ABSTRACT Introduction: Infection is a major complication in patients with chronic lymphocytic leukemia (CLL). Newly diagnosed patients are at high risk of developing infection caused by encapsulated bacteria, such as Streptococcus pneumoniae and Haemophylus influenzae. Method and Results: However, once treatment is initiated, the spectrum of pathogens causing infection broadens, depending on the treatment regimens. With disease progression, cumulative immunosuppression occurs as a consequence of multiple treatment lines and the risk of infection further increases. On the other hand, the use of targeted therapies in the treatment of CLL have brought new risks of infection, with an increased incidence of invasive fungal diseases, particularly aspergillosis, in patients receiving Bruton kinase inhibitors. Conclusion: In this article, we review the epidemiology of infection in patients with CLL, taking into account the treatment regimen, and briefly discuss the management of infection.

ABSTRACT Introduction: Although several combination therapies for acute myeloid leukemia (AML) have emerged recently, there has been a lack of published surveys and educational projects focused on these important treatment options. We aimed to improve the oncology team members’ knowledge and awareness of several FDA approved combination therapies for AML, including glasdegib (DAURISMO®), venetoclax (VENCLEXTA®), GO (MYOLOTARG®),CPX-351 (VYXEOS®), and midostaurin (RYDAPT®). Additionally, we aimed to examine these teams’ perspectives, views, and attitudes towards these topics and finally identify barriers to the implementationof such therapies in clinical practice. Method: Initially, we developed booklets and then distributed them to each participating oncology and hematology office. Subsequently, all participating oncology and hematology team members were asked to complete an anonymous online survey to test their knowledge of and attitudes toward the subjects. Main results: There was a total of 52 survey respondents. The correct answer regarding various combination therapies for AML was identified by nearly 70% or more of survey takers. The level of awareness of project subjects significantly improved after reading our printing materials. Many survey respondents were motivated to learn more about combination therapies for AML as well as discuss these topics with others. Conclusions: Our booklets effectively improved understanding and awareness of combination therapies for AML. Future studies should explore awareness, knowledge, and perception of other new and emerging combination therapies for AML amongoncology and hematology team members in other areas.

Abstract Introduction Stewardship programs have been developed to optimize the use of antibiotics, but programs focusing on antifungal agents are less frequent. Objective To evaluate the quality of antifungal prescriptions in a tertiary care hospital, and to test if a simple educational activity could improve the quality of prescriptions. Methods The study comprised three phases: 1) Retrospective audit of all antifungal prescriptions in a 6-month period, applying a score based on six parameters: indication, drug, dosage, route of administration, microbiologic adequacy after results of cultures, switching to an oral agent, and duration of treatment; 2) Creation of text boxes in the electronic medical records with information about antifungal agents, shown during prescription; 3) Retrospective audit of all antifungal prescriptions in a 6-month period, applying the same 6-parameters score, and comparison between the two periods. Results Among 333 prescriptions, fluconazole was the most frequently (80.5%) prescribed agent. Hematology (26.7%), Infectious Diseases Department (22.8%), Internal Medicine (15.9%) and Intensive Care Unit (14.4%) were the units with most antifungal prescriptions. The median score for the 333 prescriptions was 8.0 (range 0 – 10), and 72.7% of prescriptions were considered inappropriate. The median and mean scores in the first and second audit were 8.0 and 6.9, and 8.0 and 7.9, respectively (p<0.001). All items that comprised the score improved from the first to the second audit. Likewise, there was a reduction of inappropriate prescriptions (80.2% in the first audit vs. 64.6% in the second audit, p=0.001). Conclusions A large proportion of inappropriate prescriptions was observed, which improved with the implementation of simple educational activities.

