RESUMEN
OBJECTIVES: Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix (APX001A; active moiety) targets fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, inhibiting cell wall synthesis causing loss of viability. This open-label, multicentre, Phase 1b study in patients with AML and neutropenia (absolute neutrophil count <500 cells/µL; >10 days) undergoing chemotherapy aimed to assess tolerability, safety and pharmacokinetics (PK) of IV and PO fosmanogepix. METHODS: Of 21 adult AML patients undergoing remission induction chemotherapy, 10 received IV fosmanogepix (600 mg; q24h) and 11 received oral fosmanogepix (500 mg; q24h) over 14 days, with a 28 day follow-up. Patients also received remission induction chemotherapy [sequential high-dose cytarabine and mitoxantrone (S-HAM) or 7â+â3 regimen] for AML and IFD prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was fitted to manogepix plasma data. RESULTS: Of 26 fosmanogepix-related adverse events (AEs; IV: 14; PO: 12) in 9 (42.9%) patients [IV: 5 (50%); PO: 4 (36.4%)], none were serious or resulted in fosmanogepix discontinuation. Most frequently occurring fosmanogepix-related AEs were Grade 1/2 nausea [four events in three patients (14.3%)]; vomiting, ALT increase, and delirium [two events; two patients (9.5%) each]. One patient experienced fosmanogepix-related Grade 3 hypertension. Dose-corrected geometric mean ratio of AUC (PO-to-IV) was 95%. Elimination half-lives (â¼2 days) were consistent with prior studies in healthy volunteers. CONCLUSIONS: Fosmanogepix was safe and well tolerated in AML patients with neutropenia receiving remission induction chemotherapy. Safety and PK profiles were comparable to healthy volunteers.
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Leucemia Mieloide Aguda , Neutropenia , Adulto , Humanos , Antifúngicos/efectos adversos , Antifúngicos/farmacocinética , Aminopiridinas/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Neutropenia/inducido químicamenteRESUMEN
Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendation to administer antifungal prophylaxis in patients with HM with long-lasting neutropenia, i.e. <500 cells/µL for >7 days remains unchanged. Posaconazole remains the drug of choice for mould-active prophylaxis in these patients. Novel treatment options in HM, such as CAR-T-cell treatment or novel targeted therapies for acute myeloid leukaemia (AML) were considered, however, data are insufficient to give general recommendations for routine antifungal prophylaxis in these patients. Major changes regarding specific recommendations compared to the 2017 edition are the now moderate instead of mild support for the recommendations of isavuconazole and voriconazole. Furthermore, published evidence on micafungin allows recommending it at moderate strength for its use in HM. For the first time we included recommendations for non-pharmaceutical measures regarding IFD, comprising the use of high-efficiency particulate air (HEPA) filters, smoking, measures during construction work and neutropenic diets. We reviewed the impact of antifungal prophylaxis with triazoles on drug-drug interactions with novel targeted therapies that are metabolized via cytochrome p450 where triazoles inhibit CYP3A4/5. The working group recommends reducing the dose of venetoclax when used concomitantly with strong CYP3A4 inhibiting antifungals. Furthermore, we reviewed data on the prophylactic use of novel antifungal agents. Currently there is no evidence to support their use in a prophylactic setting in clinical practice.
