RESUMEN
BACKGROUND: Based on the new data from the primary analysis of the OPTIC (Optimizing Ponatinib Treatment in CP-CML) trial on dose optimization of ponatinib in patients with chronic phase (CP)-CML, the German consensus paper on ponatinib published in 2020 (Saussele S et al., Acta Haematol. 2020) has been updated in this addendum. SUMMARY: Focus is on the update of efficacy and safety of ponatinib, reflecting the new data set, as well as the update of the benefit-risk assessment and recommendations for ponatinib starting dose in CP-CML - provided that the decision to use ponatinib has already been made. Furthermore, based on OPTIC and additional empirical data, the expert panel collaborated to develop a decision tree for ponatinib dosing, specifically for intolerant and resistant patients. The recommendations on cardiovascular management have also been updated based on the most recent 2021 guidelines of the European Society of Cardiology (ESC) on cardiovascular disease prevention in clinical practice. KEY MESSAGES: The OPTIC data confirm the high efficacy of ponatinib in patients with CP-CML and provide the basis for individualized dose adjustment during the course of treatment.
RESUMEN
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.
Asunto(s)
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
Treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute leukemia (Ph+ ALL) has been revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Most patients with CML achieve long-term survival similar to individuals without CML due to treatment with TKIs not only in frontline but also in further lines of therapy. The third-generation TKI ponatinib has demonstrated efficacy in patients with refractory CML and Ph+ ALL. Ponatinib is currently the most potent TKI in this setting demonstrating activity against T315I mutant clones. However, ponatinib's safety data revealed a dose-dependent, increased risk of serious cardiovascular (CV) events. Guidance is needed to evaluate the benefit-risk profile of TKIs, such as ponatinib, and safety measures to prevent treatment-associated CV events. An expert panel of German hematologists and cardiologists summarize current evidence regarding ponatinib's efficacy and CV safety profile. We propose CV management strategies for patients who are candidates for ponatinib.
Asunto(s)
Antineoplásicos/uso terapéutico , Enfermedades Cardiovasculares/inducido químicamente , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Imidazoles/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridazinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/tratamiento farmacológico , Hiperlipidemias/complicaciones , Hiperlipidemias/tratamiento farmacológico , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Piridazinas/administración & dosificación , Piridazinas/efectos adversos , Medición de RiesgoRESUMEN
Invasive fungal diseases (IFD) are a primary cause of morbidity and mortality in patients with haematological malignancies. These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other Non-Aspergillus moulds are increasingly identified in case of documented IFD. For definite diagnosis of IFD, a combination of diagnostic tools have to be applied, including conventional mycological culture and non-conventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. Although varying widely in cancer patients, the risk of invasive fungal infection is highest in those with allogeneic stem cell transplantation and those with acute leukaemia and markedly lower in patients with solid cancer. Since the last edition of Diagnosis of Invasive Fungal Diseases recommendations of the German Society for Hematology and Oncology in 2012, integrated care pathways have been proposed for the management and therapy of IFDs with either a diagnostic driven strategy as opposed to a clinical or empirical driven strategy. This update discusses the impact of this additional evidence and effective revisions.
Asunto(s)
Infecciones Fúngicas Invasoras/diagnóstico , Antifúngicos/uso terapéutico , Hongos/genética , Hongos/aislamiento & purificación , Hongos/fisiología , Alemania , Hematología , Humanos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/microbiología , Oncología Médica , Guías de Práctica Clínica como AsuntoRESUMEN
Objectives: To prevent invasive fungal disease (IFD) in adult patients undergoing remission-induction chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL). Patients and methods: In a double-blind multicentre Phase 3 study, patients received prophylactic liposomal amphotericin B (L-AMB) at 5 mg/kg intravenously or placebo twice weekly in a 2:1 random allocation during remission-induction treatment. The primary endpoint was the development of proven or probable IFD. Secondary endpoints included those focused on the safety and tolerability of prophylactic L-AMB. Results: Three hundred and fifty-five patients from 86 centres in Europe and South America received at least one dose of L-AMB ( n = 237) or placebo ( n = 118). Rates of proven and probable IFD assessed independently were 7.9% (18/228) in the L-AMB group and 11.7% (13/111) in the placebo group ( P = 0.24). Rates of possible IFD were 4.8% (11/228) in the L-AMB and 5.4% (6/111) in the placebo group ( P = 0.82). The remission-induction phase was a median of 22 days for both groups. Overall mortality was similar between the groups: 7.2% (17/237) for L-AMB and 6.8% (8/118) for placebo ( P = 1.00). Hypokalaemia and creatinine increase were significantly more frequent with L-AMB. Conclusions: The IFD rate among adult patients undergoing remission-induction chemotherapy for newly diagnosed ALL was 11.7% in the placebo group, and was not significantly different in patients receiving L-AMB, suggesting that the L-AMB regimen studied is not effective as prophylaxis against IFD. The IFD rate appears higher than previously reported, warranting further investigation. Tolerability of L-AMB was what might be expected. Further studies are needed to determine the optimal antifungal strategy during remission-induction chemotherapy of ALL.
