Patients' preferences for chronic lymphocytic leukemia treatment: The CHOICE study.

Chronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio-demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W&W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage). Health-related quality of life was assessed with the EQ-5D-5L, EORTC QLQ-C30 and QLQ CLL-16. Previously treated patients had longer disease duration (7 vs. 5 years), higher prevalence of serious comorbidities (45.5% vs. 36.2%) and high-risk molecular markers (unmutated IGHV 55.6% vs. 17.1%; TP53 mutation 15.2% vs. 4.0%). Health-related quality of life scores were similar between groups. In the DCE, W&W patients rated "possible occurrence of infections" highest (relative importance [RI] = 36.2%), followed by "treatment and relevant duration" (RI = 28.0%) and "progression-free survival (PFS)" (RI = 16.9%). Previously treated patients rated "treatment and relevant duration" highest (RI = 33.3%), followed by "possible occurrence of infections" (RI = 28.8%), "possible occurrence of organ damage" (RI = 19.4%), and "PFS" (RI = 9.8%). Concern over infection was rated highest overall; unexpectedly PFS was not among the most important criteria in either group, suggesting that the first COVID-19 pandemic wave may have influenced patient preferences and concerns about CLL therapy options.

Real-world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience.

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. In Italy, venetoclax was approved for use in patients with CLL as monotherapy in 2017 and in combinations in 2019. As a result of this delayed approval, there are relatively few real-world studies from Italian clinical practice and much of the data are in heavily pretreated patients. We have collected the available studies in Italian routine practice. Three studies confirm the effectiveness and tolerability of this agent in patients with relapsed/refractory CLL and high-risk disease characteristics, many of whom had received prior B-cell receptor signaling treatment. Addition of rituximab to venetoclax produced more complete responses in patients with relapsed/refractory CLL, while higher disease burden and progression while receiving a prior Bruton's tyrosine kinase inhibitor were both associated with poorer outcomes in patients treated with venetoclax. Venetoclax was well-tolerated with low discontinuation rates. No studies of venetoclax plus obinutuzumab for the first-line treatment of patients with CLL were available due to the short time since approval in Italy. Several cohorts addressed the impact of COVID-19 on patient management and outcomes, suggesting that treated patients and those in clinical observation had similar rates of COVID-19-related hospital admission, intensive care unit admission, and mortality. Overall, the responses and tolerance to venetoclax observed in the Italian real-world setting confirm the tolerability and effectiveness of venetoclax regimens in high-risk patients.

Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation.

BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P=0.003) and the confirmation study (adjusted odds ratio, 2.78; P=0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT. (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others.).

Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study).

Correct definition of the level of risk of invasive fungal infections is the first step in improving the targeting of preventive strategies. We investigated the potential relationship between pre-hospitalization exposure to sources of fungi and the development of invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia after their first course of chemotherapy. From January 2010 to April 2012, all consecutive acute myeloid leukemia patients in 33 Italian centers were prospectively registered. Upon first admission, information about possible pre-chemotherapy risk factors and environmental exposure was collected. We recorded data regarding comorbid conditions, employment, hygienic habits, working and living environment, personal habits, hobbies, and pets. All invasive fungal infections occurring within 30 days after the first course of chemotherapy were recorded. Of the 1,192 patients enrolled in this study, 881 received intensive chemotherapy and were included in the present analysis. Of these, 214 developed an invasive fungal infection, including 77 proven/probable cases (8.7%). Of these 77 cases, 54 were proven/probable invasive mold infections (6.1%) and 23 were proven yeast infections (2.6%). Upon univariate analysis, a significant association was found between invasive mold infections and age, performance status, diabetes, chronic obstructive pulmonary disease, smoking, cocaine use, job, hobbies, and a recent house renovation. Higher body weight resulted in a reduced risk of invasive mold infections. Multivariate analysis confirmed the role of performance status, job, body weight, chronic obstructive pulmonary disease, and house renovation. In conclusion, several hospital-independent variables could potentially influence the onset of invasive mold infections in patients with acute myeloid leukemia. Investigation of these factors upon first admission may help to define a patient's risk category and improve targeted prophylactic strategies. (Clinicaltrial.gov: NCT01315925)

Systemic antifungal treatment after posaconazole prophylaxis: results from the SEIFEM 2010-C survey.