ABSTRACT Background: The impact of central venous catheter (CVC) removal on the outcome of patients with candidemia is controversial, with studies reporting discrepant results depending on the time of CVC removal (early or any time during the course of candidemia). Objective: Evaluate the effect of time to CVC removal, early (within 48 h from the diagnosis of candidemia) vs. removal at any time during the course of candidemia, on the 30-day mortality. Methods: Retrospective cohort study of 285 patients with candidemia analyzing CVC removal within 48 h (first analysis) or at any time (second analysis). Results: A CVC was in place in 212 patients and was removed in 148 (69.8%), either early (88 patients, 41.5%) or late (60 patients, 28.3%). Overall, the median time to CVC removal was one day (range 1-28) but was six days (range 3-28) for those removed later. In the first analysis, APACHE II score (odds ratio [OR] 1.111, 95% confidence interval [95% CI] 1.066-1.158), removal at any time (OR 0.079, 95% CI 0.021-0.298) and Candida parapsilosis infection (OR 0.291, 95% CI 0.133-0.638) were predictors of 30-day mortality. Early removal was not significant. In the second analysis APACHE II score (OR 1.122, 95% CI 1.071-1.175) and C. parapsilosis infection (OR 0.247, 95% CI 0.103-0.590) retained significance. Conclusions: The impact of CVC removal is dependent on whether the optimal analysis strategy is deployed and should be taken into consideration in future analyses.

ABSTRACT Background Candidemia is the most frequent invasive fungal disease in hospitalized patients, and is associated with high mortality rates. The main objective of this study was to evaluate changes in the epidemiology of candidemia at a tertiary care hospital in a 21-year period. Methods We evaluated all episodes of candidemia diagnosed between 1996 and 2016 at a University-affiliated tertiary care hospital in Brazil. We arbitrarily divided the study period in 3: 1996-2002 (period 1), 2003-2009 (period 2) and 2010-2016 (period 3). Incidence rates were calculated using hospital admissions as denominator. Results We observed 331 episodes of candidemia. The incidence was 1.30 episodes per 1000 admissions, with no significant change over time. Candida albicans (37.5%), C. tropicalis (28.1%), C. parapsilosis (18.4%) and C. glabrata (6.9%) were the most frequent species. The proportion of patients receiving treatment increased (65.5%, 79.4% and 74.7% in periods 1, 2 and 3, respectively, p= 0.04), and the median time from candidemia to treatment initiation decreased from 4 days in period 1 (range 0-32 days) to 2 days in period 2 (range 0-33 days) and 2 days in period 3 (range 0-14 days, p< 0.001). We observed a significant decrease in the use of deoxycholate amphotericin B (47.4%, 14.8% and 11.9%), and an increase in the use of echinocandins (0%, 2.8% and 49.1%; p< 0.001). The APACHE II score increased over time (median 16, 17.5, and 22, p< 0.001). The overall 30-day mortality was 58.9%, and did not change significantly over the study period. Conclusions There was an improvement in patient care, with an increase in the proportion of patients receiving treatment and a decrease in the time to treatment initiation, but no improvement in the outcome, possibly because the proportion of sicker patients increased over time.

Abstract Introduction Invasive mold disease is an important complication of patients with hematologic malignancies, and is associated with high mortality. A diagnostic-driven approach has been an alternative to the classical empiric antifungal therapy. In the present study we tested an algorithm that incorporated risk stratification using the D-index, serial serum galactomannan and computed tomographic-scan to guide the decision to start antifungal therapy in neutropenic patients. Patients and methods Between May 2010 and August 2012, patients with acute leukemia in induction remission were prospectively monitored from day 1 of chemotherapy until discharge or death with the D-index and galactomannan. Patients were stratified in low, intermediate and high risk according to the D-index and an extensive workup for invasive mold disease was performed in case of positive galactomannan (≥0.5), persistent fever, or the appearance of clinical manifestations suggestive of invasive mold disease. Results Among 29 patients, 6 (21%), 11 (38%), and 12 (41%) were classified as high, intermediate, and low risk, respectively. Workup for invasive mold disease was undertaken in 67%, 73% and 58% (p = 0.77) of patients in each risk category, respectively, and antifungal therapy was given to 67%, 54.5%, and 17% (p = 0.07). Proven or probable invasive mold disease was diagnosed in 67%, 45.5%, and in none (p = 0.007) of high, intermediate, and low risk patients, respectively. All patients survived. Conclusion A risk stratification using D-index was a useful instrument to be incorporated in invasive mold disease diagnostic approach, resulting in a more comprehensive antifungal treatment strategy, and to guide an earlier start of treatment in afebrile patients under very high risk.

