LUIS ALBERTO DE PADUA COVAS LAGE
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances(2023) LAGE, Luis Alberto de Padua Covas; CULLER, Hebert Fabricio; REICHERT, Cadiele Oliana; SIQUEIRA, Sheila Aparecida Coelho da; PEREIRA, JulianaAngioimmunoblastic T-cell lymphoma (AITL) is the second most frequent subtype of mature T-cell lymphoma (MTCL) in the Western world. It derives from the monoclonal proliferation of T-follicular helper (TFH) cells and is characterized by an exacerbated inflammatory response and immune dysregulation, with predisposition to autoimmunity phenomena and recurrent infections. Its genesis is based on a multistep integrative model, where age-related and initiator mutations involve epigenetic regulatory genes, such as TET-2 and DNMT3A. Subsequently, driver-mutations, such as RhoA G17V and IDH-2 R172K/S promote the expansion of clonal TFH-cells (""second-hit""), that finally begin to secrete cytokines and chemokines, such as IL-6, IL-21, CXCL-13 and VEGF, modulating a network of complex relationships between TFH-cells and a defective tumor microenvironment (TME), characterized by expansion of follicular dendritic cells (FDC), vessels and EBV-positive immunoblasts. This unique pathogenesis leads to peculiar clinical manifestations, generating the so-called ""immunodysplastic syndrome"", typical of AITL. Its differential diagnosis is broad, involving viral infections, collagenosis and adverse drug reactions, which led many authors to use the term ""many-faced lymphoma"" when referring to AITL. Although great advances in its biological knowledge have been obtained in the last two decades, its treatment is still an unmet medical need, with highly reserved clinical outcomes. Outside the setting of clinical trials, AITL patients are still treated with multidrug therapy based on anthracyclines (CHOP-like), followed by up-front consolidation with autologous stem cell transplantation (ASCT). In this setting, the estimated 5-year overall survival (OS) is around 30-40%. New drugs, such as hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDAi), have been used for relapsed/refractory (R/R) disease with promising results. Such agents have their use based on a biological rationale, have significant potential to improve the outcomes of patients with AITL and may represent a paradigm shift in the therapeutic approach to this lymphoma in the near future.
- Splenic Diffuse Red Pulp Small B Cell Lymphoma: Transformation To Diffuse Large Cells B Lymphoma(2013) BEZERRA, Evandro Dantas; FONTENELE, Leila Patricia; PEREIRA, Juliana; LAGE, Luis Alberto de Padua Covas; MACIEL, Felipe; BARQUINERO, Leticia; CARVALHO, Priscila R.; SIQUEIRA, Scheila; VELLOSO, Elvira R. P.
- A difficult case of angioimmunoblastic T-cell lymphoma to diagnose(2016) SACHSIDA-COLOMBO, Elisabetta; MARIANO, Livia Caroline Barbosa; BASTOS, Fernanda Queiróz; RASSI, Amanda Bruder; LAGE, Luís Alberto de Pádua Covas; BARRETO, Ariel; SIQUEIRA, Sheila; PEREIRA, Juliana
- High Tumor Mutation Burden in Epigenetic Regulatory Genes Predicts Decreased Overall Survival in Nodal Peripheral T-Cell Lymphomas(2022) LAGE, Luis Alberto de Padua Covas; BARRETO, Guilherme Carneiro; CULLER, Hebert Fabricio; CAVALCANTI, Jessica Billar; REICHERT, Cadiele Oliana; COSTA, Renata Oliveira; LEVY, Debora; ZERBINI, Maria Claudia Nogueira; ROCHA, Vanderson; PEREIRA, Juliana
- Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations(2015) LAGE, Luis Alberto de Pádua Covas; CABRAL, Tamara Carvalho dos Santos; COSTA, Renata de Oliveira; GONÇALVES, Marianne de Castro; LEVY, Debora; ZERBINI, Maria Cláudia Nogueira; PEREIRA, JulianaNodal peripheral T-cell lymphomas are a rare group of neoplasms derived from post-thymic and activated T lymphocytes. A review of scientific articles listed in PubMed, Lilacs, and the Cochrane Library databases was performed using the term ""peripheral T-cell lymphomas"". According to the World Health Organization classification of hematopoietic tissue tumors, this group of neoplasms consists of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+), and a provisional entity called anaplastic large cell lymphoma-anaplastic lymphoma kinase negative (ALCL-ALK-). Because the treatment and prognoses of these neoplasms involve different principles, it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients.
