LUIS ALBERTO DE PADUA COVAS LAGE
Projetos de Pesquisa
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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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- 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.
- Acquired hemophagocytic lymphohistiocytosis as initial manifestation of multiple myeloma A case report and literature review(2020) MENDES, Fernanda Rodrigues; SOBRAL, Karine Marques; CULLER, Hebert Fabricio; COUTO, Samuel Campanelli Freitas; PEREIRA, Juliana; ROCHA, Vanderson; MARTINEZ, Gracia Aparecida; LAGE, Luis Alberto de Padua CovasIntroduction: Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by a hyperinflammatory state and persistent macrophage activation, resulting in reactive phagocytosis of the hematopoietic elements. In children, it is usually a hereditary disorder, while in adults it is usually acquired secondary to viral infections, collagenoses, or tumors. Although accounting for 10% of hematologic malignancies, HLH is rarely associated with multiple myeloma (MM) and other plasmacytic dyscrasias. Patient concerns: A 64-year-old Brazilian man seeked medical care with a 3-month history of intermittent fever, weight loss, night sweats, and progressive anemic symptoms. Diagnosis: Total blood count showed severe bicytopenia (normocytic-normochromic anemia and thrombocytopenia), biochemical exams showed elevation of creatinine, as well as monoclonal peak in serum protein electrophoresis, high IgA dosage, and serum immunofixation with IgA kappa paraprotein. Bone marrow biopsy showed 30% of monoclonal and phenotypically anomalous plasmocytes, confirming the diagnosis of MM. Diagnosis of HLH was established by the presence of clinical and laboratory criteria: fever, splenomegaly, cytopenias, hypofibrinogenemia, hyperferritinemia, elevation of triglycerides, and several figures of erythrophagocytosis in bone marrow aspirate. Interventions: The patient experienced pulse therapy with methylprednisolone for hemophagocytic lymphohistiocytosis, followed by initial therapy for multiple myeloma with cyclophosphamide and dexamethasone. Outcomes: Once the diagnosis of MM and secondary hemophagocytic syndrome was established, the patient had a rapid clinical deterioration despite the established therapeutic measures, evolving with cardiovascular failure, acute liver failure, acute disseminated intravascular coagulation, worsening renal dysfunction requiring dialysis support, respiratory dysfunction, and lowering of consciousness, characterizing rapid multiple organ dysfunction, ultimately leading to the death of the patient. Innovation: Here, we aimed to describe the sixth reported case of HLH associated with MM, according to cases cataloged in the PubMed database, and the first case evaluated by 18-fluordeoxyglucose positron emission tomography (18-FDG-PETCT). Conclusion: Our case report seeks to provide support for a better clinical and laboratory characterization of this rare paraneoplastic entity associated with MM, and aims to call the attention of hematologists and intensivists to this condition that falls within the scope of the differential diagnosis of rapid onset multiple organ failure in patients with plasmacytic neoplasms.
- FOXP3-positive T-cell lymphomas in non-HTLV1 carriers include ALK-negative anaplastic large cell lymphoma: expanding the spectrum of T-cell lymphomas with regulatory phenotype(2018) FERREIRA, Cristiane R.; ZHAO, Shuchun; SAHOO, Malaya K.; PINSKY, Benjamin; WEBER, Jenna; LAGE, Luis A. P. C.; PEREIRA, Juliana; ZERBINI, Maria C. N.; NATKUNAM, YasodhaForkhead box P3 (FOXP3) is a specific marker for regulatory T-cells (Tregs). We report 6 cases of T-cell lymphomas with Treg phenotype based on diffuse positivity for FOXP3 in tumor cells. The patients showed a median age of 56 years with a male predominance. Sites of disease included lymph nodes (4), skin (2), subcutaneous tissue (1) and bone marrow (1). All cases showed monomorphic large cells, some with Hodgkin-like or anaplastic cells. All cases expressed pan T-cell markers and lacked cytotoxic markers; one case showed diffuse PD1 staining. Only one case harbored human T-lymphotrophic virus (HTLV)-1 DNA within tumor cells and was classified as adult T-cell leukemia/lymphoma (ATLL). Among 5 HTLV1-negative cases, 3 were classified as peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) and 2 fulfilled criteria for ALK-negative anaplastic large cell lymphoma (ALCL) with diffuse and strong CD30 positivity. We concluded that Treg phenotype may be rarely seen in HTLV1-negative cases, such as PTCL, NOS and ALK-negative ALCL. Our findings expand the spectrum of T-cell lymphomas with regulatory phenotype and suggest that consideration should be given to HTLV1 DNA testing in the appropriate clinical setting to rule out ATLL.
