Publications by authors named "Pablo Mozas"

21 Publications

  • Page 1 of 1

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

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

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

Follicular lymphoma: an update on diagnosis, prognosis, and management.

Med Clin (Barc) 2021 Jun 28. Epub 2021 Jun 28.

Servicio de Hematología, Hospital Clínic, Barcelona, España; Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, España.

Follicular lymphoma, the most common indolent lymphoma, originates from germinal centre B-cells of the lymphoid follicle, and is characterized by t(14;18). Clinical manifestations include the presence of lymphadenopathy, sometimes accompanied by constitutional symptoms or cytopenia. Diagnosis is established through the identification of a B-cell proliferation of nodular pattern in the lymph node biopsy. Upon staging with PET-CT and bone marrow biopsy, a significant proportion of patients do not need immediate treatment. When therapy is indicated, commonly used regimens include anti-CD20 immunotherapy with or without chemotherapy. Although overall survival for most patients is prolonged, relapses are very frequent, and early relapse and transformation to an aggressive lymphoma portend a much worse prognosis. New therapies are under development, which will most likely change outcomes for FL patients in the near future.
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http://dx.doi.org/10.1016/j.medcli.2021.03.041DOI Listing
June 2021

Past, present and future of prognostic scores in follicular lymphoma.

Blood Rev 2021 Jun 24:100865. Epub 2021 Jun 24.

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

Although most follicular lymphoma (FL) patients have prolonged survival, the identification of those at risk of early progression, multiple relapses or histological transformation is essential for the improvement of long-term outcomes. In this sense, a plethora of prognostic indexes have been developed in the last decades. However, determining which one is more accurate and clinically meaningful remains a challenge. Key factors for the external validity of available indexes include characteristics of the study population, treatment intervention, and design of the study. While initial risk scores were composed of clinical, biochemical, and hematological variables, genomic and imaging data have been incorporated in recent years. Despite an obvious step forward in the knowledge of the natural history and biology of FL, predictions remain inaccurate. Further research will likely incorporate information from circulating tumor DNA and artificial intelligence models to refine the prognostic classification of the heterogeneous FL population.
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http://dx.doi.org/10.1016/j.blre.2021.100865DOI Listing
June 2021

Response to: The lymphocyte-to-monocyte ratio in follicular lymphoma.

Leuk Lymphoma 2021 Oct 1;62(10):2562-2563. Epub 2021 Jun 1.

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

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http://dx.doi.org/10.1080/10428194.2021.1933482DOI Listing
October 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

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

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

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

Analysis of criteria for treatment initiation in patients with progressive chronic lymphocytic leukemia.

Blood Cancer J 2018 01 16;8(1):10. Epub 2018 Jan 16.

Department of Hematology, Institute of Hematology and Oncology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1038/s41408-017-0044-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802533PMC
January 2018

Chronic lymphocytic leukemia: A prognostic model comprising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL-IPI.

Am J Hematol 2017 Apr 13;92(4):375-380. Epub 2017 Feb 13.

Department of Hematology, Institute of Hematology and Oncology, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain.

Rai and Binet staging systems are important to predict the outcome of patients with chronic lymphocytic leukemia (CLL) but do not reflect the biologic diversity of the disease nor predict response to therapy, which ultimately shape patients' outcome. We devised a biomarkers-only CLL prognostic system based on the two most important prognostic parameters in CLL (i.e., IGHV mutational status and fluorescence in situ hybridization [FISH] cytogenetics), separating three different risk groups: (1) low-risk (mutated IGHV + no adverse FISH cytogenetics [del(17p), del(11q)]); (2) intermediate-risk (either unmutated IGHV or adverse FISH cytogenetics) and (3) high-risk (unmutated IGHV + adverse FISH cytogenetics). In 524 unselected subjects with CLL, the 10-year overall survival was 82% (95% CI 76%-88%), 52% (45%-62%), and 27% (17%-42%) for the low-, intermediate-, and high-risk groups, respectively. Patients with low-risk comprised around 50% of the series and had a life expectancy comparable to the general population. The prognostic model was fully validated in two independent cohorts, including 417 patients representative of general CLL population and 337 patients with Binet stage A CLL. The model had a similar discriminatory value as the CLL-IPI. Moreover, it applied to all patients with CLL independently of age, and separated patients with different risk within Rai or Binet clinical stages. The biomarkers-only CLL prognostic system presented here simplifies the CLL-IPI and could be useful in daily practice and to stratify patients in clinical trials.
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http://dx.doi.org/10.1002/ajh.24660DOI Listing
April 2017

The biology behind B-cell lymphoma 2 as a target in chronic lymphocytic leukemia.

Ther Adv Hematol 2016 Dec 3;7(6):321-329. Epub 2016 Oct 3.

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

B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main 'hallmarks of cancer', BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trials have shown efficacy of these agents in patients with relapsed/refractory disease with a favorable toxicity profile. Moreover, some clinical trials indicate that combination with monoclonal antibodies and other novel agents may enhance their effect.
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http://dx.doi.org/10.1177/2040620716671313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089327PMC
December 2016

[Advances in the treatment of chronic lymphocytic leukaemia].

Med Clin (Barc) 2016 Nov 16;147(10):447-454. Epub 2016 Jul 16.

Servicio de Hematología, Instituto Clínico de Enfermedades Hemato-Oncológicas, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España. Electronic address:

Chronic lymphocytic leukemia (CLL), a proliferation of mature B cells, is one of the most prevalent haematological malignancies. Progress has been made in its treatment during the last few decades, and chemoimmunotherapy based on fludarabine, cyclophosphamide and rituximab is considered the treatment of choice for patients with standard-risk CLL and good performance status. However, due to the characterization of high-risk biological subgroups and its presentation in elderly patients and/or with comorbidities, targeted therapies, such as B-cell receptor inhibitors, have been developed and approved during the last few years. The current review examines traditional therapeutic strategies and focuses on new small molecules that already represent promising elements of the CLL treatment landscape.
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http://dx.doi.org/10.1016/j.medcli.2016.05.034DOI Listing
November 2016
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