OBJECTIVES: To investigate the incidence, treatment and outcome of breakthrough invasive fungal infections (IFIs) in adult acute myeloid leukaemia (AML) patients after posaconazole prophylaxis. METHODS: From January 2010 to April 2012, all consecutive patients with newly diagnosed AML were prospectively registered at 33 participating Italian centres. All cases of IFIs occurring within 30 days after the end of the first induction chemotherapy were recorded. The strategy of antifungal treatment (empirical, pre-emptive or targeted) and the drugs used were analysed. ClinicalTrials.gov code: NCT01315925. RESULTS: In total, 1192 patients with newly diagnosed AML were enrolled in the study, of whom 510 received posaconazole prophylaxis and were included in the present analysis. Of these patients, 140 (27%) needed systemic antifungal treatment. Among the 127 evaluable cases, an empirical approach was utilized in 102 patients (80%), a pre-emptive approach in 19 patients (15%) and targeted therapy in 6 patients (5%). Only five patients died of IFIs (three in the empirical group and two in the targeted group; 4%). A critical review of IFI diagnoses at 30 days demonstrated that among the patients treated empirically, ∼30% were not affected by IFIs but rather only by fever of unidentified origin. A comparison between the empirical and the pre-emptive groups showed no significant differences regarding the attributable and overall mortalities. CONCLUSIONS: This study confirms that posaconazole prophylaxis reduces the incidence of breakthrough IFIs and does not modify the efficacy of subsequent systemic antifungal treatment, regardless of the approach (empirical or pre-emptive) or the antifungal drug used.

A prospective, multicentre survey on antifungal therapy in neutropenic paediatric haematology patients.

Invasive fungal infections are a frequent complication after intensive chemotherapy. The aims of this prospective study were to describe the use of antifungal therapy and to report which strategy was routinely adopted to guide the introduction of antifungal therapy. A total of 321 febrile episodes in 160 paediatric patients affected by acute leukaemia or non-Hodgkin-lymphoma were investigated. Antifungal therapy was used in 100 of 321 febrile episodes (31%), and classified as empiric in 73 episodes, diagnostic-driven in 25 episodes and targeted in 2 episodes. Switching to a second-line antifungal therapy was needed in 28 of 100 episodes (28%) and was classified as empiric in 10 episodes (36%), diagnostic-driven in 17 episodes (61%) and targeted in 1 episode (4%). In 9 of 28 episodes (32%), switching to a third-line antifungal therapy was performed and was classified as empiric in 2 episodes (22%), diagnostic-driven in 6 episodes (67%) and targeted in 1 episode (11%). Invasive fungal infections was reported in 23 of 100 episodes: confirmed in 4 episodes, probable in 8 episodes, and possible in 11 episodes. Attributable mortality was 2.8%. Antifungal therapy was still used mostly empirically, whereas as fever persisted, its modification was guided by a diagnostic-driven approach.

Assessing eligibility for treatment in acute myeloid leukemia in 2023.

INTRODUCTION: Age has historically been considered the main criterion to determine eligibility for intensive chemotherapy in patients with acute myeloid leukemia (AML), but age alone can no longer be considered an absolute indicator in determining which patients should be defined as unfit. Assessment of fitness for a given treatment today serves an important role in tailoring therapeutic options. AREAS COVERED: This review examines the main options used in real life to define eligibility for intensive and nonintensive chemotherapy in patients with AML, with a main focus on the Italian SIE/SIES/GITMO Consensus Criteria. Other published real-life experiences are also reviewed, analyzing the correlation between these criteria and short-term mortality, and thus expected outcomes. EXPERT OPINION: Assessment of fitness is mandatory at diagnosis to tailor treatment to the greatest degree possible, evaluating the patient's individual profile. This is especially relevant when considering the availability of newer, less toxic therapeutic regimens, which have shown promising results in patients with AML who are older or considered unfit for intensive treatment. Fitness assessment is now a fundamental part of AML management and a critical step that can potentially influence outcomes and not just predict them.

In patients with acute myeloid leukemia (AML), age has generally been considered as the main factor to determine if intensive chemotherapy can be carried out (fitness). However, this has been gradually changing in recent years. In addition to age, comorbidities and overall performance status are also important in determining if the patient should undergo intensive chemotherapy and have an important role in tailoring therapeutic options. Consensus criteria to define eligibility for intensive and nonintensive chemotherapy in patients with AML have been proposed, which have been shown to correlate well with expected outcomes. Today, given the evolution of the treatment armamentarium, assessment of a patient's 'fitness' is compulsory to select the most appropriate treatment for each patient.

