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Patients with advanced-stage Hodgkin lymphoma treated with ABVD who have a positive interim FDG-PET (iPET) have a poor prognosis. Escalation to BEACOPP has been shown to improve progression-free survival (PFS). However, randomized trials are lacking to determine the best strategy for intensification. We report on A-AVD escalation treatment outcomes for 15 iPET-positive patients post-ABVD. Overall response and complete response rates were 80% and 60%, respectively. Four patients underwent salvage therapy followed by autologous stem cell transplantation. At a median 17-month follow-up, all patients are alive, 87% in complete remission, and 1-year PFS was 57.8%. For patients ineligible for BEACOPP due to age, comorbidities, or preference, A-AVD escalation may be a viable alternative.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Brentuximab Vedotin , Dacarbazina , Doxorrubicina , Doença de Hodgkin , Tomografia por Emissão de Pósitrons , Vimblastina , Humanos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/terapia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Brentuximab Vedotin/uso terapêutico , Masculino , Feminino , Adulto , Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-Idade , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Vimblastina/uso terapêutico , Vimblastina/administração & dosagem , Dacarbazina/uso terapêutico , Dacarbazina/administração & dosagem , Adulto Jovem , Estadiamento de Neoplasias , Idoso , Resultado do Tratamento , SeguimentosRESUMO
Letermovir for CMV prevention in CMV-seropositive adults undergoing allo-HCT was implemented at our program in 2021. This study investigates the results from the use of letermovir. The study includes all the 140 CMV-seropositive patients who underwent an allo-HCT during the years 2020, 2021, and 2022 at our institution. Thirty-eight (27.4%) of these patients received letermovir, administered from day + 7 to day + 100 and restarted if patients were on treatment with steroids. The day + 180 and 1-year cumulative incidences of CMV reactivation were 5.3% and 12.1% for patients who received letermovir and 52.9% and 53.9% for those who did not (P < 0.001) (HR 0.19, P < 0.001). Four (10.5%) of these thirty-eight patients had a CMV reactivation, but only 2 (5.3%) cases occurred during the administration of letermovir. During the first year after allo-HCT, 13 (9.2%) patients had CMV disease; the day + 180 and 1-year cumulative incidences were 2.6% and 6.0% for patients who received letermovir and 9.9% and 12.3% for those who did not (P = 0.254) (HR 1.01, P = 0.458). Two (4.2%) of the patients included in the letermovir group had CMV disease, but both of them after letermovir discontinuation. Letermovir induced a protective effect on CMV reactivation risk, but its use was not associated with a significant reduction of CMV disease. The fact that the CMV disease in patients who received letermovir occurred after the discontinuation of the drug, questions whether CMV prophylaxis should be used in patients with high risk for CMV reactivation or disease.
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Acetatos , Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Quinazolinas , Adulto , Humanos , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus , Antivirais/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C0/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C0/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.
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Since 2021 the use of G-CSF was implemented in allo-HCT with PTCY-based prophylaxis with the aim of shortening the aplastic phase and reducing infectious complications. This study investigates the effectiveness of this change in protocol performed at our institution. One-hundred forty-six adults undergoing allo-HCT with PTCY-based prophylaxis were included, and among them, 58 (40%) received G-CSF. The median of days to neutrophil engraftment was shorter in the G-CSF group (15 vs. 20 days, p < 0.001). Patients receiving G-CSF had a lower incidence of day +30 bacterial bloodstream infections (BSI) than the rest (20.7% vs. 47.7%, p < 0.001). GVHD, SOS, and TA-TMA incidences were comparable between groups, and using G-CSF did not impact on survival. Endothelial activation was investigated using EASIX and by the measurement of soluble biomarkers in cryopreserved plasma samples obtained on days 0, +7, +14 and +21 of 39 consecutive patients (10 received G-CSF) included in the study. EASIX, VWF:Ag, sVCAM-1, sTNFRI, ST2, REG3α, TM and NETs medians values were comparable in patients receiving G-CSF and those who did not. Compared with allo-HCT performed without G-CSF, the addition of G-CSF to PTCY-based allo-HCT accelerated neutrophil engraftment contributing on decreasing BSI incidence, and without inducing additional endothelial activation.