Candida infections account for 80% of all fungal infections in the hospital environment, including bloodstream, urinary tract and surgical site infections. Bloodstream infections are now a major challenge for tertiary hospitals worldwide due to their high prevalence and mortality rates. The incidence of candidemia in tertiary public hospitals in Brazil is approximately 2.5 cases per 1000 hospital admissions. Due to the importance of this infection, the authors provide a review of the diversity of the genus Candida and its clinical relevance, the therapeutic options and discuss the treatment of major infections caused by Candida. Each topography is discussed with regard to epidemiological, clinical and laboratory diagnostic and therapeutic recommendations based on levels of evidence.

Invasive fungal disease represents a major complication in hematological patients. Antifungal agents are frequently used in hematologic patients for different purposes. In neutropenic patients, antifungal agents may be used as prophylaxis, as empiric or preemptive therapy, or to treat an invasive fungal disease that has been diagnosed. The hematologist must be familiar with the epidemiology, diagnostic tools and strategies of antifungal use, as well as the pharmacologic proprieties of the different antifungal agents. In this paper the principal antifungal agents used in hematologic patients will be discussed as will the clinical scenarios where these agents have been used.

OBJECTIVE: To evaluate the use of high-dose sequential chemotherapy in a Brazilian population. METHODS: High-dose cyclophosphamide followed by autologous hematopoietic stem cell transplantation is an effective and feasible therapy for refractory/relapsed lymphomas; this regimen has never before been evaluated in a Brazilian population. All patients (106 with high-grade non-Hodgkin lymphoma and 77 with Hodgkin's lymphoma) submitted to this treatment between 1998 and 2006 were analyzed. Chemotherapy consisted of the sequential administration of high-dose cyclophosphamide (4 or 7 g/m²) and granulocyte-colony stimulating factor (300 µg/day), followed by peripheral blood progenitor cell harvesting, administration of etoposide (2g/m²) and methotrexate (8 g/m² only for Hodgkin's lymphoma) and autologous hematopoietic stem cell transplantation. RESULTS: At diagnosis, non-Hodgkin lymphoma patients had a median age of 45 (range: 8-65) years old, 78% had diffuse large B-cell lymphoma and 83% had stage III/IV disease. The Hodgkin's lymphoma patients had a median age of 23 (range: 7-68) years old, 64.9% had the nodular sclerosis subtype and 65% had stage III/IV disease. Nine Hodgkin's lymphoma patients (13%) and 10 (9%) non-Hodgkin lymphoma patients had some kind of cardiac toxicity. The overall survival, disease-free survival and progression-free survival in Hodgkin's lymphoma were 29%, 59% and 26%, respectively. In non-Hodgkin lymphoma, these values were 40%, 49% and 31%, respectively. High-dose cyclophosphamide-related mortality was 10% for Hodgkin's lymphoma and 5% for non-Hodgkin lymphoma patients. High-dose cyclophosphamide dosing had no impact on toxicity or survival for both groups. CONCLUSIONS: Despite a greater prevalence of poor prognostic factors, our results are comparable to the literature. The incidence of secondary neoplasias is noteworthy. Our study suggests that this approach is efficient and feasible, regardless of toxicity-related mortality.

A infecção em receptores de transplante de células-tronco hematopoéticas (TCTH) está relacionada a altas taxas de morbidade e mortalidade. O tipo de transplante, a fonte de célula-tronco hematopoética, a utilização de doadores alternativos e outras medidas relacionadas ao procedimento influenciam diretamente no tipo e na intensidade da imunossupressão, modificando o risco de desenvolver uma infecção. Nesta seção são discutidas as estratégias para monitorização, diagnóstico e tratamento das infecções em receptores de TCTH em três fases: na fase pré-transplante, durante a fase de neutropenia, e na fase pós-pega do enxerto.

Infectious complications following stem cell transplantation are frequent and associated with high morbidity and mortality. Several factors related to the transplant procedure, such as type of transplant, the source of stem cells, the utilization of alternative donors are important determinants of the immune status of the host, and impact on the risk of infection. In this section we will discuss the different approaches for monitoring patients at risk and diagnosing and treating infectious complications in three time periods: before transplant, during neutropenia, and after engraftment.