Evaluation of the practice of antifungal prophylaxis use in patients with newly diagnosed acute myeloid leukemia: results from the SEIFEM 2010-B registry.

BACKGROUND: To analyze the efficacy of antifungal prophylaxis (AFP) with posaconazole and itraconazole in a real-life setting of patients with acute myeloid leukemia (AML) during the first induction of remission. METHODS: From January 2010 to June 2011, all patients with newly diagnosed AML were consecutively registered and prospectively monitored at 30 Italian hematological centers. Our analysis focused on adult patients who received intensive chemotherapy and a mold-active AFP for at least 5 days. To determine the efficacy of prophylaxis, invasive fungal disease (IFD) incidence, IFD-attributable mortality, and overall survival were evaluated. RESULTS: In total, 515 patients were included in the present analysis. Posaconazole was the most frequently prescribed drug (260 patients [50%]) followed by fluconazole (148 [29%]) and itraconazole (93 [18%]). When comparing the groups taking posaconazole and itraconazole, there were no significant differences in the baseline clinical characteristics, whereas there were significant differences in the percentage of breakthrough IFDs (18.9% with posaconazole and 38.7% with itraconazole, P< .001). The same trend was observed when only proven/probable mold infections were considered (posaconazole, 2.7% vs itraconazole, 10.7%, P= .02). There were no significant differences in the IFD-associated mortality rate, while posaconazole prophylaxis had a significant impact on overall survival at day 90 (P= .002). CONCLUSIONS: During the last years, the use of posaconazole prophylaxis in high-risk patients has significantly increased. Although our study was not randomized, it demonstrates in a real-life setting that posaconazole prophylaxis confers an advantage in terms of both breakthrough IFDs and overall survival compared to itraconazole prophylaxis. CLINICAL TRIALS REGISTRATION: NCT01315925.

Risks for infection in patients with myelodysplasia and acute leukemia.

PURPOSE OF REVIEW: The aim of the present review is to analyze the main parameters that may influence the onset of bacterial, fungal and viral infections in patients with myelodysplastic syndromes, acute myeloid leukemia and acute lymphoid leukemia. RECENT FINDINGS: The identification of factors influencing the onset of infections in high-risk patients is becoming one of the most important strategies to identify those patients who would really benefit from prophylactic and timely treatment. During the past few years several studies have been conducted to evaluate the impact of risk factors that may influence both the onset and the outcome of infections. The role of some of them is well defined (i.e. neutropenia, central venous catheters), whereas other factors are now emerging as new possible causative factors (i.e. iron overload, hospitalization). SUMMARY: Many factors have to be considered when evaluating the infectious risk in hematological patients. In current clinical practice the good knowledge of these factors may favor a better management of infectious risk, with a reduction of mortality rate.

First case of breakthrough pneumonia due to Aspergillus nomius in a patient with acute myeloid leukemia.

We report the first known case of a breakthrough pulmonary infection caused by Aspergillus nomius in an acute myeloid leukemia patient receiving caspofungin therapy. The isolate was identified using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and sequencing-based methods. The organism was found to be fully susceptible, in vitro, to echinocandin antifungal agents.

Diagnosis of invasive aspergillosis by a commercial real-time PCR assay for Aspergillus DNA in bronchoalveolar lavage fluid samples from high-risk patients compared to a galactomannan enzyme immunoassay.

Culture-independent molecular techniques such as real-time PCRs offer the potential for early diagnosis of invasive aspergillosis (IA), thereby reducing the disease-associated mortality rate. PCR-based testing is presently excluded from disease-defining consensus criteria due to lack of standardization and clinical validation. A single-center prospective study was conducted to investigate the performance of the commercially available MycAssay Aspergillus test for detecting Aspergillus DNA in patients with suspicion of IA. To this end, a total of 158 bronchoalveolar lavage (BAL) fluid specimens that were consecutively collected from hematology (n = 68) and intensive care unit (n = 90) patients were examined. Sixteen of 17 (94.1%) specimens from patients with proven/probable IA were MycAssay positive, and 15 of these 16 patients were also positive by an "in-house" PCR assay. A total of 139 of 141 (98.6%) specimens from patients without proven/probable IA were MycAssay negative. Fifteen of 16 (94.1%) MycAssay-positive patients were also positive for BAL fluid galactomannan (GM) at an index cutoff of ≥1.0 (index range, 1.1 to 8.3), as were 3 patients without IA but with pulmonary fusariosis. Interestingly, in seven of the PCR-positive BAL specimens that tested culture positive for Aspergillus species, cycle threshold values were earlier than those of specimens with a culture-negative result. In conclusion, the MycAssay Aspergillus PCR appears to be a sensitive and specific molecular test for the diagnosis of IA, and its performance is comparable to that of the GM assay. However, more large studies are necessary to firmly establish its clinical utility in high-risk settings.