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Enfermedades Transmisibles , Neoplasias Hematológicas , Hematología , Infecciones Fúngicas Invasoras , Humanos , Antifúngicos/uso terapéutico , Citocromo P-450 CYP3A , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/prevención & control , Infecciones Fúngicas Invasoras/microbiología , Enfermedades Transmisibles/tratamiento farmacológico , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/tratamiento farmacológico , Oncología Médica , Triazoles/uso terapéuticoRESUMEN
OBJECTIVES: Chlorhexidine gluconate (CHG)-coated gel pad dressings for central venous catheter (CVC) may prevent CVC-related bloodstream infections (CRBSI). However, real-world data showing beneficial effects in patients with hematologic malignancies are scarce. METHODS: In a matched-pair analysis with data from a multicenter CVC registry, non-tunneled jugular and subclavian vein CVC in adults with hematologic malignancies or germ cell tumors (including patients receiving autologous hematopoietic stem cell transplantation [ASCT]) with CHG were compared with non-CHG dressings. The primary endpoint was definite CRBSI rate within 14 days (dCRBSI14) of CVC insertion; secondary endpoints were combined rate of definite or probable CRBSI within 14 days (dpCRBSI14), overall (dpCRBSI), and CRBSI incidences of all estimates. RESULTS: In total, 2070 CVCs were assessed. There was no statistically significant difference in dCRBSI14 (2.3% vs. 3.5%) between patients with and without CHG gel dressings. Likewise, with regards to dpCRBSI14 (6.2% vs. 6.3%) and the overall dpCRBSI rate (9.2% vs. 10.5%), no significant difference was detected. Furthermore, dCRBSI14 incidence (2.0 vs. 3.2/1000 CVC days), dpCRBSI14 incidence (5.4 vs. 5.6/1000 CVC days), and overall CRBSI incidence (5.5 vs. 6.0/1000 CVC days) showed no significant differences. CONCLUSIONS: CRBSI rates were not reduced by the use of CHG gel dressings in patients with hematologic malignancies and/or ASCT.
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Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Catéteres Venosos Centrales , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Sepsis , Adulto , Humanos , Catéteres Venosos Centrales/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Análisis por Apareamiento , Infecciones Relacionadas con Catéteres/diagnóstico , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/etiología , Trasplante Autólogo , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Vendajes , Cateterismo Venoso Central/efectos adversosRESUMEN
PURPOSE: Overall, insertion of central venous catheter (CVC) into femoral veins (FV) has been shown to be associated with a higher risk of infection compared with subclavian and internal jugular (IJV/SCV) CVC, but no data are available on the impact of the FV insertion site on the CVC-related bloodstream infections (CRBSI) risk in patients with cancer. The objective of the study is to compare CRBSI rates and incidences of FV with those of internal jugular and subclavian vein (IJV/SCV CVC) as observed in the prospective SECRECY registry. METHODS: SECRECY is an ongoing observational, prospective, clinical CRBSI registry active in six departments of hematology/oncology in Germany. Each case of FV CVC was matched at a ratio of 1:1 to a case with IJV/SCV CVC. The propensity score was estimated using a multivariable logistic regression model adjusting for age, sex, cancer type, and duration of indwelling catheter. RESULTS: Of 4268 CVCs included in this analysis, 52 (1.2%) were inserted into the FV and 4216 (98.8%) into the IJV/SCV. 52 cases of FV CVC were matched with 52 IJV/SCV CVC. There was no significant difference in the CRBSI rate (3.8% vs. 9.6%), the CRBSI incidence (5.7 vs. 14.2/1000 CVC days), and the median CVC time (5.5 vs. 5 days) between the FV and the IJV/SCV group. CONCLUSION: Based on this data, inserting FV CVCs in patients with cancer does, at least in the short-term, not appear to be associated with an increased risk of CRBSI as compared to IJV/SCV CVC.
