RESUMO
A patient with gastrointestinal stroma tumor (GIST) and KIT p.V559D and BRAF p.G469A alterations was referred to our institutional molecular tumor board (MTB) to discuss therapeutic implications. The patient had been diagnosed with B-cell chronic lymphocytic leukemia (CLL) years prior to the MTB presentation. GIST had been diagnosed 1 month earlier. After structured clinical annotation of the molecular alterations and interdisciplinary discussion, we considered BRAF/KIT co-mutation unlikely in a treatment-naïve GIST. Discordant variant allele frequencies furthermore suggested a second malignancy. NGS of a CLL sample revealed the identical class 2 BRAF alteration, thus supporting admixture of CLL cells in the paragastric mass, leading to the detection of 2 alterations. Following the MTB recommendation, the patient received imatinib and had a radiographic response. Structured annotation and interdisciplinary discussion in specialized tumor boards facilitate the clinical management of complex molecular findings. Coexisting malignancies and clonal hematopoiesis warrant consideration in case of complex and uncommon molecular findings.
Assuntos
Tumores do Estroma Gastrointestinal , Mutação , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas c-kit , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/diagnóstico , Proteínas Proto-Oncogênicas c-kit/genética , Masculino , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/diagnóstico , Pessoa de Meia-IdadeRESUMO
The updated edition of the German, Austrian and Swiss Guidelines for Systemic Treatment of Gastric Cancer was completed in August 2023, incorporating new evidence that emerged after publication of the previous edition. It consists of a text-based "Diagnosis" part and a "Therapy" part including recommendations and treatment algorithms. The treatment part includes a comprehensive description regarding perioperative and palliative systemic therapy for gastric cancer and summarizes recommended standard of care for surgery and endoscopic resection. The guidelines are based on a literature search and evaluation by a multidisciplinary panel of experts nominated by the hematology and oncology scientific societies of the three involved countries.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/terapia , Áustria , OncologiaRESUMO
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.
Assuntos
Doenças Transmissíveis , Neoplasias Hematológicas , Hematologia , Infecções Fúngicas Invasivas , Humanos , Antifúngicos/uso terapêutico , Citocromo P-450 CYP3A , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/prevenção & controle , Infecções Fúngicas Invasivas/microbiologia , Doenças Transmissíveis/tratamento farmacológico , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Oncologia , Triazóis/uso terapêuticoRESUMO
A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.
Assuntos
Leucemia Mieloide Aguda , Mitoxantrona , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/efeitos adversos , Intervalo Livre de Doença , Leucemia Mieloide Aguda/tratamento farmacológico , Mitoxantrona/efeitos adversos , Prognóstico , Indução de RemissãoRESUMO
Mantle cell lymphoma (MCL) is a non-Hodgkin's lymphoma with an often aggressive course, incurable by chemotherapy. Consolidation with high-dose therapy and autologous stem cell transplantation (autoSCT) has a low transplant-related mortality but does not lead to a survival plateau. Allogeneic stem cell transplantation (alloSCT) is associated with a higher early mortality, but can cure MCL. To investigate alloSCT for therapy of MCL, we conducted two prospective trials for de novo MCL (OSHO#74) and for relapsed or refractory MCL (OSHO#60). Fifteen and 24 patients were recruited, respectively. Induction was mainly R-DHAP alternating with R-CHOP. Conditioning was either Busulfan/Cyclophosphamide or Treosulfan/Fludarabin. Either HLA-identical siblings or matched-unrelated donors with not more than one mismatch were allowed. ATG was mandatory in mismatched or unrelated transplantation. Progression-free survival (PFS) was 62% and overall survival (OS) was 68% after 16.5-year follow-up. Significant differences in PFS and OS between both trials were not observed. Patients below 56 years and patients after myeloablative conditioning had a better outcome compared to patients of the corresponding groups. Nine patients have died between day +8 and 5.9 years after SCT. Data from 7 long-term surviving patients showed an excellent Quality-of-life (QoL) after alloSCT. AlloSCT for MCL delivers excellent long-term survival data. The early mortality is higher than after autoSCT; however, the survival curves after alloSCT indicate the curative potential of this therapy. AlloSCT is a standard of care for all feasible patients with refractory or relapsed MCL and should offer to selected patients with de novo MCL and a poor risk profile. For defining the position of alloSCT in the therapeutic algorithm of MCL therapy, a randomized comparison of autoSCT and alloSCT is mandatory.