Asunto(s)
Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Quimioprevención/métodos , Infecciones Fúngicas Invasoras/prevención & control , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , América del Sur , Resultado del Tratamiento , Adulto JovenRESUMEN
Antifungal posaconazole prophylaxis for AML patients receiving induction chemotherapy has been routine at our centre since 2009. This retrospective study examined the feasibility and practicability of our prophylaxis guidelines in clinical practice. Data sets of 90 patients undergoing induction-chemotherapy for AML between 2011 and 2014 were evaluated regarding adherence to local guidelines for the administration of antifungal prophylaxis with posaconazole. 75.5% of the 90 patients received posaconazole prophylaxis. All but eight patients received the recommended dosage. A total of 77.95% on prophylaxis had serum galactomannan measured twice weekly. Contradicting our guidelines, 89.70% of patients received concomitant therapy with PPI. Overall, 16.17% of patients had prophylaxis discontinued and started empirical antifungal treatment in the absence of diagnostic criteria for IFI. The breakthrough IFI rate was 36.76% (proven, probable and possible) with 7.35% of infections being classified as proven or probable. Although limited by a small sample size, our study demonstrates the feasibility of local guidelines in a real life setting and outlines areas for improvement in both guidelines and clinical practice. We also highlight the importance of ensuring awareness of guidelines and raise questions about a uniform approach to antifungal prophylaxis in AML patients.
Asunto(s)
Antifúngicos/uso terapéutico , Adhesión a Directriz , Leucemia Mieloide Aguda/microbiología , Micosis/prevención & control , Adulto , Anciano , Antifúngicos/administración & dosificación , Femenino , Fluconazol/administración & dosificación , Fluconazol/uso terapéutico , Galactosa/análogos & derivados , Guías como Asunto , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Mananos/sangre , Persona de Mediana Edad , Profilaxis Pre-Exposición , Estudios Retrospectivos , Triazoles/administración & dosificación , Triazoles/uso terapéuticoRESUMEN
PURPOSE: BK-virus and JC-virus are the most common polyomaviridae associated with hemorrhagic cystitis in the allogeneic transplant setting. Hemorrhagic cystitis and symptomatic viruria caused by these viruses are a major cause of morbidity in patients undergoing allogeneic stem cell transplantation. METHODS: We performed a retrospective evaluation on a highly uniform study population of 73 patients receiving allogeneic stem cell transplantation. Patients were treated according to the FLAMSA-RIC-protocol, and were examined for the incidence of BK-/JC-viruria and late-onset BK-positive hemorrhagic cystitis within a two-year period. RESULTS: The occurrence of BK-viruria was correlated with published risk factors (acute GvHD, oral mucositis, donor type, conditioning, age, gender). Thirty patients (41 %) were found to excrete either BK-virus (n = 17), JC-virus (n = 3) or both (n = 10), of whom 18 patients (60 %) developed higher-grade hemorrhagic cystitis as opposed to none in the virus-negative control group. Higher grade GvHD (grade B-D) was more common in patients with viruria (p = 0.013) and also more common in patients with manifest hemorrhagic cystitis (p = 0.048). Similarly, oral mucositis was associated both with viruria (p = 0.014) and hemorrhagic cystitis (p = 0.005). Manifest cystitis but not viruria was significantly associated with male gender (p = 0.016). No significant correlation was found with age, conditioning with busulfane vs total body irradiation or related vs unrelated donor. CONCLUSIONS: Severe GvHD and oral mucositis are significantly associated with reactivation of polyomaviridae in the genitourinary-tract already at the level of asymptomatic viruria.