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Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Catéteres Venosos Centrales , Neoplasias , Sepsis , Humanos , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/etiología , Cateterismo Venoso Central/efectos adversos , Catéteres Venosos Centrales/efectos adversos , Neoplasias/complicaciones , Sepsis/etiología , Vena Subclavia , Masculino , FemeninoRESUMEN
Although not generally recommended, scheduled central venous catheter (CVC) removal is sometimes carried out in order to reduce the CVC-related bloodstream infection (CRBSI) incidence. We conducted a simulation for scheduled CVC removal within the multicenter CRBSI registry (SECRECY). Non-tunneled jugular and subclavian CVC in patients with hematological disease or with germ cell tumors (including patients receiving autologous stem cell transplantation [SCT]) were included. Cases were randomized in a 1:1:1:1 ratio to either a simulated, scheduled CVC removal after 7, 14, and 21 days, or to non-simulated, unscheduled CVC removal (control group). The primary endpoint was definitive CRBSI incidence for a scheduled CVC removal after 14 days (dCRBSI-D14rmv). Among other, secondary endpoints were definite CRBSI incidence for a scheduled removal after 7 days (dCRBSI-D7rmv) and 21 days (dCRBSI-D21rmv). Data on 2984 CVC were included. Patients' median age was 59 (range 16-95) years, 58.8% being male. The vast majority (98.4%) were patients with hematological malignancies. Jugular veins were the main insertion site (93.2%). dCRBSI-D14rmv was 3.10/1000 CVC days as compared to 4.15/1000 CVC days in the control group (p = 0.23). There was a significant difference between dCRBSI-D7rmv (0.86/1000 CVC days) and controls (p < 0.001), but not between dCRBSI-D21rmv (4.10/1000 CVC days) and controls (p = 0.96). Our data suggest that in patients with hematological diseases or autologous SCT recipients scheduled CVC removal after 14 days does not result in a lower CRBSI incidence compared to unscheduled removal.Trial registration: DRKS00006551, 2014/09/29, retrospectively registered.
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Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Catéteres Venosos Centrales , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Sepsis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/prevención & control , Cateterismo Venoso Central/efectos adversos , Catéteres Venosos Centrales/efectos adversos , Femenino , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Trasplante Autólogo , Adulto JovenRESUMEN
PURPOSE: This study aimed to describe the cytomegalovirus (CMV) infection rate, rehospitalizations, and comorbidities following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantation (SOT). METHODS: Patients who received allo-HSCT or SOT in 01/07/2015-30/06/2018 were identified using anonymized German claims data. The transplantation-related hospital admission date was defined as the index date, and patients were followed for up to 12 months (or death, first event relevant). The frequency of CMV infections (confirmed outpatient/inpatient diagnoses, ICD-10-GM codes: B25.-/B27.1) and the rate, number, and duration of all-cause rehospitalizations in the follow-up period were evaluated. RESULTS: A total of 226 allo-HSCT and 250 SOT patients were identified (mean age 52.8 years, 38.9% female). During the 12 months after transplantation, 29.2% of allo-HSCT patients and 16.8% of SOT patients received a CMV diagnosis. The majority of these diagnoses were given during the initial hospitalization or within the following 3 months. Across transplantation types, CMV patients had more hospital readmission days per patient-year (allo-HSCT 93.3 vs. 49.4, p = 0.001; SOT 42.0 vs. 20.7, p = 0.005), with a longer mean duration of readmissions (allo-HSCT 22.4 vs. 15.4 days, p < 0.001; SOT 11.6 vs. 7.5 days, p = 0.003). Comorbidity burden in transplantation patients was substantial, with several diagnoses being significantly more common among patients with CMV vs. non-CMV. One-year mortality did not differ significantly between patients with/without CMV. CONCLUSION: Burden of transplant recipients with CMV in terms of rehospitalizations and comorbidities is substantial, highlighting the need for improved CMV prevention and treatment.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Trasplante de Órganos , Humanos , Femenino , Persona de Mediana Edad , Masculino , Trasplante Homólogo/efectos adversos , Estudios Retrospectivos , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Órganos/efectos adversos , Células Madre HematopoyéticasRESUMEN