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Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our hospital designed an at-home FCN administration model to avoid the hospitalization of patients requiring FCN treatment. This study analyzes whether the at-home administration of FCN is as safe and effective as its hospital administration. We collected and compared demographic, clinical, analytical, and economic data of patients with CMV infection post-allo-HCT who received FCN in the hospital (n = 16, 17 episodes) vs. at-home (n = 67, 88 episodes). The proportions of patients with cured CMV infections were comparable between the two groups (65.9% vs. 76.5%, p = 0.395). The median duration of FCN treatment was 15 (interquartile range [IQR] 9-23) and 14 (IQR 11-19) days in the HCU and inpatient cohorts, respectively (p = 0.692). There were no significant differences in the FCN toxicities between groups except for hypocalcemia (26.1% vs. 58.8%, p = 0.007), which was more prevalent in the inpatient cohort. A significant cost-effectiveness was found in the HCU cohort, with a median savings per episode of EUR 5270. It may be concluded that home administration of FCN is a safe, effective, and cost-efficient therapeutic option for patients with CMV infection and disease.
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Acute renal failure is frequent in critically ill patients. In those patients who need renal replacement therapy, continuous techniques are an alternative to intermittent haemodialysis. Critically ill patients often have an infection, which can lead to sepsis and renal failure. An early and adequate antibiotic treatment at correct dosage is extremely important. Methicillin resistant Staphylococcus aureus (MRSA) is a frequent nosocomial pathogen that causes a high rate of morbidity and mortality in critically ill patients. Many antibiotics are easily removed by continuous renal replacement therapies (CRRT) leading to a high risk of under dosing and therapeutic failure or resistance breakthrough. The objective of this review is to assess the clinical evidence on the pharmacokinetics and dosage recommendations of the main antibiotic groups used in MRSA treatment in patients treated with CRRT.
Assuntos
Injúria Renal Aguda/complicações , Injúria Renal Aguda/terapia , Antibacterianos/administração & dosagem , Staphylococcus aureus Resistente à Meticilina , Terapia de Substituição Renal , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/tratamento farmacológico , Acetamidas/administração & dosagem , Cálculos da Dosagem de Medicamento , Glicopeptídeos/administração & dosagem , Humanos , Linezolida , Oxazolidinonas/administração & dosagem , Guias de Prática Clínica como Assunto , Terapia de Substituição Renal/métodosRESUMO
Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C0) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV > 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p < 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV ≤ 50th percentile. Similarly, patients with IPV > 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p < 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV ≤ 75th percentile. Multivariate analyses showed that high Tac IPV (>50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD.
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In advanced breast cancer, biomarker identification and patient selection using a metastatic tumor biopsy is becoming more necessary. However, the biology of metastasis according to the organ site is largely unknown. Here, we evaluated the expression of 771 genes in 184 metastatic samples across 11 organs, including liver, lung, brain, and bone, and made the following observations. First, all PAM50 molecular intrinsic subtypes were represented across organs and within immunohistochemistry-based groups. Second, HER2-low disease was identified across all organ sites, including bone, and HER2 expression significantly correlated with ERBB2 expression. Third, the majority of expression variation was explained by intrinsic subtype and not organ of metastasis. Fourth, subtypes and individual subtype-related genes/signatures were significantly associated with overall survival. Fifth, we identified 74 genes whose expression was organ-specific and subtype-independent. Finally, immune profiles were found more expressed in lung compared to brain or liver metastasis. Our results suggest that relevant tumor biology can be captured in metastatic tissues across a variety of organ sites; however, unique biological features according to organ site were also identified and future studies should explore their implications in diagnostic and therapeutic interventions.
Assuntos
Neoplasias da Mama , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Receptor ErbB-2/metabolismo , Transcriptoma/genéticaRESUMO
Aim: To evaluate the safety of rechallenge with a different anti-PD-1 antibody after an immune-related adverse event (irAE) that has prompted the discontinuation of anti-PD-1 therapy. Patients & methods: We describe two patients with metastatic melanoma who developed potentially disabling and early irAEs following anti-PD-1 treatment. Therapy was discontinued and toxicities resolved with corticosteroids. Results: Rechallenge switching to an alternative anti-PD-1 antibody did not lead to a new or recurrent irAE. Conclusion: Switching to a different anti-PD-1 antibody when resuming therapy after an irAE might be a safe strategy and warrants further investigation. Structural and biological differences between antibodies might explain the different safety outcomes.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Substituição de Medicamentos , Inibidores de Checkpoint Imunológico/uso terapêutico , Nefrite/induzido quimicamente , Nivolumabe/uso terapêutico , Idoso , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológicoRESUMO
The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy.