Asunto(s)
Virus BK , Cistitis , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Infecciones por Polyomavirus , Estomatitis/virología , Infecciones Tumorales por Virus , Adulto , Anciano , Cistitis/mortalidad , Cistitis/virología , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/virología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/mortalidad , Infecciones por Polyomavirus/virología , Estudios Retrospectivos , Infecciones Tumorales por Virus/mortalidad , Infecciones Tumorales por Virus/virología , Infecciones Urinarias , Orina/virología , Adulto JovenRESUMEN
BACKGROUND: In Germany, about 60% of all produced platelet concentrates (PCs) are apheresis PCs (APCs). Ongoing discussions on APC reimbursement and costs might lead to a potential shift in pooled PC (PPC)/APC production. Objective of this analysis was to build a comprehensive model from the societal perspective to evaluate consequences associated with shifts in platelet supply and demand. METHODS: Literature search, desktop researches on platelet supply and demand. Model calculations, time horizon one year: model input from the Paul-Ehrlich-Institute, data 2013. Base case: 19.2% of annual whole blood donations (WBDs) were used for production of 38.5% PPCs, decay of 46,218 PCs (8.0%). Scenarios calculated: variation in PPC proportion of 10-100%. RESULTS: Base case: during PPC production 41,957-83,913 red blood cell concentrates (RBCCs) are estimated to be lost, which corresponds to 1-2% of annual RBCCs in Germany. Scenarios were calculated for a production of 60-100% PPCs: loss is estimated to be 1.5-5.0% of annual RBCCs (65,430-218,099), decay 54,189-69,022 PCs (9.4-12.0%). CONCLUSION: Production of different blood components is interlinked and sensitive to unidimensional decisions. Increasing PPC proportion has negative impact on the RBCC production and on the antigen-matched APC donor pool. Completion of the model calculations to predict the optimal PPC/APC proportion would require evidence on the number of refractory patients, donor pool sizes, and incidences of diseases requiring platelet transfusions.
RESUMEN
Invasive fungal disease (IFD) is a feared complication in patients with hematological malignancies. In 2008, the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group (EORTC/MSG) published updated criteria for the diagnostic workup within clinical studies for immunosuppressed patients with suspected fungal infection. We applied these criteria in a routine clinical setting with regard to their feasibility for bedside practice at our institution in a 1-year period. One hundred seventy consecutive patients with a recent history of chemotherapy-induced neutropenia (n = 100) or allogeneic stem cell recipients (n = 70) who had received a CT scan of the chest in search of pulmonary IFD were examined. We analyzed all available radiological and microbiological data according to the EORTC/MSG criteria. The quality of images was good in 94.7%, microbiological diagnostics performed in 94.1% patients. Five patients had histopathologic-proven IFD, 18 patients were classified as "probable," 55 patients as "possible" IFD, and 92 patients did not fulfill any criteria ("no IFD"). Microbiology revealed suggestive findings in 29 patients. These were either galactomannan antigen (Gm-AG) in serum (n = 18) and/or broncho-alveolar lavage (BAL) (n = 5). CT scan showed pulmonary infiltrates in 106 patients; 78 were classified as typical for IPA, further discriminated by morphology and number of nodules, as well as additional signs (halo, air crescent, cavity). We observed a better overall survival in patients without infiltrates compared to those with any type of infiltrate (p = 0.042) and a trend toward favorable survival in patients who had micronodular lesions (p = 0.058). We also found a higher probability of Gm-AG positivity in the group of allogeneic stem cell transplantation (allo-SCT) patients (p = 0.001) and a trend toward an association of Gm-AG positivity and positive findings on CT (p = 0.054). The applicability of criteria was good, both with regard to radiological and mycological evidence and sufficient for the categorization of IFD according to EORTC/MSG in the clinical setting. However, our findings suggest that feasibility improves with stringency of mycological workup, which is reflected in the two subgroups. Radiology harvests by far more suggestive findings which can only partly be correlated with mycological evidence. Although feasible, whether the EORTC/MSG criteria are the appropriate tool for early identification of IFD remains open for discussion.
