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1.
Blood ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32006000

RESUMO

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The extensively validated 30% of positive CLL cells cut-off value is able to separate CLL patients into two subgroups with different prognosis, but it does not consider the pattern of CD49d expression. In the present study, we analysed a cohort of 1,630 CLL samples and identified the presence of ~20% of CLL cases (n=313) characterized by a bimodal expression of CD49d, i.e. concomitant presence of a CD49dpos sub-population and a CD49dneg sub-population. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49dpos sub-population over time after therapy. The CD49dpos sub-population from CD49d bimodal CLL displayed higher levels of proliferation compared to the CD49dneg cells, was more highly represented in the bone marrow compared to peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49dpos sub-population exceeded or not the 30% cut-off, experienced a clinical behavior similar to CD49dpos CLL, both in the chemo-immunotherapy (n=1,522) and in the ibrutinib (n=158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should be also considered to improve the prognostic impact of this biomarker in CLL.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32047037

RESUMO

The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21-derived heavy chains (HCs) with IGLV3-21-derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21R110), we show that IGLV3-21R110-expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21*01 facilitates effective homotypic BCR-BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21*01-expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21R110-expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors.

3.
Haematologica ; 105(2): 448-456, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31371416

RESUMO

BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.

4.
Haematologica ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582547

RESUMO

We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count>32.0x103/microliter, 1 point. Low, intermediate and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144/395/540/322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage chronic lymphocytic leukemia, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 chronic lymphocytic leukemia being performed at the time of diagnosis to aid prognosis and treatment, particularly in today's chemo-free era.

5.
Hematol Oncol ; 37(5): 628-633, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31523839

RESUMO

The association of systemic mastocytosis with another hematologic neoplasia of myeloid or lymphoid origin is recognized as an advanced subvariant of mastocytosis. Here, we report the association of indolent or smoldering systemic mastocytosis with three cases of myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis, a recently recognized disease characterized by SF3B1 mutations. The hierarchical pattern of KIT, SF3B1, JAK2, and additional mutations was studied in whole and fractionated subpopulations of peripheral blood cells and whole bone marrow. In two cases, we could demonstrate a multilineage D816V KIT mutation, involving all myeloid lineages in one patient and also the lymphoid series in the other. Two patients displaying both SF3B1 and V617F JAK2 mutations had a very poor prognosis. Another patient bearing SF3B1, but not V617F JAK2 mutation, had a favorable response to erythropoietin treatment and long survival.


Assuntos
Eritroblastos/patologia , Mastocitose Sistêmica/complicações , Mastocitose Sistêmica/diagnóstico , Síndromes Mielodisplásicas/complicações , Transtornos Mieloproliferativos/complicações , Trombocitose/complicações , Idoso , Biomarcadores , Medula Óssea/patologia , Humanos , Imuno-Histoquímica , Masculino , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/terapia , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Linhagem , Proteínas Proto-Oncogênicas c-kit/genética , Trombocitose/diagnóstico
6.
Haematologica ; 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289209

RESUMO

In chronic lymphocytic leukemia, the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumour cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study we demonstrate that chronic lymphocytic leukemia cells from TP53-disrupted (TP53dis) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1 α) and increased HIF-1 transcriptional activity, compared to the wild type counterpart. In the TP53dis subset, HIF-1 α upregulation is due to reduced expression of the HIF-1 α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently from the TP53 status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of HIF-1A mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53dis tumour cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumour activity in Eµ-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53dis leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidences for its further investigation as a potential new drug in chronic lymphocytic leukemia.