Infecções são causas significantes de morbidade e podem levar à morte pacientes com MM. O impacto das estratégias terapêuticas sobre o sistema imunológico predispõe a várias infecções oportunistas e disfunções orgânicas que podem aumentar o risco de infecções. Estudo epidemiológico de infecções em pacientes com MM foi feito em seis centros brasileiros e um chileno. Foram observados 228 episódios de infecção (mediana 1; 1-13) em 156 pacientes durante um ano. A idade mediana foi 57 anos (33-89) e foram 112 pacientes masculinos. Estágio III de Durie-Salmon em 71% dos episódios. Os pacientes foram divididos em três fases de acordo com o tempo de ocorrência de infecção relacionado ao tratamento do mieloma: fase 1 - terapia de indução; fase 2 - durante transplante e fase 3 - terapia de manutenção ou recidiva. Fase 1 que ocorreu durante doença ativa e falência renal como fatores de risco; infecção do trato respiratório (46%) e infecção urinária (21%) ,foram os mais frequentes. Fase 2 ocorreu provavelmente devido a cateter central, neutropenia e mucosite; bacteremia (31%) e FOI (23%) foram os mais frequentes. Fase 3 ocorreu mais frequentemente em pacientes recebendo cortecosteroides; infecção do trato respiratório (44%) foi o mais frequente. As taxas de morte relacionado à infecção foram 14,5 na fase 1, 5% na fase 2 e 14% na fase 3 (NS). A introdução de terapêuticas que prolongam a vida tem transformado o MM em doença crônica. A imunossupressão acumulada tem aumentado o risco de infecção e elevado a amplitude de potencial de patógenos. Infecções continuam representando o maior desafio para os clínicos que cuidam de pacientes com MM.

Infections are significant causes of morbidity and the leading cause of death in patients with MM. Therapeutic strategies impact differently on the immune system, predisposing patients to various opportunistic infections. Myeloma and treatment-associated organ dysfunctions and co-morbidities also increase the risk of infection. Prospective epidemiologic studies of infections of myeloma patients from six centers from Brazil and one from Chile were performed. A total of 228 infectious episodes (median of 1; range: 1-13) were observed in 156 patients during one year. Median age was 57 years (range: 33-89), and 112 were men. Seventy-one percent of episodes occurred in Stage III (Durie-Salmon). Patients were divided into three phases according to the time of occurrence of infection related to the treatment of myeloma: phase 1 = induction therapy, phase 2 = during HCT and phase 3 = maintenance therapy or in relapse. Active myeloma and renal failure were risk factors in Phase 1; respiratory tract infections (46%) and urinary tract infections (21%) were the most frequent. In Phase 2, the risk factors were central venous catheters, neutropenia and mucositis; bacteremia (31%) and fever of unknown origin (23%) were the most frequent characteristics. Patients who were receiving corticosteroids were more probable to suffer infections in Phase 3 the most common being respiratory tract infections (44%). Rates of infectious-related death were 14.5% in phase 1, 5% in phase 2 and 14% in phase 3 (P=NS). The introduction of novel life-prolonging therapies has transformed myeloma into a chronic disease. Resulting cumulative immunosuppression has increased the risk of infection and expanded the spectrum of potential pathogens in this patient population. Infections continue to represent a major challenge for clinicians caring for myeloma patients.

O esquema de Durie / Salmon continua a ser utilizado para estadiar os pacientes com mieloma múltiplo. Recentemente, um novo sistema mais simples e eficaz foi proposto. O "International Myeloma Working Group" realizou um estudo retrospectivo com 11.179 pacientes e a partir destes dados propôs a criação de um "International Staging System (ISS)" utilizando os níveis séricos de ß2 microglobulina e de albumina ao diagnóstico. Além do ISS a pesquisa está voltada para identificar alterações citogenéticas e moleculares que se correlacionem com o prognóstico no mieloma múltiplo. Estes fatores prognósticos têm sido utilizados para estratificar pacientes em ensaios clínicos com resultados promissores.

The Durie/Salmon staging system continues to be used worldwide in patients with multiple myeloma. However, in recent years, new systems have been proposed. The International Myeloma Working Group performed a retrospective study with 11,179 patients and proposed an "International Staging System" utilizing serum levels of â2 microglobulin and albumin. In addition, current research has focused on the usefulness of cytogenetic and molecular data as prognostic factors. These data suggest that these parameters are powerful discriminators of a poor prognostic group of myeloma patients. Indeed, these prognostic indexes have been utilized in clinical trials, with interesting and encouraging results.