Asunto(s)
Micosis/tratamiento farmacológico , Adulto , Anciano , Antifúngicos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/tratamiento farmacológicoRESUMEN
We retrospectively compared the incidence of virus infections and outcome in the context of immune reconstitution in two different HLA-haploidentical transplantation (haplo-HSCT) settings. The first was a combined T-cell-replete and T-cell-deplete approach using antithymocyte globulin (ATG) prior to transplantation in patients with hematological diseases (cTCR/TCD group, 28 patients; median age 31 years). The second was a T-cell-replete (TCR) approach using high-dose posttransplantation cyclophosphamide (TCR/PTCY group, 27 patients; median age 43 years). The incidence of herpesvirus infection was markedly lower in the TCR/PTCY (22 %) than in the cTCR/TCD group (93 %). Recovery of CD4+ T cells on day +100 was faster in the TCR/PTCY group. CMV reactivation was 30 % in the TCR/PTCY compared to 57 % in the cTCR/TCD group, and control with antiviral treatment was superior after TCR/PTCY transplantation (100 vs 50 % cTCR/TCD). Twenty-five percent of the patients in the cTCR/TCD group but no patient in the TCR/PTCY group developed PTLD. While 1-year OS was not different (TCR/PTCY 59 % vs cTCR/TCD 39 %; p = 0.28), virus infection-related mortality (VIRM) was significantly lower after TCR/PTCY transplantation (1-year VIRM, 0 % TCR/PTCY vs 29 % cTCR/TCD; p = 0.009). On day +100, predictors of better OS were lymphocytes >300/µl, CD3+ T cells >200/µl, and CD4+ T cells >150/µl, whereas the application of steroids >1 mg/kg was correlated with worse outcome. Our results suggest that by presumably preserving antiviral immunity and allowing fast immune recovery of CD4+ T cells, the TCR approach using posttransplantation cyclophosphamide is well suited to handle the important issue of herpesvirus infection after haplo-HSCT.
Asunto(s)
Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones por Herpesviridae/epidemiología , Infecciones por Herpesviridae/inmunología , Recuperación de la Función/inmunología , Adolescente , Adulto , Linfocitos T CD4-Positivos/inmunología , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Haplotipos , Infecciones por Herpesviridae/diagnóstico , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Brentuximab Vedotin is an antibody - drug conjugate targeting CD30. We report a case of severe cytokine release syndrome (CRS) after administration of the first dose of Brentuximab Vedotin in a 64-yr-old patient with relapsed systemic anaplastic large cell lymphoma (sALCL). To our knowledge, this is the first case of CRS to Brentuximab Vedotin described in the literature. However, CRS to Brentuximab Vedotin might be underestimated, as the drug has not been tested in large phase III trials yet.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Citocinas/metabolismo , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Linfoma Anaplásico de Células Grandes/complicaciones , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Brentuximab Vedotina , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido/uso terapéutico , Humanos , Linfoma Anaplásico de Células Grandes/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Prednisolona/uso terapéutico , Inducción de Remisión , Síndrome , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
PURPOSE: Busulfan (BU) used as cytoreductive conditioning prior to hematopoietic stem cell transplantation (HSCT) is available as intravenous (IV) and oral (O) preparation. IV-BU has clinical advantages associated with relevant incremental costs. The aim was to determine the economic impact of IV-BU versus O-BU in adult HSCT recipients from a German health care providers' perspective. METHODS: A budget-impact model (BIM) including costs and risks for oral mucositis (OM), infection with OM, and hepatic sinusoidal obstruction syndrome (SOS) was developed. Model inputs are literature data comparing clinical effects of IV-BU versus O-BU and German cost data (conditioning therapy, treatment of OM, infections, SOS without/with multiorgan failure) from literature and tariff lists. RESULTS: Base case calculations resulted the following: total costs of adverse events were 86,434 with O-BU and 44,376 with IV-BU for ten patients each. Considering costs of adverse events and drugs, about 5840 for ten patients receiving IV-BU are saved. Sensitivity analyses were conducted in several ways. Cost savings range between 4910 and 12,640 per ten patients for all adverse events and 2070 or 1140 per ten patients considering SOS only. Drug treatment of SOS and treatment of multiorgan failure during severe SOS are major cost drivers. Worst case scenario calculations (assuming -25% risk of all adverse events for O-BU and +25% for IV-BU) yield up to 27,570 per ten patients with IV-BU. CONCLUSIONS: Considering costs of adverse events and drugs, IV-BU is the dominant alternative from a German providers' perspective. For more comprehensive economic evaluations, additional epidemiological data, evidence on clinical outcomes, patient-reported outcomes, and treatment patterns are needed.