- TET-2 mutations predict poor outcomes and are associated with unfavorable clinical-biological features in PTCL, not otherwise specified and angioimmunoblastic T-cell lymphoma in Brazilian patients(2022) LAGE, Luis Alberto de Padua Covas; BARRETO, Guilherme Carneiro; CULLER, Hebert Fabricio; CAVALCANTE, Jessica Billar; ALVES, Lucas Bassolli de Oliveira; NARDINELLI, Luciana; BENDIT, Israel; ZERBINI, Maria Claudia Nogueira; ROCHA, Vanderson; PEREIRA, JulianaINTRODUCTION: Nodal peripheral T-cell lymphomas [nPTCL] constitute a heterogeneous group of rare malignancies with aggressive biological behavior and poor prognosis. Epigenetic phenomena involving genes that control DNA-methylation and histone deacetylation play a central role in their pathogenesis. However, the mutational landscape involving epigenetic regulators has never been reported in Latin American patients and their prognostic impact remains controversial. PATIENTS AND METHODS: From 2000 to 2019, 59-Brazilian patients with nPTCL were eligible for screening mutations in the IDH-1, IDH-2, RHOA, TET-2 and DNMT3A genes by Sanger sequencing at Formalin-Fixed Paraffin-Embedded samples [FFPE] of diagnosis. We reported the frequency, distribution and potential prognosis of these mutations. RESULTS: With a median follow-up of 3.70 years, estimate 2-year OS and PFS were 57.1% and 49.2%, respectively. Mutations in the IDH-1 gene were not found, mutations in the IDH-2 occurred in 3.4% (2/59), RHOA in 23.7% (14/59), TET-2 in 50.8% (30/59) and DNMT3A in 62.7% (37/59). RHOA gene mutations were more frequent in PTCL, NOS and AITL (p = 0.06). Almost half of the patients had more than one mutation in concomitance, particularly RHOA-mut and TET-2-mut. Mutations in RHOA (p = 0.030) and TET-2 (p = 0.046) were associated with high-tumor burden. In the non-ALCL subgroup (PTCL, NOS and AITL) TET-2 mutations were associated with decreased 2-year PFS [HR: 2.22, p = 0.048]. Likewise with lower overall response rate [ORR] (p = 0.048) and unfavorable clinical features, as bulky disease (p = 0.012), ECOG >= 2 (p = 0.032), B-symptoms (p = 0.012), >= 2 extranodal sites compromised (p = 0.022) and high-risk Prognostic Index for T-cell lymphoma (p = 0.005). CONCLUSION: Mutations in RHOA, TET-2 and DNMT3A were frequent in Brazilian patients with nPTCL. TET-2 mutations were associated with lower ORR for CHOP-like chemotherapy, decreased PFS and unfavorable clinical-biological characteristics in non-ALCL (PTCL, NOS and AITL). Further studies using a larger cohort may validate our findings.
- Extranodal NK-/T-cell lymphoma, nasal type: what advances have been made in the last decade?(2023) COSTA, Renata de Oliveira; PEREIRA, Juliana; LAGE, Luis Alberto de Padua Covas; BAIOCCHI, Otavio Cesar GuimaraesExtranodal NK-/T-cell lymphoma (ENKTCL) is a rare and highly aggressive malignancy with significant racial and geographic variations worldwide. In addition to the formerly ""nasal-type"" initial description, these lymphomas are predominantly extranodal in origin and typically cause vascular damage and tissue destruction, and although not fully understood, Epstein-Barr virus (EBV) has an important role in its pathogenesis. Initial assessment must include a hematopathology review of representative and viable tumor areas without necrosis for adequate immunohistochemistry studies, including EBV-encoded small RNA (EBER) in situ hybridization (ISH). Positron emission tomography with 18-fluorodeoxyglucose (F-18-FDG-PET/CT) for accurate staging is essential, and most patients will have localized disease (IE/IIE) at diagnosis. Apart from other T-cell malignancies, the best treatment even for localized cases is combined modality therapy (chemotherapy plus radiotherapy) with non-anthracycline-based regimens. For advanced-stage disease, l-asparaginase-containing regimens have shown improved survival, but relapsed and refractory cases have very poor outcomes. Nowadays, even with a better understanding of pathogenic pathways, up-front therapy is completely based on chemotherapy and radiotherapy, and treatment-related mortality is not low. Future strategies targeting signaling pathways and immunotherapy are evolving, but we need to better identify those patients with dismal outcomes in a pre-emptive way. Given the rarity of the disease, international collaborations are urgently needed, and clinical trials are the way to change the future.