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In 2015, we implemented an at-home allogeneic haematopoietic cell transplant (allo-HCT) program. Between 2015 and 2018, 252 patients underwent allo-HCT; 41 patients underwent allo-HCT in the at-home program (46% myeloablative; 63% unrelated donor; 32% posttransplant cyclophosphamide), and these patients were compared with 39 in-patients; safety, capacity to release beds for other programs, and economic efficiency cost were evaluated. We observed a lower incidence of febrile neutropenia in the at-home group compared with that in the in-patient group (32% versus 90%; p < 0.0001), whereas the incidence of aspergillosis was similar among groups (at-home 1% versus in-patient 3%; p = 0.5). The at-home patients showed a lower incidence of 1-year severe graft-versus-host disease (GVHD; 10% versus 29%; p = 0.03). There were no differences in 1-year transplant-related mortality, relapse, or overall survival among groups. The re-admission rate in the at-home group was 7%. The at-home setting was less expensive (9087 /transplant), and its implementation increased capacity by 10.5 allo-HCTs/year. Moreover, a chimeric antigen receptor T-cell program could be established without increasing beds. Thus, our at-home allo-HCT program may be a safe modality to reduce febrile neutropenia and acute GVHD, resulting in lower re-admission rates.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Ciclofosfamida , Europa (Continente) , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Doadores não RelacionadosRESUMO
INTRODUCTION: In recent years, the number of oral antitumoral agents has considerably increased. Oral administration increases the risk of interactions, because most oral anticancer drugs are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Many antitumoral drugs undergo enzymatic metabolism by cytochrome P450. As some act as inducers or inhibitors of one or more isoenzymes, they can lead to decreases or increases in plasma concentrations of concomitant drugs. Hence, cytostatic drugs can act not only as victims but also as perpetrators. P-glycoprotein, an efflux transporter, can also be involved in pharmacokinetic interactions. AREAS COVERED: A Medline search was performed to summarize the available evidence of the most clinically relevant interactions between oral chemotherapy agents and other drugs. The search covered the period from 1966 until August 2012 for each antitumoral drug using the medical subject headings 'Drug Interactions' OR 'Pharmacokinetics'. While the present review is not exhaustive, it aims to increase clinicians' awareness of potential drug-drug interactions. EXPERT OPINION: As cancer patients are often polymedicated and treated by different physicians, the risk of drug interactions between antitumoral agents and other medications is high. More clinical interaction studies are encouraged to ensure appropriate antineoplastic pharmacokinetics in clinical practice.
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Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Administração Oral , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , HumanosAssuntos
Acetamidas/farmacocinética , Injúria Renal Aguda/terapia , Anti-Infecciosos/farmacocinética , Hemodiafiltração , Oxazolidinonas/farmacocinética , Acetamidas/sangue , Acetamidas/uso terapêutico , Injúria Renal Aguda/metabolismo , Idoso , Anti-Infecciosos/sangue , Anti-Infecciosos/uso terapêutico , Estado Terminal , Feminino , Humanos , Linezolida , Listeria monocytogenes , Listeriose/tratamento farmacológico , Listeriose/metabolismo , Masculino , Meningite Pneumocócica/tratamento farmacológico , Meningite Pneumocócica/metabolismo , Pessoa de Meia-Idade , Oxazolidinonas/sangue , Oxazolidinonas/uso terapêutico , Choque Séptico/tratamento farmacológico , Choque Séptico/metabolismoRESUMO
La insuficiencia renal aguda es frecuente en pacientes críticos. En aquellos que necesitan depuración extrarrenal, las técnicas contínuas de depuración extrarrenal (TCDE) son una alternativa a la hemodiálisis intermitente cada vez más empleada. En muchas ocasiones, los pacientes críticos presentan una infección, que puede ser causa de shock séptico y del fallo renal. Un tratamiento antibiótico precoz y a dosis adecuadas es fundamental. Staphylococcus aureus resistente a meticilina (SARM) es un patógeno nosocomial frecuente que provoca una eleva morbi-mortalidad en pacientes críticos. Muchos antibióticos se eliminan de forma significativa por las TCDE, con el riesgo de infradosificación y fracaso terapéutico o aparición de resistencias. El objetivo de esta revisión es analizar la evidencia clínica disponible sobre el comportamiento farmacocinético y las recomendaciones posológicas de los principales grupos de antibióticos empleados en el tratamiento de las infecciones por SARM en pacientes sometidos a técnicas continuas de depuración extrarrena (AU)
Acute renal failure is frequent in critically ill patients. In those patients who need renal replacement therapy, continuous techniques are an alternative to intermittent haemodialysis. Critically ill patients often have an infection, which can lead to sepsis and renal failure. An early and adequate antibiotic treatment at correct dosage is extremely important. Methicillin resistant Staphylococcus aureus (MRSA)is a frequent nosocomial pathogen that causes a high rate of morbidity and mortality in critically ill patients. Many antibiotics are easily removed by continuous renal replacement therapies (CRRT) leading to a high risk of under dosing and therapeutic failure or resistance breakthrough. The objective of this review is to assess the clinical evidence on the pharmacokinetics and dosage recommendations of the main antibiotic groups used in MRSA treatment in patients treated with CRRT (AU)