Asunto(s)
Administración Intravenosa/economía , Busulfano/administración & dosificación , Busulfano/economía , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante/economía , Administración Oral , Adulto , Anciano , Busulfano/efectos adversos , Costos de los Medicamentos , Femenino , Alemania/epidemiología , Neoplasias Hematológicas/economía , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/economía , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Enfermedad Veno-Oclusiva Hepática/economía , Enfermedad Veno-Oclusiva Hepática/epidemiología , Humanos , Modelos Econométricos , Estomatitis/inducido químicamente , Estomatitis/economía , Estomatitis/epidemiología , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante HomólogoRESUMEN
Invasive fungal infections cause substantial morbidity and mortality in immunocompromised patients, particularly in those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. Difficulties in diagnosing invasive fungal infections and subsequent delays in treatment initiation lead to unfavourable outcomes and emphasise the importance of prophylaxis. Since the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology in 2009, results of 14 additional clinical studies have been published comprising 2,899 patients and initiating this update. Key recommendations for adult patients are as follows: Posaconazole remains the drug of choice during remission-induction chemotherapy in acute myeloid leukaemia, myelodysplastic syndrome and allogeneic haematopoietic stem cell transplantation with graft versus host disease (AI). In the pre-engraftment period of allogeneic transplantation, several antifungals are appropriate and can be recommended with equal strength: voriconazole (BI), micafungin (BI), fluconazole (BI) and posaconazole (BII). There is poor evidence regarding antifungal prophylaxis in the post-engraftment period of allogeneic haematopoietic stem cell transplantation if no steroids for treatment of graft versus host disease are required. Aerosolised liposomal amphotericin B inhalation in conjunction with fluconazole can be used in patients with prolonged neutropenia (BII).
Asunto(s)
Antifúngicos/uso terapéutico , Quimioprevención , Neoplasias Hematológicas/tratamiento farmacológico , Micosis/prevención & control , Guías de Práctica Clínica como Asunto , Prevención Primaria/normas , Adulto , Azoles/uso terapéutico , Quimioprevención/métodos , Quimioprevención/normas , Alemania , Humanos , Huésped Inmunocomprometido , Infecciones Oportunistas/prevención & control , Prevención Primaria/métodos , Sociedades Médicas/normasRESUMEN
The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
Asunto(s)
Antifúngicos/uso terapéutico , Micosis/tratamiento farmacológico , Neoplasias/complicaciones , Anfotericina B/administración & dosificación , Anfotericina B/efectos adversos , Anfotericina B/uso terapéutico , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Candidiasis Invasiva/tratamiento farmacológico , Candidiasis Invasiva/etiología , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Infecciones Relacionadas con Catéteres/prevención & control , Neutropenia Febril Inducida por Quimioterapia/complicaciones , Ensayos Clínicos como Asunto , Terapia Combinada , Monitoreo de Drogas , Quimioterapia Combinada , Equinocandinas/administración & dosificación , Equinocandinas/efectos adversos , Equinocandinas/uso terapéutico , Fungemia/tratamiento farmacológico , Fungemia/prevención & control , Humanos , Huésped Inmunocomprometido , Inmunoterapia , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/etiología , Aspergilosis Pulmonar Invasiva/cirugía , Micosis/etiología , Micosis/cirugía , Micosis/terapia , Terapia Recuperativa , Triazoles/administración & dosificación , Triazoles/efectos adversos , Triazoles/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Hydrophobic bile salts such as glycochenodeoxycholate (GCDC) accumulate in cholestatic liver disease and induce hepatocellular apoptosis, promoting profibrotic signalling. The tissue microenvironment is an integral player in cellular pathophysiology, but it is not routinely incorporated into laboratory studies. Tissue oxygen partial pressure (pO2) may be an underestimated component of the microenvironment: in the liver, a pO2 of 30-45 mmHg (approximately 6% O2) is physiological, because of predominant portal blood supply. It was the aim of this project to investigate the impact of physiological hypoxia (i.e. 6% O2) on