O fluxo salivar reduzido está associado a maior quantidade de Candida spp. na boca, predispondo a candidíase. O objetivo deste estudo foi comparar o efeito da estimulação salivar ao efeito do uso de bochechos de clorexidina sobre a intensidade de colonização por Candida em pacientes com fluxo salivar reduzido. Trinta e um pacientes de ambulatório foram aleatoriamente incluídos nos protocolos de estimulação salivar (grupo 1) ou de bochecho com clorexidina (grupo 2). As avaliações foram realizadas no dia inicial (T0), ao final do tratamento (T1) e 15 dias após o final do tratamento (T2). A cada consulta foram coletadas amostras de saliva total estimulada. O grupo 1 mostrou uma redução constante nas contagens medianas de UFC de Candida, embora a diferença estatística tenha sido apenas entre T0 e T2 (p = 0,004). O grupo 2 mostrou redução nas contagens de UFC de Candida entre T0 e T1 (p = 0,01), mas a contagem de UFC aumentou em T2 (p = 0,01), sendo a diferença entre T0 e T2 não significante (p = 0,8). Concluiu-se que os pacientes que realizaram procedimentos de estimulação salivar apresentaram a quantidade de UFC de Candida salivar reduzida, além de apresentarem tendência ao aumento do fluxo. O uso de bochechos de clorexidina reduziu drasticamente a quantidade de UFC de Candida salivar, mas após o final do tratamento houve novo aumento.

Low salivary flow rates are associated with higher oral Candida spp. counts, which may predispose to oral candidiasis. The aim of this study was to compare the effect of stimulating salivary flow rates with that of a regimen of chlorhexidine mouth rinse on the intensity of Candida colonization in patients with reduced salivary flow rates. Thirty-one outpatients were randomized to stimulate salivary output (group 1) or to receive chlorhexidine mouth rinses (group 2). Evaluations were performed at baseline (T0), at end of treatment (T1), and 15 days after last day of treatment (T2). Chewing-stimulated whole saliva samples were collected at each visit. Group 1 showed a constant reduction in median cfu counts, although the difference was significant only between T0 and T2 (p = 0.004). Group 2 showed a reduction in median Candida cfu counts between T0 and T1 (p = 0.01), but the counts increased at T2 (p = 0.01), and the difference between T0 and T2 was not significant (p = 0.8). In conclusion, patients who received salivary stimulation showed reductions of Candida cfu counts in saliva and a trend for increasing salivary flow rates between baseline and end of study evaluations. The use of chlorhexidine mouth rinses dramatically reduced Candida cfu counts, but when patients discontinued treatment, intensity of colonization rose again.

Infecção é a principal causa de óbito em pacientes com mieloma múltiplo (MM). Na última década ocorreram mudanças substanciais no espectro de infecções em pacientes com MM, relacionadas com as mudanças no tratamento, ocorridas neste período. Embora as bactérias (particularmente encapsuladas e Gram-negativas) continuem a ser os principais agentes etiológicos, infecções fúngicas invasivas causadas por fungos filamentosos (Aspergillus sp. e Fusarium sp.) têm sido relatadas com freqüência crescente. Enquanto o aumento na intensidade do tratamento do MM resultou em melhora na sobrevida, novos problemas infecciosos emergiram. Assim, uma abordagem prática às infecções em pacientes com MM deve incluir o reconhecimento dos patógenos prováveis, de acordo com vários fatores, como a história patológica pregressa, estado da doença de base, e tratamento atual e anterior para o MM. Estratégias específicas de diagnóstico, profilaxia e terapia empírica são direcionadas de acordo com esta abordagem.

Infection is the leading cause of death in patients with multiple myeloma. Over the past decade, significant chances have occurred in the spectrum of infections in patients with multiple myeloma, paralleling the changes in the treatment of the disease. Although bacteria (particularly encapsulated and Gram-negative organisms) remain the most frequent etiologic agents, invasive fungal infections caused by moulds (Aspergillus sp. and Fusarium sp.) have been increasingly reported. While the increase in the intensity of the treatment of multiple myeloma represents a major advance, with a positive impact on survival, new infectious problems have emerged. Therefore, a practical approach to infections in MM patients must include the recognition of the likely pathogens according to several factors, such as past medical history, status of the underlying disease, and past and current treatment for MM. Specific strategies of diagnosis, prophylaxis, and empiric and specific therapy are driven according to this approach.