Assuntos
Linfoma de Célula do Manto/terapia , Transplante de Células-Tronco , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Alemanha/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Humanos , Linfoma de Célula do Manto/epidemiologia , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Estudos Prospectivos , Qualidade de Vida , Rituximab/uso terapêutico , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Vincristina/uso terapêuticoRESUMO
To ensure the safety of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT), evidence-based recommendations on infectious complications after HDC/ASCT are given. This guideline not only focuses on patients with haematological malignancies but also addresses the specifics of HDC/ASCT patients with solid tumours or autoimmune disorders. In addition to HBV and HCV, HEV screening is nowadays mandatory prior to ASCT. For patients with HBs antigen and/or anti-HBc antibody positivity, HBV nucleic acid testing is strongly recommended for 6 months after HDC/ASCT or for the duration of a respective maintenance therapy. Prevention of VZV reactivation by vaccination is strongly recommended. Cotrimoxazole for the prevention of Pneumocystis jirovecii is supported. Invasive fungal diseases are less frequent after HDC/ASCT, therefore, primary systemic antifungal prophylaxis is not recommended. Data do not support a benefit of protective room ventilation e.g. HEPA filtration. Thus, AGIHO only supports this technique with marginal strength. Fluoroquinolone prophylaxis is recommended to prevent bacterial infections, although a survival advantage has not been demonstrated.
Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Hepacivirus/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/prevenção & controle , Hepatite C/prevenção & controle , Pneumocystis carinii/metabolismo , Pneumonia por Pneumocystis/prevenção & controle , Alemanha , Hematologia , Hepatite B/sangue , Anticorpos Anti-Hepatite B/sangue , Hepatite C/sangue , Humanos , Oncologia , Pneumonia por Pneumocystis/sangue , Guias de Prática Clínica como Assunto , RNA Viral/sangue , Sociedades Médicas , Transplante Autólogo , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
Hematologic and oncologic patients with chemo- or immunotherapy-related immunosuppression are at substantial risk for bacterial infections and Pneumocystis jirovecii pneumonia (PcP). As bacterial resistances are increasing worldwide and new research reshapes our understanding of the interactions between the human host and bacterial commensals, administration of antibacterial prophylaxis has become a matter of discussion. This guideline constitutes an update of the 2013 published guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). It gives an overview about current strategies for antibacterial prophylaxis in cancer patients while taking into account the impact of antibacterial prophylaxis on the human microbiome and resistance development. Current literature published from January 2012 to August 2020 was searched and evidence-based recommendations were developed by an expert panel. All recommendations were discussed and approved in a consensus conference of the AGIHO prior to publication. As a result, we present a comprehensive update and extension of our guideline for antibacterial and PcP prophylaxis in cancer patients.
Assuntos
Antibacterianos/uso terapêutico , Neoplasias Hematológicas/complicações , Pneumocystis carinii/efeitos dos fármacos , Pneumonia por Pneumocystis/prevenção & controle , Antineoplásicos/uso terapêutico , Farmacorresistência Bacteriana , Fluoroquinolonas/uso terapêutico , Alemanha , Neoplasias Hematológicas/tratamento farmacológico , Hematologia , Humanos , Oncologia , Microbiota/efeitos dos fármacos , Pneumonia por Pneumocystis/complicações , Sociedades MédicasRESUMO
Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17-85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4-16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8-48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5-31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha/epidemiologia , Humanos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
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.
Assuntos
Antifúngicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Hematologia/organização & administração , Infecções Fúngicas Invasivas/tratamento farmacológico , Neoplasias/complicações , Guias de Prática Clínica como Assunto , Agranulocitose/complicações , Agranulocitose/microbiologia , Neoplasias Hematológicas/complicações , Hematologia/métodos , Humanos , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/etiologia , Neoplasias/microbiologiaRESUMO
Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fluordesoxiglucose F18/administração & dosagem , Linfoma de Células B , Tomografia por Emissão de Pósitrons , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
BACKGROUND: The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. METHODS: In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8â×âeBEACOPP in total) or eBEACOPP with rituximab (8â×âR-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8â×âeBEACOPP) or experimental treatment with two additional cycles (4â×âeBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6â×âeBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6â×âeBEACOPP and patients with negative PET-2 were randomly assigned to 6â×âeBEACOPP (standard) or 4â×âeBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554. FINDINGS: Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8â×âeBEACOPP or 6â×âeBEACOPP (n=504) or 4â×âeBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4â×âeBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8â×âeBEACOPP or 6â×âeBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8â×âeBEACOPP group, three [1%] in the 8â×âR-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8â×âeBEACOPP or 6â×âeBEACOPP group). INTERPRETATION: The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkin's lymphoma. FUNDING: Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Áustria , Bleomicina/uso terapêutico , Ciclofosfamida/uso terapêutico , República Tcheca , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Alemanha , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos , Tomografia por Emissão de Pósitrons , Prednisona/uso terapêutico , Procarbazina/uso terapêutico , Rituximab/administração & dosagem , Suíça , Resultado do Tratamento , Vincristina/uso terapêutico , Adulto JovemRESUMO
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.