The use and efficacy of empirical versus pre-emptive therapy in the management of fungal infections: the HEMA e-Chart Project.

BACKGROUND: Neutropenic patients with persistent fever despite antibiotic therapy are managed with empirical or pre-emptive antifungal therapy. The aim of the present study was to evaluate the current clinical use and efficacy of these two approaches in patients with high risk hematologic conditions. DESIGN AND METHODS: An electronic medical record system, the "Hema e-Chart", was designed and implemented to collect information prospectively on infectious complications, particularly on invasive fungal diseases, in patients with hematologic malignancies treated with chemotherapy and/or autologous or allogenic hemopoietic stem cell transplantation. The patients were enrolled from Hematology units distributed widely across Italy. RESULTS: Three hundred and ninety-seven adults with hematologic malignancies treated with chemotherapy with persistent fever and suspected invasive fungal disease were evaluable for the study (190 treated had been treated with empirical antifungal therapy and 207 with preemptive antifungal therapy). There was a significantly lower incidence of proven/probable invasive fungal diseases in patients treated with empirical antifungal therapy (n=14, 7.4%) than in patients treated with pre-emptive therapy (n=49, 23.7%) (P<0.001). The rate of deaths attributable to invasive fungal diseases was significantly lower in subjects treated with empirical antifungal therapy (1 case; 7.1%) than in subjects treated with pre-emptive therapy (11 cases; 22.5%) (P=0.002). CONCLUSIONS: These data indicate that empirical antifungal treatment decreased the incidence of invasive fungal disease and of attributable mortality with respect to a pre-emptive antifungal approach in neutropenic febrile patients with hematologic malignancies. (ClinicalTrials.gov Identifier: NCT01069887).

Invasive aspergillosis in acute leukemias: old and new risk factors and epidemiological trends.

In recent years, there has been increased interest in the development of prophylactic and diagnostic tools for patients at high risk for invasive aspergillosis (IA), resulting in a significant investment of human, technical, and economic resources. There are several classic risk factors for the development of IA, including neutropenia, graft-versus-host disease, and corticosteroid use. However, despite having similar risk profiles, only a subset of at-risk individuals will develop this fungal complication. At present, there is a significant expansion of the classically defined 'high-risk' group due to the ageing of the general population, the intensification of treatment strategies, and the introduction of new drugs into clinical practice (e.g., monoclonal antibodies, TNF inhibitors). Therefore, an improved categorization of patients would be useful in order to better target available resources and avoid the risk of potential overtreatment and toxicities.

Adherence to international guidelines for the treatment of invasive aspergillosis in acute myeloid leukaemia: feasibility and utility (SEIFEM-2008B study).

OBJECTIVES AND METHODS: In order to assess physicians' compliance with international guidelines for the targeted treatment of invasive aspergillosis, 136 patients with acute myeloid leukaemia and proven/probable invasive aspergillosis were analysed. RESULTS: Compliance with Infectious Diseases Society of America (IDSA) and European Conference on Infections in Leukaemia (ECIL) guidelines was found to be relatively low (28% for ECIL and 55% for IDSA), although no significant differences were found between the two groups (adherence versus non-adherence). In both subgroup analyses (IDSA and ECIL), compliance with the guidelines did not impact the 120 day survival rate. Instead, adherence to guidelines led to a higher response rate to first-line antifungal treatment (76% in the IDSA group and 84% in the ECIL group). CONCLUSIONS: Guidelines establish categories of patients with homogeneous characteristics, and suggest optimal diagnostic and therapeutic options for them. Acquisition of good results through adherence to guidelines is confirmed by our series. Unfortunately, there are frequently reasons to deviate from these general recommendations, particularly in patients with acute myeloid leukaemia. Despite evidence-based recommendations, adherence to the guidelines does not constitute the best therapeutic choice in each and every patient. Subjects' clinical conditions and co-morbidities vary widely, and sometimes render the 'recommended' drug a non-applicable strategy.

Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study.