Despite a broad cell-type tropism, cytomegalovirus (CMV) is an evidentially pulmonary pathogen. Predilection for the lungs is of medical relevance in immunocompromised recipients of hematopoietic cell transplantation, in whom interstitial CMV pneumonia is a frequent and, if left untreated, fatal clinical manifestation of human CMV infection. A conceivable contribution of CMV to airway diseases of other etiology is an issue that so far attracted little medical attention. As the route of primary CMV infection upon host-to-host transmission in early childhood involves airway mucosa, coincidence of CMV airway infection and exposure to airborne environmental antigens is almost unavoidable. For investigating possible consequences of such a coincidence, we established a mouse model of airway co-exposure to CMV and ovalbumin (OVA) representing a protein antigen of an inherently low allergenic potential. Accordingly, intratracheal OVA exposure alone failed to sensitize for allergic airway disease (AAD) upon OVA aerosol challenge. In contrast, airway infection at the time of OVA sensitization predisposed for AAD that was characterized by airway inflammation, IgE secretion, thickening of airway epithelia, and goblet cell hyperplasia. This AAD histopathology was associated with a T helper type 2 (Th2) transcription profile in the lungs, including IL-4, IL-5, IL-9, and IL-25, known inducers of Th2-driven AAD. These symptoms were all prevented by a pre-challenge depletion of CD4+ T cells, but not of CD8+ T cells. As to the underlying mechanism, murine CMV activated migratory CD11b+ as well as CD103+ conventional dendritic cells (cDCs), which have been associated with Th2 cytokine-driven AAD and with antigen cross-presentation, respectively. This resulted in an enhanced OVA uptake and recruitment of the OVA-laden cDCs selectively to the draining tracheal lymph nodes for antigen presentation. We thus propose that CMV, through activation of migratory cDCs in the airway mucosa, can enhance the allergenic potential of otherwise poorly allergenic environmental protein antigens.
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Alérgenos/metabolismo , Citomegalovirus/metabolismo , Células Dendríticas/inmunología , Alérgenos/efectos adversos , Animales , Presentación de Antígeno/inmunología , Antígenos CD11/inmunología , Citomegalovirus/patogenicidad , Células Dendríticas/microbiología , Modelos Animales de Enfermedad , Femenino , Hipersensibilidad , Inflamación , Pulmón/fisiopatología , Pulmón/virología , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/virología , Ratones , Ratones Endogámicos C57BL , Ovalbúmina , Células Th2 , Activación Viral/inmunologíaRESUMEN
Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirus-specific cellular immunity was measured using a standardized IFN-γ ELISpot assay (T-Track® CMV). Primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. 40/101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; p=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 post-transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #NCT02156479.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Citomegalovirus , Infecciones por Citomegalovirus/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Prospectivos , Medición de Riesgo , Activación ViralRESUMEN
Diagnosis, treatment, and management of invasive mould infections (IMI) are challenged by several risk factors, including local epidemiological characteristics, the emergence of fungal resistance and the innate resistance of emerging pathogens, the use of new immunosuppressants, as well as off-target effects of new oncological drugs. The presence of specific host genetic variants and the patient's immune system status may also influence the establishment of an IMI and the outcome of its therapy. Immunological components can thus be expected to play a pivotal role not only in the risk assessment and diagnosis, but also in the treatment of IMI. Cytokines could improve the reliability of an invasive aspergillosis diagnosis by serving as biomarkers as do serological and molecular assays, since they can be easily measured, and the turnaround time is short. The use of immunological markers in the assessment of treatment response could be helpful to reduce overtreatment in high risk patients and allow prompt escalation of antifungal treatment. Mould-active prophylaxis could be better targeted to individual host needs, leading to a targeted prophylaxis in patients with known immunological profiles associated with high susceptibility for IMI, in particular invasive aspergillosis. The alteration of cellular antifungal immune response through oncological drugs and immunosuppressants heavily influences the outcome and may be even more important than the choice of the antifungal treatment. There is a need for the development of new antifungal strategies, including individualized approaches for prevention and treatment of IMI that consider genetic traits of the patients. LAY ABSTRACT: Anticancer and immunosuppressive drugs may alter the ability of the immune system to fight invasive mould infections and may be more important than the choice of the antifungal treatment. Individualized approaches for prevention and treatment of invasive mold infections are needed.