hepatocellular function, namely, bile salt-induced apoptosis. METHODS: Human hepatoma cells (HepG2-Ntcp) and primary rat hepatocytes were cultured at standard laboratory (hyperoxic) conditions (21% O2) and at physiological hypoxia (6% O2) in parallel for 1-8 days to study hepatocellular apoptosis and activation of signalling pathways. Standard laboratory analyses were applied for bile salt uptake, caspase-3/-7 activity, western blotting and gene-array analysis. RESULTS: Culturing at physiological hypoxia protected both human and rat hepatocytes against GCDC-induced apoptosis: caspase-3/-7 activation was diminished by 3.1 ± 0.5-fold in human HepG2-Ntcp and completely abolished in primary rat hepatocytes. Bile salt uptake was unaffected. Induction of hypoxia-inducible factor-1α indicated adaption to physiological hypoxia. The MEK/ERK cascade was activated and anti-apoptotic mediators were induced: N-Myc down-regulated gene, gelsolin and carbonic anhydrase IX were upregulated 12.4-, 6.5- and 5.2-fold respectively. CONCLUSIONS: We conclude from these data that (i) physiological hypoxia protects hepatocytes from bile salt-induced apoptosis, (ii) tissue pO2 is a crucial, underestimated component of the microenvironment and should (iii) be considered when studying hepatocellular physiology in vitro.
Asunto(s)
Apoptosis/fisiología , Puntos de Control del Ciclo Celular/fisiología , Hipoxia de la Célula/fisiología , Hepatocitos/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Animales , Apoptosis/efectos de los fármacos , Ácidos y Sales Biliares/efectos adversos , Western Blotting , Puntos de Control del Ciclo Celular/efectos de los fármacos , Citometría de Flujo , Células Hep G2 , Humanos , Análisis por Micromatrices , Ratas , Transducción de Señal/fisiologíaRESUMEN
Since two large-scale, randomised studies on posaconazole prophylaxis have demonstrated a clear benefit for patients at high risk for contracting invasive fungal disease (IFD), posaconazole prophylaxis has been adopted as standard of care for this patient collective. Several years on from implementation at our institution, we wanted to evaluate its impact on the incidence and use of empirical antifungal therapy in a real-life setting. We analysed retrospectively incidence and severity of IFD in high-risk patients with prophylaxis, using a historical cohort as comparator. A total of 200 patients had either received the extended spectrum triazole posaconazole in prophylactic dosage of 200 mg tid or empirical antifungal therapy. Disease events were analysed by application of the revised EORTC/MSG definitions for IFD. Before posaconazole prophylaxis, we recorded 57/100 cases of IFD which was reduced to 28/100 with prophylaxis. The empirical use of antifungal drugs was reduced to 41% from 91% in the non-prophylaxis cohort. Furthermore, we observed a shift in the categorisation of IFD according to EORTC/MSG criteria. Our data suggest that posaconazole was effective in reducing the rate and probability of invasive fungal disease in high-risk patients.
Asunto(s)
Antifúngicos/uso terapéutico , Quimioprevención/métodos , Neoplasias Hematológicas/complicaciones , Micosis/epidemiología , Micosis/prevención & control , Triazoles/uso terapéutico , Adolescente , Adulto , Anciano , Femenino , Humanos , Huésped Inmunocomprometido , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
The novel coronavirus SARS-CoV-2 and the associated infectious disease COVID-19 pose a significant challenge to healthcare systems worldwide. Patients with cancer have been identified as a high-risk population for severe infections, rendering prophylaxis and treatment strategies for these patients particularly important. Rapidly evolving clinical research, resulting in the recent advent of various vaccines and therapeutic agents against COVID-19, offers new options to improve care and protection of cancer patients. However, ongoing epidemiological changes and rise of new virus variants require repeated revisions and adaptations of prophylaxis and treatment strategies to meet these new challenges. Therefore, this guideline provides an update on evidence-based recommendations with regard to vaccination, pharmacological prophylaxis and treatment of COVID-19 in cancer patients in light of the currently dominant omicron variants. It was developed by an expert panel of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) based on a critical review of the most recent available data.