7.
Hematol Oncol ; 37(4): 368-374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325190

RESUMO

In 2009, the four laboratories of the Fondazione Italiana Linfomi (FIL) minimal residual disease (MRD) Network started a collaborative effort to harmonize and standardize their methodologies at the national level, performing quality control (QC) rounds for follicular lymphoma (FL) and mantle cell lymphoma (MCL) MRD assessment. In 16 QC rounds between 2010 and 2017, the four laboratories received 208 bone marrow (BM) samples (126 FL; 82 MCL); 187 were analyzed, according to the EuroMRD Consortium guidelines, by both nested (NEST) polymerase chain reaction (PCR) and real-time quantitative (RQ) PCR for BCL2/IGH MBR or IGHV rearrangements. Here, we aimed at analyzing the samples that challenged the interlaboratory reproducibility and data interpretation. Overall, 156/187 BM samples (83%) were concordantly classified as NEST+/RQ+ or NEST-/RQ- by all the four laboratories. The remaining 31 samples (17%) resulted alternatively positive and negative in the interlaboratory evaluations, independently of the method and the type of rearrangement, and were defined "borderline" (brd) samples: 12 proved NEST brd/RQ brd, 7 NEST-/RQ brd, 10 NEST brd/RQ positive not quantifiable (PNQ), and 2 NEST brd/RQ-. Results did not change even increasing the number of replicates/sample. In 6/31 brd samples, droplet digital PCR (ddPCR) was tested and showed no interlaboratory discordance. Despite the high interlaboratory reproducibility in the MRD analysis obtained and maintained by the QC round strategy, samples with the lowest MRD levels can still represent a challenge: 17% (31/187) of our samples showed discordant results in interlaboratory assessments, with 6.4% (12/187) remained brd even applying the two methods. Thus, although representing a minority, brd samples are still problematic, especially when a clinically oriented interpretation of MRD results is required. Alternative, novel methods such as ddPCR and next-generation sequencing have the potential to overcome the current limitations.


Assuntos
Exame de Medula Óssea , Medula Óssea/patologia , Ensaio de Proficiência Laboratorial , Linfoma não Hodgkin/patologia , Reação em Cadeia da Polimerase , Exame de Medula Óssea/normas , Células Clonais , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Genes de Imunoglobulinas , Genes bcl-2 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Itália/epidemiologia , Linfoma não Hodgkin/genética , Neoplasia Residual , Proteínas de Fusão Oncogênica/análise , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/normas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Garantia da Qualidade dos Cuidados de Saúde , Reprodutibilidade dos Testes , Translocação Genética
12.
Haematologica ; 103(12): 2049-2058, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30076183

RESUMO

Aberrant changes in microRNA expression contribute to lymphomagenesis. Bromodomain and extra-terminal domain inhibitors such as OTX015 (MK-8628, birabresib) have demonstrated preclinical and clinical activity in hematologic tumors. MicroRNA profiling of diffuse large B-cell lymphoma cells treated with OTX015 revealed changes in the expression levels of a limited number of microRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p and miR-96-5p. Analysis of publicly available chromatin immunoprecipitation sequencing data of diffuse large B-cell lymphoma cells treated with bromodomain and extra-terminal domain (BET) inhibitors showed that the BET family member BRD4 bound to the upstream regulatory regions of multiple microRNA genes and that this binding decreased following BET inhibition. Alignment of our microRNA profiling data with the BRD4 chromatin immunoprecipitation sequencing data revealed that microRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following treatment with another bromodomain and extra-terminal domain inhibitor, JQ1, indicating that BRD4 contributes directly to microRNA expression in lymphoma. Treatment with bromodomain and extra-terminal domain inhibitors also decreased the expression of the arginine methyltransferase PRMT5, which plays a crucial role in B-cell transformation and negatively modulates the transcription of miR-96-5p. The data presented here indicate that in addition to previously observed effects on the expression of coding genes, bromodomain and extra-terminal domain inhibitors also modulate the expression of microRNAs involved in lymphomagenesis.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Linfoma Difuso de Grandes Células B/genética , MicroRNAs/genética , Proteínas Nucleares/genética , Domínios Proteicos , Fatores de Transcrição/genética , Acetanilidas/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Ligação Proteica/efeitos dos fármacos , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
13.
Haematologica ; 103(5): 849-856, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29472356

RESUMO

Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptorlow and B-cell receptorhigh) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK), was used to classify the 83 cases (43 B-cell receptorlow and 40 B-cell receptorhigh). The B-cell receptorhigh signature associated with shorter progression-free survival (P=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (P=0.0014 and P=0.029, respectively) in combination with high (>30%) Ki-67 staining, and was an independent predictor of short progression- free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6- gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homogenously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL- 0208 clinical trial. (clinicaltrials.gov identifier: 02354313).


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/mortalidade , Receptores de Antígenos de Linfócitos B/genética , Adulto , Idoso , Feminino , Seguimentos , Humanos , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
14.
J Exp Med ; 215(2): 681-697, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29301866

RESUMO

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.