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Antifúngicos/uso terapéutico , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/etiología , Neoplasias/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Invasive fungal diseases remain a major cause of morbidity and mortality in cancer patients undergoing intensive cytotoxic therapy. The choice of the most appropriate antifungal treatment (AFT) depends on the fungal species suspected or identified, the patient's risk factors (eg length and depth of granulocytopenia) and the expected side effects. OBJECTIVES: Since the last edition of recommendations for 'Treatment of invasive fungal infections in cancer patients' of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) in 2013, treatment strategies were gradually moving away from solely empirical therapy of presumed or possible invasive fungal diseases (IFDs) towards pre-emptive therapy of probable IFD. METHODS: The guideline was prepared by German clinical experts for infections in cancer patients in a stepwise consensus process. MEDLINE was systematically searched for English-language publications from January 1975 up to September 2019 using the key terms such as 'invasive fungal infection' and/or 'invasive fungal disease' and at least one of the following: antifungal agents, cancer, haematological malignancy, antifungal therapy, neutropenia, granulocytopenia, mycoses, aspergillosis, candidosis and mucormycosis. RESULTS: AFT of IFDs in cancer patients may include not only antifungal agents but also non-pharmacologic treatment. In addition, the armamentarium of antifungals for treatment of IFDs has been broadened (eg licensing of isavuconazole). Additional antifungals are currently under investigation or in clinical trials. CONCLUSIONS: Here, updated recommendations for the treatment of proven or probable IFDs are given. All recommendations including the levels of evidence are summarised in tables to give the reader rapid access to key information.
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Antifúngicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Hematología/organización & administración , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Neoplasias/complicaciones , Guías de Práctica Clínica como Asunto , Agranulocitosis/complicaciones , Agranulocitosis/microbiología , Neoplasias Hematológicas/complicaciones , Hematología/métodos , Humanos , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/etiología , Neoplasias/microbiologíaRESUMEN
There is a growing body of evidence for immunomodulatory side effects of antifungal agents on different immune cells, e.g., T cells. Therefore, the aim of our study was to clarify these interactions with regard to the effector functions of polymorphonuclear neutrophils (PMN). Human PMN were preincubated with fluconazole (FLC), voriconazole (VRC), posaconazole (POS), isavuconazole (ISA), caspofungin (CAS), micafungin (MFG), conventional amphotericin B (AMB), and liposomal amphotericin B (LAMB). PMN then were analyzed by flow cytometry for activation, degranulation, and phagocytosis and by dichlorofluorescein assay to detect reactive oxygen species (ROS). Additionally, interleukin-8 (IL-8) release was measured by enzyme-linked immunosorbent assay. POS led to enhanced activation, degranulation, and generation of ROS, whereas IL-8 release was reduced. In contrast, ISA-pretreated PMN showed decreased activation signaling, impaired degranulation, and lower generation of ROS. MFG caused enhanced expression of activation markers but impaired degranulation, phagocytosis, generation of ROS, and IL-8 release. CAS showed increased phagocytosis, whereas degranulation and generation of ROS were reduced. AMB led to activation of almost all effector functions besides impaired phagocytosis, whereas LAMB did not alter any effector functions. Independent from class, antifungal agents show variable influence on neutrophil effector functions in vitro Whether this is clinically relevant needs to be clarified.
