HEBERT FABRICIO CULLER
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
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.
- Follicular Lymphoma: Refining Prognostic Models and Impact of Pod-24 in Clinical Outcomes(2022) NOGUEIRA, Daniel Silva; LAGE, Luis Alberto de Padua Covas; CULLER, Hebert Fabricio; PEREIRA, JulianaFollicular lymphoma (FL) is the most common indolent lymphoma, accounting for 20%-25% of all non-Hodgkin's lymphomas (NHLs). It is a malignancy with variable biologic presentation and heterogeneous clinical outcomes. Several models incorporating clinical laboratory variables and molecular biomarkers are able to predict its prognosis, allowing to stratify patients into different risk groups. However, these prognostic scores should not be used to indicate first-line treatment or risk-adapted therapeutic recommendations. Over the past 5 years, progression of disease within 24 months (POD-24) of first-line chemo-immunotherapy has emerged as a robust adverse prognostic factor, capable of assessing overall survival and identifying high-risk patients with indication for more aggressive therapeutic approaches, such as consolidation based in autologous stem cell transplantation. It should be reinforced that POD-24 is not a baseline measurement, it is based on a post-treatment strategy, and is usually applied to patients with a high tumor burden. The identification of newly diagnosed patients at high risk for disease progression, particularly those with low tumor volume is still a challenge in the context of FL. Therefore, the primary purpose of this review is to provide an overview of the main prognostic models validated to date for FL. Moreover, using these scores, which incorporate clinical and genetic variables, we aim to identify individuals with newly diagnosed FL, advanced disease, and low tumor burden with a high probability of progression or relapse within 24 months of first treatment. Thus, a decision regarding risk-adapted induction therapy could be better stablished for these subset of patients.
- 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.