- Up-front Therapy With CHOP Plus Etoposide in Brazilian nodal PTCL Patients: Increased Toxicity and No Survival Benefit Compared to CHOP Regimen–Results of a Real-Life Study From a Middle-Income Country(2022) LAGE, L. A. D. P. C.; BRITO, C. V.; BARRETO, G. C.; CULLER, H. F.; REICHERT, C. O.; LEVY, D.; COSTA, R. D. O.; ZERBINI, M. C. N.; ROCHA, V.; PEREIRA, J.Background: Nodal peripheral T-cell lymphoma (nPTCL) constitute a heterogeneous group of neoplasms with aggressive behavior and poor-survival. They are more prevalent in Latin America and Asia, although data from Brazil are scarce. Its primary therapy is still controversial and ineffective. Therefore, we aim to describe clinical-epidemiological characteristics, outcomes, predictors factors for survival and compare the results of patients treated with CHOP and CHOEP regimens. Methods: Retrospective, observational and single-center study involving 124 nPTCL patients from Brazil treated from 2000 to 2019. Results: With a median follow-up of 23.7 months, the estimated 2-year overall survival (OS) and progression-free survival (PFS) were 59.2% and 37.3%, respectively. The median age was 48.5 years and 57.3% (71/124) were male, 81.5% (101/124) had B-symptoms, 88.7% (110/124) had advanced disease (stage III/IV) and 58.1% (72/124) presented International Prognostic Index (IPI) score ≥3, reflecting a real-life cohort. ORR to first-line therapy was 58.9%, 37.9% (N = 47) received CHOP-21 and 35.5% (N = 44) were treated with CHOEP-21; 30.1% (37/124) underwent to consolidation with involved field radiotherapy (IF-RT) and 32.3% (40/124) were consolidated with autologous hematopoietic stem cell transplantation (ASCT). The overall response rate (ORR) was similar for CHOP-21 (76.6%) and CHOEP-21 (65.9%), P =.259. Refractory disease was less frequent in the CHOEP-21 group (4.5% vs. 21.2%, P =.018). However, few patients were able to complete 6-cycles of CHOEP-21 (31.8%) than to CHOP-21 (61.7%), P =.003. Delays ≥2 weeks among the cycles of chemotherapy were more frequent for patients receiving CHOEP-21 (43.1% vs. 10.6%), P =.0004, as well as the toxicities, including G3-4 neutropenia (88% vs. 57%, P =.001), febrile neutropenia (70% vs. 38%, P =.003) and G3-4 thrombocytopenia (63% vs. 27%, P =.0007). The 2-year OS was higher for CHOP (78.7%) than CHOEP group (61.4%), P =.05, as well as 2-year PFS (69.7% vs. 25.0%, P <.0001). In multivariate analysis, high LDH (HR 3.38, P =.007) was associated with decreased OS. CR at first line (HR: 0.09, P <.001) and consolidation with ASCT (HR: 0.08, P =.015) were predictors of increased OS. Conclusion: In the largest cohort of nPTCL from Latin America, patients had poor survival and high rate of chemo-resistance. In our cohort, the addition of etoposide to the CHOP-21 backbone showed no survival benefit and was associated with high-toxicity and frequent treatment interruptions. Normal LDH values, obtaintion of CR and consolidation with ASCT were independent factors associated with better outcomes. © 2022 Elsevier Inc.
- Up-Front ASCT Overcomes the Survival Benefit Provided by HDAC-Based Induction Regimens in Mantle Cell Lymphoma: Data from a Real-Life and Long-Term Cohort(2023) LAGE, Luis Alberto de Padua Covas; ELIAS, Marcela do Vale; REICHERT, Cadiele Oliana; CULLER, Hebert Fabricio; FREITAS, Fabio Alessandro de; COSTA, Renata de Oliveira; ROCHA, Vanderson; SIQUEIRA, Sheila Aparecida Coelho da; PEREIRA, JulianaSimple Summary This study aimed to assess clinical outcomes, determine survival predictors, and compare responses between different primary therapeutic modalities in a large real-world cohort of patients with mantle cell lymphoma (MCL), with a focus on assessing the impact of intensified immunochemotherapy regimens based on high doses of cytarabine (HDAC) on outcomes in ASCT-eligible patients. A total of 165 Brazilian patients with biopsy-proven MCL were included from 2010 to 2022. After a long follow-up, our results demonstrated that patients treated with (R)-HDAC-based regimens had higher ORR (85.9% vs. 65.7%, p = 0.007) compared to those treated with (R)-CHOP, as well as lower rates of early relapses (61.9% vs. 80.4%, p = 0.043) and lower mortality (43.9% vs. 68.6%, p = 0.004). However, enhanced induction regimens employing (R)-HDAC were not associated with a real overall survival benefit in MCL patients undergoing ASCT (2-year OS: 88.7% for (R)-HDAC plus ASCT vs. 78.8% for (R)-CHOP plus ASCT, p = 0.289). Additionally, up-front ASCT was independently associated with improvement in OS (p < 0.001), EFS (p = 