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Antifúngicos/farmacología , Neutrófilos/metabolismo , Anfotericina B/farmacología , Interleucina-8/metabolismo , Neutrófilos/efectos de los fármacos , Nitrilos/farmacología , Fagocitosis/efectos de los fármacos , Piridinas/farmacología , Triazoles/farmacología , Voriconazol/farmacologíaRESUMEN
In patients with hematological malignancies, bronchoalveolar lavage fluid (BALF) specimens are commonly used for the diagnosis of mold infections. However, it is not clear whether the cell pellet (P) or the supernatant fraction (S) of the BALF specimen is optimal for molecular diagnostic testing. Thus, 99 BALF specimens were collected from 96 hematology patients with or without allogeneic hematopoietic stem cell transplant. The cell pellets and supernatants were processed alone and in combination (S/P) for testing by two fungus-specific real-time PCR assays compliant with international recommendations. The results achieved with S/P were revealed to be superior in comparison to those achieved with S and P alone, with the use of each single fraction showing a reduced sensitivity for the detection of Aspergillus DNA (82% and 43% for S and P, respectively). In 57% of the samples, testing of the combination of S and P generated a lower quantification cycle value than testing of S or P alone. Molds would have been missed in 5 and 16 out of 28 samples if only S or P, respectively, was analyzed. No sample was positive by testing of S or P only. Similar results were obtained for the detection of Mucorales DNA in BALF specimens (reduced sensitivity of 67% and 50% for S and P, respectively). Study patients were categorized according to the current European Organization for the Research and Treatment of Cancer/Mycoses Study Group classification for invasive fungal disease (IFD), revealing that 35 patients had proven/probable IFD (36%), 47 patients had possible IFD (49%), and 14 patients had undetermined IFD (15%).
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Aspergillus/aislamiento & purificación , Líquido del Lavado Bronquioalveolar/microbiología , Infecciones Fúngicas Invasoras/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Mucorales/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto , Anciano , Anciano de 80 o más Años , Aspergillus/genética , ADN de Hongos/genética , Humanos , Aspergilosis Pulmonar Invasiva/diagnóstico , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular/normas , Mucorales/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/normas , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Immunocompromised patients are at high risk of invasive fungal infections (IFI), in particular those with haematological malignancies undergoing remission-induction chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) and recipients of allogeneic haematopoietic stem cell transplants (HSCT). Despite the development of new treatment options in the past decades, IFI remains a concern due to substantial morbidity and mortality in these patient populations. In addition, the increasing use of new immune modulating drugs in cancer therapy has opened an entirely new spectrum of at risk periods. Since the last edition of antifungal prophylaxis recommendations of the German Society for Haematology and Medical Oncology in 2014, seven clinical trials regarding antifungal prophylaxis in patients with haematological malignancies have been published, comprising 1227 patients. This update assesses the impact of this additional evidence and effective revisions. Our key recommendations are the following: prophylaxis should be performed with posaconazole delayed release tablets during remission induction chemotherapy for AML and MDS (AI). Posaconazole iv can be used when the oral route is contraindicated or not feasible. Intravenous liposomal amphotericin B did not significantly decrease IFI rates in acute lymphoblastic leukaemia (ALL) patients during induction chemotherapy, and there is poor evidence to recommend it for prophylaxis in these patients (CI). Despite substantial risk of IFI, we cannot provide a stronger recommendation for these patients. There is poor evidence regarding voriconazole prophylaxis in patients with neutropenia (CII). Therapeutic drug monitoring TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of suspicious adverse events or of dose changes of interacting drugs (BIItu). General TDM during posaconazole prophylaxis is not recommended (CIItu), but may be helpful in cases of clinical failure such as breakthrough IFI for verification of compliance or absorption.