BACKGROUND: The aim of this study was to evaluate prognostic factors, treatments and outcome of invasive aspergillosis in patients with acute myeloid leukemia based on data collected in a registry. DESIGN AND METHODS: The registry, which was activated in 2004 and closed in 2007, collected data on patients with acute myeloid leukemia, admitted to 21 hematologic divisions in tertiary care centers or university hospitals in Italy, who developed proven or probable invasive aspergillosis. RESULTS: One hundred and forty cases of invasive aspergillosis were collected, with most cases occurring during the period of post-induction aplasia, the highest risk phase in acute myeloid leukemia. The mortality rate attributable to invasive aspergillosis was 27%, confirming previous reports of a downward trend in this rate. Univariate and multivariate analyses revealed that the stage of acute myeloid leukemia and the duration of, and recovery from, neutropenia were independent prognostic factors. We analyzed outcomes after treatment with the three most frequently used drugs (liposomal amphotericin B, caspofungin, voriconazole). No differences emerged in survival at day 120 or in the overall response rate which was 71%, ranging from 61% with caspofungin to 84% with voriconazole. CONCLUSIONS: Our series confirms the downward trend in mortality rates reported in previous series, with all new drugs providing similar survival and response rates. Recovery from neutropenia and disease stage are crucial prognostic factors. Efficacious antifungal drugs bridge the period of maximum risk due to poor hematologic and immunological reconstitution.

Therapeutic Strategies for the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Positive (HR+/HER2+) Breast Cancer: A Review of the Current Literature.

Enormous advances have been made in the understanding and treatment of human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) in the last 30 years that have resulted in survival gains for affected patients. A growing body of evidence suggests that hormone receptor-positive (HR+)/HER2+ BC and HR-negative (HR-)/HER2+ BC are biologically different, with complex molecular bidirectional crosstalk between the estrogen receptor and HER2 pathway potentially affecting sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ BC. Subgroup analyses from trials enrolling patients with HER2+ BC and the results of clinical trials specifically designed to evaluate therapy in patients with HR+/HER2+ BC are helping to guide treatment decisions. In this context, encouraging results with strategies aimed at delaying or reversing drug resistance, including extended adjuvant therapy and the addition of drugs targeting alternative pathways, such as cyclin-dependent kinase (CDK) 4 and 6 inhibitors, have recently emerged. We have reached the point where tailoring the treatment according to risk and biology has become the paradigm in early BC. However, further clinical trials are needed that integrate translational research principles and identify and consider specific patient subgroups and biomarkers.

ZYGOMYCOSIS: current approaches to management of patients with haematological malignancies.

Zygomycosis is an invasive infection that can occur particularly in patients with haematological malignancy. The causative fungi are members of the order Mucorales, and individual species within this group require a high level of laboratory skill to be identified. Zygomycosis can present as rhinocerebral, pulmonary, or disseminated disease, with a rapid clinical course. The optimal management of these cases requires early diagnosis, aggressive antifungal therapy and, when possible, surgical debridement. Founded on clinical experience, but without the benefit of comparative studies, liposomal amphotericin B has become the therapeutic agent of choice. Posaconazole is an orally administered triazole with a demonstrated in vitro and in vivo activity against most Zygomycetes that is comparable to that of amphotericin B. Studies on salvage therapy with posaconazole have yielded promising results, and successful case reports are also available. As an adjuvant approach, iron chelation with deferasirox has shown promising results, although clinical experience is still limited.

Soft tissue sarcoma in Italy: From epidemiological data to clinical networking to improve patient care and outcomes.

Sarcomas are rare malignant neoplasms that develop from mesenchymal cells and include a heterogeneous and large group of histological subtypes that may occur at any anatomical site. Soft tissue sarcomas (STS), the focus of this review, account for ≈70‒80% of sarcomas and represent <1% of all cancers. The heterogeneity of STS applies to both their topography and morphology, and 5-year survival can vary widely depending on disease stage and the complex interplay between anatomical site and histology for different STS subtypes. The rarity and heterogeneity of STS, together with other factors, such as the lack of clinical expertise often lead to difficulties and delays in making an accurate diagnosis and to the inappropriate management of each STS subtype. Therefore, this group of cancers requires special attention and approaches to diagnosis and treatment. Epidemiological data on STS are limited, and concerns have been raised regarding accurate registration of STS in cancer registries, including issues related to details of the histotypes. This review provides an overview of the epidemiology of STS in Italy, focusing on data from the Italian Association of Cancer Registries (AIRTUM), and compares findings with those from other European countries. Based on these data, and considering that STS is among the most common group of rare cancers, the relevance of multidisciplinary care for STS patients through reference centres, clinical networks and collaborative disease-specific groups is discussed.