Asunto(s)
COVID-19 , Enfermedades Transmisibles , Neoplasias , Humanos , COVID-19/prevención & control , COVID-19/complicaciones , SARS-CoV-2 , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Enfermedades Transmisibles/complicaciones , Enfermedades Transmisibles/tratamiento farmacológico , VacunaciónRESUMEN
Patients with cancer are at particular risk for infection but also have diminished vaccine responses, usually quantified by the level of specific antibodies. Nonetheless, vaccines are specifically recommended in this vulnerable patient group. Here, we discuss the cellular part of the vaccine response in patients with cancer. We summarize the experience with vaccines prior to and during the SARS-CoV-2 pandemic in different subgroups, and we discuss why, especially in patients with cancer, T cells may be the more reliable correlate of protection. Finally, we provide a brief outlook on options to improve the cellular response to vaccines.
RESUMEN
INTRODUCTION: In Germany, up to 75% of platelet concentrates (PCs) are administered to haematological and oncological patients. Only limited transparency exists on the characteristics of haematological/oncological patients receiving PC transfusions, treatment patterns, and guideline adherence in daily clinical routine care. This information would be key for managing platelet supply and optimal platelet usage strategies. This study aimed to analyse data from clinical routine transfusions to fill the aforementioned information gaps and to create an inventory as a blueprint for electronic data capturing systems that allow simplified, recurring analyses. METHODS: Prospective open-label, single-centre, observational study in a German tertiary teaching haematological/oncological setting. All inpatients who received any transfusion of PCs (pathogen-inactivated or conventional) in routine use over a period of 3 months (March 2015-May 2015) were consecutively included. Except for age (≥18 years), no exclusion criteria were applied. For guideline adherence, the Cross-Sectional Guidelines for Therapy with Blood Components and Plasma Derivatives - amended edition 2020 were used. An inventory blueprint was created through a narrative literature review and the data collected in this study. RESULTS: Ninety-four patients received 942 PCs. The mean (±SD) age was 54.6 (±13.9) years, 68% were male and 86% were diagnosed with a haematological disease. Thirteen patients received 42% of all transfused PCs. The mean ± SD number of transfused PC per patient was 10.81 ± 9.24. Five (0.5% per transfusion) minor adverse events were documented. Approximately 19% of PCs were not administered according to existing guidelines. The mean transfusion interval was 1.71 ± 1.1 days, and the mean increment was 12.62 ± 14.7 G/L. The inventory showed which platelet transfusion-specific data should be documented for answering questions in terms of quality, effectiveness, and management of PC transfusions. CONCLUSIONS: Platelet transfusions in a haematological/oncological setting are highly individual in terms of the total number of transfusions and transfusion intervals. The majority of all PC transfusions were given to only a small group of patients. Continuous, structured real-world data collection/evaluation and benchmarking with data from more centres seems essential in determining specific needs in this vulnerable patient group, assessing the quality of transfusion practices, determining effectiveness, and anticipating future demand for platelets and a sustainable blood supply. So far, not all relevant data are collected routinely. The advancing digitalization of health systems offers opportunities to collect and link data and thus make them more accessible and evaluable.
Asunto(s)
Neoplasias , Trombocitopenia , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/etiología , Neoplasias/terapia , Estudios Observacionales como Asunto , Transfusión de Plaquetas/efectos adversos , Estudios Prospectivos , Trombocitopenia/terapiaRESUMEN
BACKGROUND: Extensive sets of data are required to investigate the potential use of a therapeutic drug monitoring with individualization of dosage of the antimycotic compound caspofungin. The goal was to develop an improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for this aim. METHODS: Following protein precipitation, on-line solid phase extraction was performed for sample preparation. As the internal standard compound the veterinary drug tylosin was used. A standard validation protocol was applied. RESULTS: Good reproducibility and accuracy of the method were observed. On-line solid phase extraction resulted in a convenient work-flow and good robustness of the method. CONCLUSIONS: This improved LC-MS/MS method was found reliable and convenient. It can be suggested for further work on the clinical pharmacology of caspofungin in the setting of clinical research laboratories.