RESUMO
BACKGROUND: Odronextamab, a CD20×CD3 bispecific antibody that engages cytotoxic T cells to destroy malignant B cells, has demonstrated encouraging activity across multiple subtypes of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. PATIENTS AND METHODS: This phase II study (ELM-2; NCT03888105) evaluated odronextamab in patients with R/R follicular lymphoma (FL) after ≥2 lines of systemic therapy. Patients received intravenous odronextamab in 21-day cycles, with step-up dosing in Cycle 1 to help mitigate the risk of cytokine release syndrome (CRS), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review. RESULTS: Among 128 patients evaluated, 95% completed Cycle 1, and 85% completed ≥4 cycles. At 20.1 months' efficacy follow-up, ORR was 80.0% and complete response rate was 73.4%. Median duration of complete response was 25.1 months. Median progression-free survival was 20.7 months, and median overall survival was not reached. Discontinuation of odronextamab due to adverse events (AEs) occurred in 16% of patients. The most common treatment-emergent AEs were CRS (56%; grade ≥3 1.7% [1/60] with 0.7/4/20 mg step-up), neutropenia (39%), and pyrexia (38%). CONCLUSIONS: Odronextamab achieved high complete response rates with generally manageable safety in patients with heavily pretreated R/R FL.
RESUMO
BACKGROUND: Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved. METHODS: An open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy. RESULTS: Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference -1.16, 90% CI -1.48 to -0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype-guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R2 = 42.4% (P < 0.001) and mean percentage error of -7.4%. CONCLUSIONS: Among Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00700895 . Registered on June 19, 2008.
Assuntos
Anticoagulantes/uso terapêutico , Dose Máxima Tolerável , Varfarina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacologia , Povo Asiático , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Varfarina/administração & dosagem , Varfarina/farmacologia , Adulto JovemRESUMO
Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has been performed primarily with an HLA-matched donor. Outcomes of haploidentical transplantation have recently improved, and a comparison between donor sources in a uniform cohort of patients has not been performed. We evaluated outcomes of 227 patients with AML/MDS treated with melphalan-based conditioning. Donors were matched related (MRD) (n = 87, 38%), matched unrelated (MUD) (n = 108, 48%), or haploidentical (n = 32, 14%). No significant differences were found between haploidentical and MUD transplantation outcomes; however, there was a trend for improved outcomes in the MRD group, with 3-year progression-free survival for patients in remission of 57%, 45%, and 41% for MRD, MUD, and haploidentical recipients, respectively (P = .417). Recovery of T cell subsets was similar for all groups. These results suggest that haploidentical donors can safely extend transplantation for AML/MDS patients without an HLA-matched donor. Prospective studies comparing haploidentical and MUD transplantation are warranted.
Assuntos
Antígenos HLA , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transplante de Células-Tronco , Doadores não Relacionados , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Teste de Histocompatibilidade , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
There is currently no consensus on the role of upfront autologous transplantation (ASCT) for patients with peripheral T-cell lymphomas (PTCL), especially in patients achieving first complete remission (CR1) following chemotherapy, and data in the literature is conflicting. A systematic review and meta-analysis was performed to address this question. We searched key databases from January 2000 to February 2022. Six prospective and eleven retrospective studies were included among 2959 unique records. Median follow up in these studies ranged from 22 to 94 months. There was a trend towards benefit in PFS (HR = 0.80, 95% CI 0.62-1.05, p = 0.11) and OS (HR = 0.79, 95% CI 0.57-1.09, p = 0.15) in the ASCT compared to chemotherapy only group. Importantly, in transplant eligible patients in CR1, a significant benefit was demonstrated in both OS (HR = 0.59, 95% CI 0.36-0.95, p = 0.03) and PFS (HR = 0.61, 95% CI 0.47-0.81, p = 0.0004) in the ASCT group. Amongst the nodal PTCL subgroups, ASCT showed a significant PFS benefit for the AITL subgroup (HR = 0.43, 95% CI 0.20-0.94, p < 0.03) but not PTCL-NOS or ALK-ve ALCL subgroups. Our findings support upfront ASCT for transplant eligible PTCL patients achieving CR1 post chemotherapy. In particular, patients with AITL exhibited a significantly better PFS after upfront ASCT.
Assuntos
Linfoma de Células T Periférico , Indução de Remissão , Transplante Autólogo , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/mortalidade , Humanos , Transplante Autólogo/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , AutoenxertosAssuntos
Encéfalo/patologia , Imunoconjugados/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Terapia de Salvação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Barreira Hematoencefálica , Encéfalo/diagnóstico por imagem , Brentuximab Vedotin , Feminino , Humanos , Imunoconjugados/farmacocinética , Linfoma Anaplásico de Células Grandes/diagnóstico por imagem , Linfoma Anaplásico de Células Grandes/patologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Recidiva , Indução de RemissãoRESUMO
Hepatosplenic candidiasis (HSC) in patients with acute leukemia poses management challenges because the therapeutic limitations of the present antifungal armamentarium may adversely impact on treatment outcomes of the underlying leukemia. We report a patient with acute myeloid leukemia who developed HSC during post-remission consolidation chemotherapy and was treated with a prolonged course of caspofungin followed by fluconazole. The stabilization of infection permitted further chemotherapy and autologous hematopoietic cell transplant (HCT) without breakthrough fungemia and further dissemination of candidiasis. The favorable outcome provides further evidence that with optimal treatment, the presence of stable or non-progressive HSC is not an absolute contraindication for HCT. The use of caspofungin in the primary treatment of HSC appears to be a promising approach. The favorable outcome seen in this case is encouraging, although further study on its efficacy is warranted.
