMV disease. Therefore, it would be very useful if, in practice, both techniques showed equal sensitivity and reliability. This is because PCR has many practical advantages over IHC for detecting CMV. The aim of this study was to compare quantitative PCR with IHC for the diagnosis of GI CMV disease. A total of 186 endoscopic GI biopsy specimens from 123 patients with GI symptoms after an allogeneic stem cell transplantation (allo-SCT; 2004-2017) were analyzed by IHC and PCR on 113 paraffin-embedded and 73 fresh samples. The results were then compared. Of the patients with macroscopic lesions in the mucosa and CMV-IHC-positive biopsy specimens (eg, "proven" CMV disease, n = 28), all but 1 were CMV-PCR positive. Of the patients without macroscopic lesions in the mucosa and CMV-IHC-positive biopsy specimens (eg, probable CMV disease, n = 4), only 1 was CMV-PCR positive. Eight patients had CMV-IHC-negative/CMV-PCR-positive gut biopsy specimens. These cases fall within the current definition of possible CMV disease. In 6 of these 8 cases (75%), the viral load in GI tissue was very high (>10,000 copies/µg). Taken together, the results from the proven and probable cases revealed that CMV-PCR shows the same sensitivity (100%), specificity (98%), and positive (93%) and negative predictive value (100%) as CMV-IHC. Detection of CMV in fresh GI mucosa by quantitative PCR is as useful as IHC for the diagnosis of GI CMV disease. The results show that quantitative PCR has the same sensitivity, specificity, and positive/negative predictive value as IHC.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.016DOI Listing
November 2019

Autologous stem cell transplantation may be curative for patients with follicular lymphoma with early therapy failure without the need for immunotherapy.

Hematol Oncol Stem Cell Ther 2019 Dec 9;12(4):194-203. Epub 2019 Jul 9.

Hospital Universitario, 12 de Octubre, Madrid, Spain.

Objective/background: Patients with follicular lymphoma (FL) with early therapy failure (ETF) within 2 years of frontline therapy have poor overall survival (OS). We recently reported the results of autologous stem cell transplantation (ASCT) in patients from the Grupo Español de Linfomas y Trasplantes de Médula Ósea (GELTAMO) registry treated with rituximab prior to ASCT and with ETF after first-line immunochemotherapy, leading to 81% 5-year OS since ASCT. We explored whether ASCT is also an effective option in the pre-rituximab era-that is, in patients treated in induction and rescued only with chemotherapy.

Methods: ETF was defined as relapse/progression within 2 years of starting first-line therapy. We identified two groups: the ETF cohort (n = 87) and the non-ETF cohort (n = 47 patients receiving ASCT but not experiencing ETF following first-line therapy).

Results: There was a significant difference in 5-year progression-free survival between the ETF and non-ETF cohorts (43% vs. 57%, respectively; p = .048). Nevertheless, in patients with ETF with an interval from first relapse after primary treatment to ASCT of <1 year, no differences were observed in 5-year progression-free survival (48% vs. 66%, respectively; p = .44) or in 5-year OS (69% vs. 77%, p = .4). Patients in the ETF cohort transplanted in complete remission showed a plateau in the OS curves, at 56%, beyond 13.7 years of follow-up.

Conclusion: ASCT may be a curative option for ETF in patients who respond to rescue chemotherapy, without the need for immunotherapy or other therapies, and should be considered as an early consolidation, especially in patients with difficult access to rituximab.
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http://dx.doi.org/10.1016/j.hemonc.2019.06.001DOI Listing
December 2019

Life expectancy of follicular lymphoma patients in complete response at 30 months is similar to that of the Spanish general population.

Br J Haematol 2019 05 22;185(3):480-491. Epub 2019 Feb 22.

Haematology Department, Hospital Virgen del Puerto, Plasencia, Spain.