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Antifúngicos/uso terapéutico , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/prevención & control , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Prevención Primaria/métodos , Ensayos Clínicos como Asunto , Monitoreo de Drogas , Hematología , Trasplante de Células Madre Hematopoyéticas , Humanos , Quimioterapia de Inducción , Infecciones Fúngicas Invasoras/inmunología , Infecciones Fúngicas Invasoras/microbiología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Oncología Médica , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/patología , Sociedades Médicas , Triazoles/uso terapéutico , Voriconazol/uso terapéuticoAsunto(s)
Bacteriemia , COVID-19 , Cateterismo Venoso Central , Catéteres Venosos Centrales , Neoplasias Hematológicas , Sepsis , Humanos , Catéteres Venosos Centrales/efectos adversos , SARS-CoV-2 , Pandemias , Cateterismo Venoso Central/efectos adversos , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Bacteriemia/epidemiología , Bacteriemia/etiologíaRESUMEN
Background: CV-NCOV-005 was conducted to generate additional safety and immunogenicity data for the former CVnCoV SARS-CoV-2 mRNA vaccine candidate in healthcare workers (HCW). Methods: Randomised, observer blinded, placebo-controlled, phase 3 trial performed at the University Medical Center Mainz, Germany. HCWs aged ≥18 years with no history of SARS-CoV-2 infection/positive serology were randomly assigned to receive two doses of CVnCoV, or two doses of placebo (0.9% NaCl). The primary objectives were to expand the safety database of CVnCoV and assess antibody responses against SARS-CoV-2. Primary safety and reactogenicity outcomes included solicited adverse events (AEs) within 7 days after each dose and unsolicited AEs within 28 days after each dose, with safety follow-up for 13 months after first vaccination. Since HCWs became eligible to receive an authorised vaccine during enrolment and efficacy results from HERALD CVnCoV trial were made available on 30th of June 2021, this study was unblinded and converted to an open label design. Results: Most participants in the CVnCoV group reported at least one solicited AE, a relatively high number being Grade 3 (43.3% in CVnCoV group and 6.4% in placebo group). Most AEs were short in duration and did not affect vaccine compliance. The percentage of participants with unsolicited AEs up to 28 days after any dose was slightly higher in CVnCoV group (37.0%) compared with placebo group (31.2%). IgG binding antibodies against the receptor binding domain of the SARS-CoV-2 spike protein were observed after vaccination, with higher seroconversion rates and antibody levels after the second dose. Conclusion: No safety concerns for CVnCoV were identified up to 1 year post second dose. IgG responses against SARS-CoV-2 were observed after two doses, with a higher seroconversion rate and antibody levels observed after second vaccination.Study registration: ClinicalTrials.gov NCT04674189, study period: 23rd of December 2020 to 8th of June 2022.
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BACKGROUND: Current consensus recommends hematopoietic cell transplantation (HCT) for patients with myelofibrosis with intermediate or high-risk disease and age of less than 70 years. However, a higher chronological age should not be prohibitive for the eligibility decision in general, acknowledging that current life expectancy for the general population aged 70 years is â¼15 years, and current numbers of patients transplanted at 70 years or older is steadily increasing. OBJECTIVE: The following study aimed to evaluate characteristics and outcomes of HCT in 115 myelofibrosis patients aged 70 years or older. STUDY DESIGN: This is a retrospective multicenter study, using the German Registry for Stem Cell Transplantation and Cellular Therapy (DRST). Adult myelofibrosis patients were included who received HCT up until 2021. Patients with secondary leukemia were excluded. Main endpoints were HCT demographics over time and outcomes after HCT (including overall survival, relapse incidence, non-relapse mortality, and graft-versus-host disease/relapse-free survival). RESULTS: Numbers of HCT increased over the past decade, with a significant spike since 2019. Comorbidity status of transplanted patients improved over time, while reduced intensity conditioning was the preferred HCT platform especially in most recent years. The 3-year overall survival was 55% (95% confidence interval, 44-65%). The 1-year cumulative incidence of relapse was 7% (95% CI, 3-13%) and the 1-year cumulative incidence of non-relapse mortality was 22% (95% CI, 14-31%). The 3-year graft-versus-host disease and relapse-free survival was 37% (95% CI, 27-47%). Driver mutation genotype (in particular non-CALR/MPL genotype) appeared to be the only variable that was significantly and independently associated with better survival in multivariable analysis, whereas neither comorbidity index nor dose intensity of pre-transplant conditioning appeared to influence outcome. CONCLUSION: This study demonstrated feasibility of curative treatment with HCT for myelofibrosis aged 70 or older, with significant increases in HCT numbers and improved fitness of the elderly over recent years.