Assuntos
Antifúngicos/uso terapêutico , Candida tropicalis , Candidíase/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/cirurgia , Hepatopatias/tratamento farmacológico , Esplenopatias/tratamento farmacológico , Adulto , Candidíase/diagnóstico , Candidíase/etiologia , Caspofungina , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Equinocandinas/uso terapêutico , Feminino , Fluconazol/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Lipopeptídeos , Hepatopatias/diagnóstico por imagem , Hepatopatias/microbiologia , Radiografia , Esplenopatias/diagnóstico por imagem , Esplenopatias/microbiologia , Tomógrafos ComputadorizadosRESUMO
Loss of heterozygosity (LOH) has been shown to be associated with leukemia relapse after haploidentical transplantation. Whether such changes are an important cause of relapse after HLA-matched transplantation remains unclear. We retrospectively HLA-typed leukemic blasts for 71 patients with AML/myelodysplastic syndrome obtained from stored samples, and the results were compared with those obtained at diagnosis and/or before the transplant. No LOH or any other changes in HLA Ag were found in any of the samples tested post transplant as compared with pretransplant specimens. One patient had LOH in HLA class I Ag (HLA-A,-B and -C); however, these changes were present in the pretransplant sample indicating that they occurred before the transplant. We concluded that, in contrast with haploidentical transplantation, HLA loss does not have a major role as a mechanism of relapse after allogeneic transplantation with a closely HLA-matched donor.
Assuntos
Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/imunologia , Leucemia/terapia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Transplante Homólogo , Adulto JovemAssuntos
Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/patogenicidade , Macrófagos/virologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas não Estruturais Virais/genética , Animais , Células Cultivadas , Galinhas , Humanos , Influenza Aviária , Influenza Humana , VirulênciaAssuntos
Infecções por Coronavirus/mortalidade , Influenza Humana/mortalidade , Vigilância da População , Infecções por Vírus Respiratório Sincicial/mortalidade , Adolescente , Adulto , Idoso , Autopsia , Criança , Doenças Transmissíveis Emergentes/diagnóstico , Doenças Transmissíveis Emergentes/mortalidade , Coronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Feminino , Hong Kong/epidemiologia , Humanos , Incidência , Lactente , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/diagnóstico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase/métodos , Infecções por Vírus Respiratório Sincicial/diagnóstico , Adulto JovemAssuntos
Neoplasias Hematológicas/complicações , Infecções Fúngicas Invasivas/diagnóstico , Volvariella/isolamento & purificação , Antifúngicos/uso terapêutico , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/patologia , Infecções Fúngicas Invasivas/fisiopatologia , Masculino , Técnicas Microbiológicas , Pessoa de Meia-Idade , Estudos Retrospectivos , Singapura , Resultado do TratamentoRESUMO
For patients with ALL who relapse following allo-SCT, only a second SCT provides a realistic chance for long-term disease remission. We retrospectively analyzed the outcomes of 31 patients with relapsed ALL after a prior allo-SCT, who received a second SCT (SCT2) at our center. With a median follow-up of 3 years, 1- and 3-year PFS was 23 and 11% and 1- and 3 year OS rates were 23 and 11%. Twelve patients (39%) were transplanted with active disease, of whom 75% attained a CR. We found a significant relationship between the time to treatment failure following first allograft (SCT1) and PFS following SCT2 (P=0.02, hazard ratio=0.93/month). In summary, a second transplant remains a potential treatment option for achieving response in a highly refractory patient population. While long-term survival is limited, a significant proportion of patients remains disease-free for up to 1 year following SCT2, providing a window of time to administer preventive interventions. Notably, our four long-term survivors received novel therapies with their second transplant underscoring the need for a fundamental change in the methods for SCT2 to improve outcome.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an effective post-remission therapy in patients with acute lymphoblastic leukemia (ALL), but is associated with significant toxicity, so the optimal timing and use of this modality remains an issue of debate. Increased advances in reduced-intensity transplant preparative regimens and alternative donors has increased the accessibility of allogeneic transplantation. A risk adapted paradigm, using minimal residual disease analysis, may help in the selection of patients at highest risk for relapse, who may benefit most from alloHSCT. In this review, we summarize the indications for allogeneic transplantation within the risk-oriented paradigm, and also explore the latest literature on reduced intensity transplant regimens, as well as alternative donor transplantation for patients with ALL.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Humanos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Condicionamento Pré-Transplante/métodos , Transplante HomólogoRESUMO
NDM-1 is a new metallo-beta-lactamase that readily hydrolyses carbapenems, penicillins and cephalosporins. Its rising incidence has been reported in many countries around the world, with many cases linked to a possible origin from the Indian subcontinent. Due to the lack of effective antibiotic regimes to treat these infections, the increased prevalence of NDM-1 is alarming. We describe a case of NDM-1 infection in an immunocompromised foreign patient, and discuss its implications.