0.005), and POD-24 (p < 0.001) in MCL. In conclusion, in the largest real-world Latin American study involving MCL patients, we were able to ratify the benefit of up-front ASCT in young and physically fit patients regardless of the intensity of the induction immunochemotherapy regimen used. Although HDAC-based induction regimens were not associated with improved survival in ASCT-eligible patients, it was associated with higher ORR and lower rates of early relapses in the whole cohort. These findings can decisively impact the therapeutic management of MCL patients in different clinical settings.Abstract Background: Mantle cell lymphoma (MCL) is a rare malignancy with heterogeneous behavior. Despite the therapeutic advances recently achieved, MCL remains incurable. Currently, the standard of care for young and fit patients involves induction immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). However, the role of more intensive induction regimens, such as those based on high doses of cytarabine (HDAC), remains controversial in the management of ASCT-eligible patients. Methods: This retrospective, observational, and single-center study involved 165 MCL patients treated at the largest oncology center in Latin America from 2010 to 2022. We aimed to assess outcomes, determine survival predictors, and compare responses between different primary therapeutic strategies, with a focus on assessing the impact of HDAC-based regimens on outcomes in ASCT-eligible patients. Results: The median age at diagnosis was 65 years (38-89 years), and 73.9% were male. More than 90% of the cases had a classic nodal form (cnMCL), 76.4% had BM infiltration, and 56.4% presented splenomegaly. Bulky >= 7 cm, B-symptoms, ECOG >= 2, and advanced-stage III/IV were observed in 32.7%, 64.8%, 32.1%, and 95.8%, respectively. Sixty-four percent of patients were categorized as having high-risk MIPI. With a median follow-up of 71.1 months, the estimated 2-year OS and EFS were 64.1% and 31.8%, respectively. Patients treated with (R)-HDAC-based regimens had a higher ORR (85.9% vs. 65.7%, p = 0.007) compared to those receiving (R)-CHOP, as well as lower POD-24 rates (61.9% vs. 80.4%, p = 0.043) and lower mortality (43.9% vs. 68.6%, p = 0.004). However, intensified induction regimens with (R)-HDAC were not associated with a real OS benefit in MCL patients undergoing up-front consolidation with ASCT (2-year OS: 88.7% vs. 78.8%, p = 0.289). Up-front ASCT was independently associated with increased OS (p < 0.001), EFS (p = 0.005), and lower POD-24 rates (p < 0.001) in MCL. Additionally, CNS infiltration, TLS, hypoalbuminemia, and the absence of remission after induction were predictors of poor OS. Conclusions: In the largest Latin American cohort of MCL patients, we confirmed the OS benefit promoted by up-front consolidation with ASCT in young and fit patients, regardless of the intensity of the immunochemotherapy regimen used in the pre-ASCT induction. Although HDAC-based regimens were not associated with an unequivocal increase in OS for ASCT-eligible patients, it was associated with higher ORR and lower rates of early relapses for the whole cohort.
- Clinical Outcomes, Prognostic Factors and Therapeutic Management in Extranodal Natural-Killer/T-Cell Lymphoma, Nasal-Type (ENKTL-NT) - Results of the Multicenter T-Cell Brazil Project(2022) LAGE, Luis Alberto de Padua Covas; MACHADO, Pedro Paulo Faust; REICHERT, Cadiele Oliana; MIRANDA, Eliana C. M. Cristina Martins; CULLER, Hebert Fabricio; SIQUEIRA, Sheila Aparecida Coelho de; COSTA, Renata Oliveira; MIYASHIRO, Denis; SANCHES, Jose; ROCHA, Vanderson; CHIATTONE, Carlos S.; PEREIRA, Juliana
- Overexpression of the OCT-1 Gene Is a Biomarker Associated with Poor Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) - Data from a Retrospective Cohort from Latin America: Defining a Very High-Risk Clinical-Molecular Subgroup(2020) LAGE, Luis Alberto de Padua Covas; GOUVEIA, Gisele Rodrigues; FERREIRA, Suzete Cleusa; SIQUEIRA, Sheila Aparecida Coelho de; HALLACK NETO, Abrahao Elias; COSTA, Renata Oliveira; PEREIRA, Juliana
- Whole Brain Radiotherapy Is an Effective and Safe Strategy to Consolidate Primary Central Nervous System Lymphoma Patients in Middle-Income Countries: A Real-Life Experience from Brazil(2022) LAGE, Luis Alberto de Padua Covas; SOARES, Vinicius Araujo; MENEGUIN, Thales Dalessandro; CULLER, Hebert Fabricio; REICHERT, Cadiele Oliana; JACOMASSI, Mayara D'Auria; REIS, Diego Gomes Candido; ZERBINI, Maria Claudia Nogueira; COSTA, Renata Oliveira; ROCHA, Vanderson; PEREIRA, Juliana