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OBJECTIVES: Efficacy and safety of letermovir as prophylaxis for clinically significant cytomegalovirus infections (csCVMi) was evaluated in randomised controlled trials while most of the real-world studies are single-centre experiences. METHODS: We performed a retrospective, multi-centre case-control study at six German university hospitals to evaluate clinical experiences in patients receiving CMV prophylaxis with letermovir (n = 200) compared to controls without CMV prophylaxis (n = 200) during a 48-week follow-up period after allogeneic hematopoietic cell transplantation (aHCT). RESULTS: The incidence of csCMVi after aHCT was significantly reduced in the letermovir (34%, n = 68) compared to the control group (56%, n = 112; p < 0.001). Letermovir as CMV prophylaxis (OR 0.362) was found to be the only independent variable associated with the prevention of csCMVi. Patients receiving letermovir showed significantly better survival compared to the control group (HR = 1.735, 95% CI: 1.111-2.712; p = 0.014). Of all csCMVi, 46% (n = 31) occurred after discontinuation of letermovir prophylaxis. Severe neutropenia (<500 neutrophils/µL) on the day of the stem cell infusion was the only independent variable for an increased risk of csCMVi after the end of letermovir prophylaxis. CONCLUSIONS: Our study highlights the preventive effects of letermovir on csCMVi after aHCT. A substantial proportion of patients developed a csCMVi after discontinuation of letermovir. In particular, patients with severe neutropenia require specific attention after drug discontinuation.
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Acetatos , Antivirales , Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Quinazolinas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , Infecciones por Citomegalovirus/prevención & control , Femenino , Persona de Mediana Edad , Quinazolinas/uso terapéutico , Estudios Retrospectivos , Antivirales/uso terapéutico , Adulto , Acetatos/uso terapéutico , Acetatos/administración & dosificación , Estudios de Casos y Controles , Anciano , Trasplante Homólogo/efectos adversos , Adulto Joven , Citomegalovirus , Adolescente , Alemania/epidemiología , IncidenciaRESUMEN
Tuberculosis (TB) is one of the leading causes of death by an infectious disease. It remains a major health burden worldwide, in part due to misdiagnosis. Therefore, improved diagnostic tests allowing the faster and more reliable diagnosis of patients with active TB are urgently needed. This prospective study examined the performance of the new molecular whole-blood test T-Track® TB, which relies on the combined evaluation of IFNG and CXCL10 mRNA levels, and compared it to that of the QuantiFERON®-TB Gold Plus (QFT-Plus) enzyme-linked immunosorbent assay (ELISA). Diagnostic accuracy and agreement analyses were conducted on the whole blood of 181 active TB patients and 163 non-TB controls. T-Track® TB presented sensitivity of 94.9% and specificity of 93.8% for the detection of active TB vs. non-TB controls. In comparison, the QFT-Plus ELISA showed sensitivity of 84.3%. The sensitivity of T-Track® TB was significantly higher (p < 0.001) than that of QFT-Plus. The overall agreement of T-Track® TB with QFT-Plus to diagnose active TB was 87.9%. Out of 21 samples with discordant results, 19 were correctly classified by T-Track® TB while misclassified by QFT-Plus (T-Track® TB-positive/QFT-Plus-negative), and two samples were misclassified by T-Track® TB while correctly classified by QFT-Plus (T-Track® TB-negative/QFT-Plus-positive). Our results demonstrate the excellent performance of the T-Track® TB molecular assay and its suitability to accurately detect TB infection and discriminate active TB patients from non-infected controls.
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Introduction: Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. Methods: We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells. Results: Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation. Discussion: Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease. Clinical trial registration: https://clinicaltrials.gov, identifier NCT02227641.