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1.
Cancer ; 129(7): 992-1004, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36692409

RESUMO

BACKGROUND: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. METHODS: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. RESULTS: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event. CONCLUSIONS: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.


Assuntos
Leucemia Mieloide Aguda , Humanos , Idoso , Estudos de Coortes , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Sulfonamidas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
2.
Clin Immunol ; 220: 108598, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32961333

RESUMO

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.


Assuntos
Betacoronavirus/patogenicidade , Complemento C3/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , COVID-19 , Estudos de Coortes , Ativação do Complemento/efeitos dos fármacos , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/genética , Complemento C5/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/virologia , Pandemias , Peptídeos Cíclicos/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2 , Índice de Gravidade de Doença
3.
Hematol Rep ; 16(2): 234-243, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38651452

RESUMO

Background: Post-transplant cyclophosphamide (PTCY) is widely used as graft versus host disease (GvHD) prophylaxis in allogeneic hematopoietic stem cell transplant (HSCT) recipients, with reported clinical benefits in patients who underwent transplant from a matched unrelated donor (MUD). However, real-life data on clinical efficacy and safety of PTCY in haploidentical and MUD transplantations are still poor. Methods: In our real-life retrospective observational study, we included a total of 40 consecutive adult patients who underwent haploidentical or MUD HSCT for various hematological malignancies and who received PTCY (n = 24) or ATG (n = 16) as GvHD prophylaxis at Hematology Units from hospitals of Salerno and Avellino, Italy, and clinical outcomes were compared. Results: We showed protective effects of PTCY against disease relapse with the relapse rate after transplantation of 16% versus 50% in the ATG arm (p = 0.02). All-cause mortality was lower (36% vs. 75%; p = 0.02) and the 2-year overall survival was slightly superior in patients administered PTCY (61% vs. 42%; p = 0.26). Conclusions: We support the use of PTCY, even in a real-life setting; however, the optimization of this protocol should be further investigated to better balance relapse prevention and GvHD prophylaxis.

4.
Bone Marrow Transplant ; 54(Suppl 2): 698-702, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31431717

RESUMO

In patients with hematological malignancies at high risk for relapse, a mismatched hematopoietic stem cells transplants can be offered with no undue delay between decision-making and transplantation as virtually all patients have a full-haplotype mismatched member who could serve immediately as a donor. Using a T-cell depletion approach, these patients can benefit from a graft-vs-leukemia effect in the absence of both acute and chronic graft-vs-host disease. Over the past decade, efforts have concentrated on developing new conditioning regimens, optimizing the graft processing and improving the posttransplant immunological recovery. The innovative strategy based on the selective depletion of alpha/beta-positive T lymphocytes from G-CSF-mobilized peripheral blood precursor cells has shown very promising results in the setting of the pediatric transplantation. This paper reports the outcome in adult patients with hematological malignancies.


Assuntos
Antígenos CD19/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco de Sangue Periférico/imunologia , Condicionamento Pré-Transplante/métodos , Transplante Haploidêntico/métodos , Adulto , Idoso , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco , Adulto Jovem
5.
Oxf Med Case Reports ; 2018(3): omx103, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29527312

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by intravascular hemolysis, thrombosis and bone marrow failure. Acute kidney injury, including acute renal failure, have been reported in patients with PNH. We report the case of a 36-year-old male patient with PNH who developed acute kidney injury following an infection of undetermined diagnosis. Although hemolysis was initially controlled and renal function stabilized following packed red blood cell transfusion and empirical levofloxacin and prednisone, he later experienced recurrent episodes of hemolysis and hematuria requiring monthly red blood cell support. Given the high risk of thromboembolic events, treatment with standard-dose eculizumab was started. The patient's hematologic values improved, renal function was maintained, and no thromboembolic events occurred.

6.
Blood Adv ; 1(24): 2166-2175, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29296864

RESUMO

The establishment of safe approaches to attain durable donor-type chimerism and immune tolerance toward donor antigens represents a major challenge in transplantation biology. Haploidentical hematopoietic stem cell transplantation (HSCT) is currently used for cancer therapy either as a T-cell-depleted megadose HSCT following myeloablative conditioning or with T-cell-replete HSCT following nonmyeloablative conditioning (NMAC) and high-dose posttransplant cyclophosphamide (PTCY). The latter approach suffers from a significant rate of chronic graft-versus-host disease (GVHD), despite prolonged immunosuppression. The use of T-depleted grafts, although free of GVHD risk, is not effective after NMAC because of graft rejection. We now demonstrate in mice conditioned with NMAC that combining the power of high-dose PTCY with T-cell-depleted megadose HSCT can overcome this barrier. This approach was evaluated in 2 patients with multiple myeloma and 1 patient with Hodgkin lymphoma. The first myeloma patient now followed for 25 months, exhibited full donor-type chimerism in the myeloid and B-cell lineages and mixed chimerism in the T-cell compartment. The second myeloma patient failed to attain chimerism. Notably, the low toxicity of this protocol enabled a subsequent successful fully myeloablative haploidentical HSCT in this patient. The third patients was conditioned with slightly higher total body irradiation and engrafted promptly. All patients remain in remission without GVHD. Both engrafted patients were able to control cytomegalovirus reactivation. Enzyme-linked immunospot analysis revealed immune tolerance toward donor cells. Our results demonstrate a novel and safer nonmyeloablative haplo-HSCT offering a platform for immune tolerance induction as a prelude to cell therapy and organ transplantation.

7.
Mediterr J Hematol Infect Dis ; 8(1): e2016057, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27872737

RESUMO

The advantage of using a Human Leukocyte Antigen (HLA)-mismatched related donor is that almost every patient who does not have an HLA-identical donor or who urgently needs hematopoietic stem cell transplantation (HSCT) has at least one family member with whom shares one haplotype (haploidentical) and who is promptly available as a donor. The major challenge of haplo-HSCT is intense bi-directional alloreactivity leading to high incidences of graft rejection and graft-versus-host disease (GVHD). Advances in graft processing and pharmacologic prophylaxis of GVHD have reduced these risks and have made haplo-HSCT a viable alternative for patients lacking a matched donor. Indeed, the haplo-HSCT has spread to centers worldwide even though some centers have preferred an approach based on T cell depletion of G-CSF-mobilized peripheral blood progenitor cells (PBPCs), others have focused on new strategies for GvHD prevention, such as G-CSF priming of bone marrow and robust post-transplant immune suppression or post-transplant cyclophosphamide (PTCY). Today, the graft can be a megadose of T-cell depleted PBPCs or a standard dose of unmanipulated bone marrow and/or PBPCs. Although haplo-HSCT modalities are based mainly on high intensity conditioning regimens, recently introduced reduced intensity regimens (RIC) showed promise in decreasing early transplant-related mortality (TRM), and extending the opportunity of HSCT to an elderly population with more comorbidities. Infections are still mostly responsible for toxicity and non-relapse mortality due to prolonged immunosuppression related, or not, to GVHD. Future challenges lie in determining the safest preparative conditioning regimen, minimizing GvHD and promoting rapid and more robust immune reconstitution.

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