The use of immunochemotherapy has improved the outcome of follicular lymphoma (FL). Recently, complete response at 30 months (CR30) has been suggested as a surrogate for progression-free survival. This study aimed to analyse the life expectancy of FL patients according to their status at 30 months from the start of treatment in comparison with the sex and age-matched Spanish general population (relative survival; RS). The training series comprised 263 patients consecutively diagnosed with FL in a 10-year period who needed therapy and were treated with rituximab-containing regimens. An independent cohort of 693 FL patients from the Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO) group was used for validation. In the training cohort, 188 patients were in CR30, with a 10-year overall survival (OS) of 53% and 87% for non-CR30 and CR30 patients, respectively. Ten-year RS was 73% and 100%, showing no decrease in life expectancy for CR30 patients. Multivariate analysis indicated that the FL International Prognostic Index was the most important variable predicting OS in the CR30 group. The impact of CR30 status on RS was validated in the independent GELTAMO series. In conclusion, FL patients treated with immunochemotherapy who were in CR at 30 months showed similar survival to a sex- and age-matched Spanish general population.
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http://dx.doi.org/10.1111/bjh.15805DOI Listing
May 2019

Differential expression of long non-coding RNAs are related to proliferation and histological diversity in follicular lymphomas.

Br J Haematol 2019 02 22;184(3):373-383. Epub 2018 Nov 22.

Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Long non-coding RNAs (lncRNAs) comprise a family of non-coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL) we performed RNA-sequencing at high depth sequencing in primary FL samples ranging from grade 1-3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNAs (dif-lncRNAs) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif-lncRNAs were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL. RP4-694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP4-694A7.2 silencing in the WSU-FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP4-694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki-67 proliferation index. In summary, lncRNAs are differentially expressed across the clinico-biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours.
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http://dx.doi.org/10.1111/bjh.15656DOI Listing
February 2019

Response duration and survival shorten after each relapse in patients with follicular lymphoma treated in the rituximab era.

Br J Haematol 2019 03 4;184(5):753-759. Epub 2018 Dec 4.

Department of Haematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Follicular lymphoma (FL) is an indolent disease characterized by long survival but frequent relapses. Before the introduction of rituximab, the clinical course of these patients showed a shorter response duration (RD) after each relapse. In this study, we analysed if this pattern of shortened responses remains in patients treated in the rituximab era. We selected 348 patients newly diagnosed with FL in two institutions between 2001 and 2014 that received chemoimmunotherapy. After a median follow-up of 6·3 years, 10-year progression-free and overall survivals were 53% and 72%, respectively. All patients received first-line, 111 second-line and 41 third-line treatments, with a 5-year RD of 62%, 39% and 24%, respectively (P < 0·0001). Variables predicting longer RD after first-line treatment were normal β2microglobulin, complete remission achievement and maintenance with rituximab. Patients with longer RD after first-line showed significantly longer RD after second-line therapy. Autologous stem-cell transplantation after second-line therapy did not significantly impact RD. Median survival after first, second and third therapies was not reached, 7·6 and 4·8 years, respectively, whereas relative survival with respect to a sex- and age-matched Spanish population, the decrease in the life expectancy at 10 years was 17%, 45% and 79%, respectively. Thus, RD still shortens after each relapse in patients with FL treated in first line with rituximab combinations.
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http://dx.doi.org/10.1111/bjh.15708DOI Listing
March 2019

Mutations in the RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia.

Haematologica 2019 03 27;104(3):576-586. Epub 2018 Sep 27.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERONC, Barcelona.

Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the response of primary cells to BRAF and ERK inhibitors. Putative damaging mutations were found in 25 of 452 patients (5.5%). Among these, was mutated in nine patients (2.0%), genes upstream of (, , , , and ) were mutated in 12 patients (2.6%), and genes downstream of (, , and ) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydrogenase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, =0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical features and could be pharmacologically inhibited.
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http://dx.doi.org/10.3324/haematol.2018.196931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395334PMC
March 2019
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