Assuntos
Integrina alfa4beta1/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Adesão Celular/efeitos dos fármacos , Humanos , Imunoglobulina M/metabolismo , Estimativa de Kaplan-Meier , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Linfocitose/metabolismo , Linfocitose/patologia , Análise Multivariada , Fosfatidilinositol 3-Quinases/metabolismo , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo
16.
Sci Rep ; 7(1): 7104, 2017 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-28769043

RESUMO

Standard of care for Epithelial Ovarian Cancer (EOC) patients relies on platinum-based therapy. However, acquired resistance to platinum occurs frequently and predicts poor prognosis. To understand the mechanisms underlying acquired platinum-resistance, we have generated and characterized three platinum-resistant isogenic EOC cell lines. Resistant cells showed 3-to 5- folds increase in platinum IC50. Cross-resistance to other chemotherapeutic agents commonly used in the treatment of EOC patients was variable and dependent on the cell line utilized. Gene expression profiling (GEP) of coding and non-coding RNAs failed to identify a common signature that could collectively explain the mechanism of resistance. However, we observed that all resistant cell lines displayed a decreased level of DNA platination and a faster repair of damaged DNA. Furthermore, all platinum resistant cell lines displayed a change in their morphology and a higher ability to grown on mesothelium. Overall, we have established and characterized three new models of platinum-resistant EOC cell lines that could be exploited to further dissect the molecular mechanisms underlying acquired resistance to platinum. Our work also suggests that GEP studies alone, at least when performed under basal culture condition, do not represent the optimal way to identify molecular alterations linked to DNA repair pathway defects.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Fenótipo , Platina/farmacologia , Adesão Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Humanos , Transdução de Sinais , Células Tumorais Cultivadas
19.
Clin Cancer Res ; 23(14): 3769-3780, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28174235

RESUMO

Purpose: Head and neck squamous cell carcinomas (HNSCCs) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients' overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected miRNAs could be used as biomarkers of recurrence in HNSCC.Experimental Design: A NanoString array was used to identify miRNAs associated with locoregional recurrence in 44 patients with HNSCC. Bioinformatic approaches validated the signature and identified potential miRNA targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines. In vivo experiments validated the in vitro results.Results: Our data identified a four-miRNA signature that classified HNSCC patients at high- or low-risk of recurrence. These miRNAs collectively impinge on the epithelial-mesenchymal transition process. In silico and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, whereas miR-1, miR-133, and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFß pathways. A six-gene signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFß pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence.Conclusions: By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development. Clin Cancer Res; 23(14); 3769-80. ©2017 AACR.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , MicroRNAs/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Animais , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Queratina-13/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Transdução de Sinais , Fator de Transcrição Sp1/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fator de Crescimento Transformador beta/genética , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Hematol Oncol ; 35(4): 472-479, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27781290

RESUMO

Low-dose radiotherapy (LDRT) given in 2 × 2 Gy is a highly effective and safe treatment for palliation of indolent lymphomas. Otherwise, very little regarding the use of LDRT for diffuse large B-cell lymphoma (DLBCL) has been investigated. We designed a phase 2 trial of LDRT in patients with DLBCL with indication for palliative radiation. Low-dose radiotherapy was administered on symptomatic areas only. Clinical response was assessed 21 days after LDRT and defined as reduction >50% of maximum diameter of the radiated lesions. Quality of life was scored by the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Tumor subtype (germinal center B-cell type versus activated B-cell type) and the presence of TP53 mutations in pathologic specimens of the target lesion were also evaluated. Twenty-three of twenty-five radiated patients were evaluable for response, and 2 died of disease before the visit at 21 days. The overall response rate was 70% (16 of 23 patients), with 7 complete responses and 9 partial responses (mean duration of response, 6 months; range, 1-39 months). Fifteen patients answered to the QLQ-C30 questionnaires, and an improved quality of life was documented in 9 cases. TP53 mutations were detected in 2 of 6 (33%) nonresponders and in none of the responders (P = .12). Germinal center B-cell type responded better than activated B-cell type (response rate was 83% and 29%, respectively, P = .01). These findings indicate that LDRT is effective for palliation in patients with DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/radioterapia , Qualidade de Vida/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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