Assuntos
Antifúngicos/uso terapêutico , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/prevenção & controle , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Prevenção Primária/métodos , Ensaios Clínicos como Assunto , Monitoramento de Medicamentos , Hematologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Quimioterapia de Indução , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/microbiologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Oncologia , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Sociedades Médicas , Triazóis/uso terapêutico , Voriconazol/uso terapêuticoRESUMO
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.
Assuntos
Infecções Fúngicas Invasivas/diagnóstico , Antifúngicos/uso terapêutico , Fungos/genética , Fungos/isolamento & purificação , Fungos/fisiologia , Alemanha , Hematologia , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Oncologia , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPescalated) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. METHODS: In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPescalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated (BEACOPPescalated group) or BEACOPPescalated plus rituximab (R-BEACOPPescalated group). PET-2 was assessed using a 5-point scale with 18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. FINDINGS: Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPescalated group (n=220) or the R-BEACOPPescalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPPescalated group and 93·0% (89·4-96·6) for those in the R-BEACOPPescalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPPescalated group vs 211 [96%] of 220 patients in the R-BEACOPPescalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPPescalated group and ten (5%) of 220 in the R-BEACOPPescalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalated group and three (1%) in the R-BEACOPPescalated group, all of them due to infection. INTERPRETATION: The addition of rituximab to BEACOPPescalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. FUNDING: Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/mortalidade , Recidiva Local de Neoplasia/mortalidade , Tomografia por Emissão de Pósitrons/métodos , Adulto , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Procarbazina/administração & dosagem , Prognóstico , Rituximab/administração & dosagem , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
ß-Lactam/ß-lactamase inhibitors (BLBLIs) were compared to carbapenems in two cohorts of hematological neutropenic patients with extended-spectrum-ß-lactamase (ESBL) bloodstream infection (BSI): the empirical therapy cohort (174 patients) and the definitive therapy cohort (251 patients). The 30-day case fatality rates and other secondary outcomes were similar in the two therapy groups of the two cohorts and also in the propensity-matched cohorts. BLBLIs might be carbapenem-sparing alternatives for the treatment of BSI due to ESBLs in these patients.
Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Infecções por Enterobacteriaceae/tratamento farmacológico , Enterobacteriaceae/efeitos dos fármacos , Neutropenia/complicações , Inibidores de beta-Lactamases/uso terapêutico , Adulto , Bacteriemia/complicações , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Carbapenêmicos/uso terapêutico , Estudos de Coortes , Enterobacteriaceae/enzimologia , Infecções por Enterobacteriaceae/complicações , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , beta-Lactamases/metabolismo , beta-Lactamas/uso terapêuticoRESUMO
We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86·2% vs. 84·3%). Further follow-up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow-up, 55·5 months); median progression-free survival (PFS) was 35·3 months and median overall survival (OS) was not reached. In patients with high-risk versus standard-risk cytogenetics, median PFS was 19·9 vs. 43·6 months (P < 0·0001), and median OS was 54·7 months versus not reached (P = 0·0022). VCD is an effective and tolerable induction regimen; results suggest that VCD induces high response rates independently of cytogenetic risk status, but after long-term follow-up, cytogenetic high risk is associated with markedly reduced PFS and OS post-ASCT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Indução/métodos , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Quimioterapia de Consolidação , Ciclofosfamida/administração & dosagem , Citogenética , Dexametasona/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Medição de Risco/métodos , Transplante de Células-Tronco , Análise de Sobrevida , Transplante Autólogo , Adulto JovemRESUMO
BACKGROUND: Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome. METHODS: This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II-IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II-IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222. FINDINGS: Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3-not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3.9 years [3.2-4.4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups. INTERPRETATION: Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma. FUNDING: European Commission, Lymphoma Research Foundation, and Roche.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/administração & dosagem , Linfoma de Célula do Manto/terapia , Adulto , Terapia Combinada , Ciclofosfamida/uso terapêutico , Citarabina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunoterapia , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Condicionamento Pré-Transplante , Falha de Tratamento , Vincristina/uso terapêuticoRESUMO
Bcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-line FL patients who were consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab (B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. From April 2005 to August 2008, 783 pre- and posttreatment PB samples were quantified by quantitative PCR. At inclusion, 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/IgH. High pretreatment Bcl-2/IgH levels had an adverse effect on progression-free survival (PFS) compared with intermediate or low levels (high vs intermediate: hazard [HR], 4.28; 95% confidence interval [CI], 1.70-10.77; P = .002; high vs low: HR, 3.02; 95% CI, 1.55-5.86; P = .001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive posttreatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs not reached; HR, 3.15; 95% CI, 1.51-6.58; P = .002). By multivariate analysis, the pretreatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and posttreatment Bcl-2/IgH levels from PB have significant prognostic value for PFS in FL patients receiving first-line immunochemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT00991211 and at the German Federal Institute for Drugs and Medical Devices as #BfArM-4021335.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/sangue , Linfoma Folicular/tratamento farmacológico , Proteínas de Fusão Oncogênica/sangue , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Prognóstico , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Vincristina/administração & dosagem , Vincristina/uso terapêuticoRESUMO
We report on a multidisciplinary management of a 68-year-old AML patient presenting with a PET-positive mediastinal tumour typical for lymph node metastasis. It was removed via minimally invasive thoracoscopic intervention and was identified as a thymus residual infiltrated by AML. Follow-up PET-CT scan after resection and remission induction chemotherapy was completely normal. To our knowledge, this is the first documented case report of AML presenting with PET-positive infiltrates of thymic and lymph node tissue along the aortic bow mimicking a second intrathoracic malignancy. Our observation indicates the usefulness of this imaging technique and supports clarification of these unusual findings in AML patients, in case of need also by invasive diagnostic procedures, to enable an adequate therapeutic decision.
Assuntos
Fluordesoxiglucose F18 , Leucemia Mieloide Aguda/diagnóstico por imagem , Leucemia Mieloide Aguda/patologia , Linfonodos/patologia , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Timo/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diagnóstico Diferencial , Transplante de Células-Tronco Hematopoéticas , Humanos , Biópsia Guiada por Imagem , Leucemia Mieloide Aguda/terapia , Masculino , Transplante Homólogo , Resultado do TratamentoRESUMO
Pulmonary complications affect up to 40% of patients with severe neutropenia lasting for more than 10 d. As they are frequently associated with fever and elevation of C-reactive protein or other signs of inflammation, they are mostly handled as pneumonia. However, the differential diagnosis is broad, and a causative microbial agent remains undetected in the majority of cases. Pulmonary side effects from cytotoxic treatment or pulmonary involvement by the underlying malignancy must always be taken into account and may provide grounds for invasive diagnostic procedures in selected patients. Pneumocystis jirovecii (in patients not receiving co-trimoxazole as prophylaxis), multi-resistant gram-negative bacilli, mycobacteria or respiratory viruses may be involved. High-risk patients may be infected by filamentous fungi, such as Aspergillus spp., but these infections are seldom proven when treatment is initiated. Microorganisms isolated from cultures of blood, bronchoalveolar lavage or respiratory secretions need careful interpretation as they may be irrelevant for determining the aetiology of pulmonary infiltrates, particularly when cultures yield coagulase-negative staphylococci, enterococci or Candida species. Non-culture based diagnostics for detecting Aspergillus galactomannan, beta-D-glucan or DNA from blood, bronchoalveolar lavage or tissue samples can facilitate the diagnosis, but must always be interpreted in the context of clinical and imaging findings. Systemic antifungal treatment with mould-active agents, given in combination with broad-spectrum antibiotics, improves clinical outcome when given pre-emptively. Co-trimoxazole remains the first-line treatment for Pneumocystis pneumonia, while cytomegalovirus pneumonia will respond to ganciclovir or foscarnet in most cases. The clinical outcome of acute respiratory failure can also be successful with proper intensive care, when indicated.