Low-Intensity and Chemo-Free Treatments in Ph+ ALL: Progression-Free Survival Based on Indirect Comparisons.

In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and chemo-free regimens. Our objective was to analyze all recent trials evaluating these treatments and to compare them in terms of efficacy. We applied the Shiny method, an artificial intelligence technique, to analyze Kaplan-Meier curves and reconstruct patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and subjected to indirect head-to-head treatment comparisons. The endpoint was progression-free survival (PFS). Based on 432 reconstructed patients, eight trials were analyzed. The survival data from these trials were pooled into three types of treatments: (i) treatments based on tyrosine kinase inhibitors (TKIs) combined with reduced-intensity chemotherapy (denoted as TKICHE); (ii) TKIs associated with steroids with no chemotherapy (TKISTE); (iii) chemotherapy-free combinations of blinatumomab plus TKIs (TKIBLI). According to the Shiny method, the three PFS curves were reported in a single Kaplan-Meier graph and subjected to survival statistics. In terms of PFS, TKIBLI ranked first, TKICHE second, and TKISTE third; the differences between these three regimens were statistically significant. This multi-treatment Kaplan-Meier graph, generated through the Shiny method, summarized the current evidence on these treatments in both qualitative and quantitative terms.

Tislelizumab plus chemotherapy vs. pembrolizumab plus chemotherapy for the first-line treatment of advanced non-small cell lung cancer: systematic review and indirect comparison of randomized trials.

BACKGROUND: Pembrolizumab (PEM) and tislelizumab (TIS), in combination with chemotherapy, have demonstrated significant clinical benefits in first-line treatment of advanced non-small cell lung cancer (NSCLC). However, no head-to-head clinical trial has yet compared these two treatments. METHODS: We conducted a literature search of randomized trials, in which TIS plus chemotherapy or PEM plus chemotherapy were studied for the first-line treatment of NSCLC. Randomized design and the endpoint of progression-free survival (PFS) were the inclusion criteria for our analysis. Adjusted indirect comparison between TIS and PEM was performed by application of the IPDfromKM-Shiny method. This method is based on the reconstruction of individual patient data from Kaplan-Meier curves. Outcomes in terms of PFS were expressed as hazard ratio (HR) with 95% and 90% confidence interval (CI). RESULTS: Data were extracted from five randomized trials involving nearly 2,000 participants. In comparing PEM plus chemotherapy (n=748) or TIS plus chemotherapy (n=462) vs. chemotherapy alone (n=782), the Shiny method found a significant advantage in terms of PFS (HR =0.5856, 95% CI: 0.4986-0.6876 for TIS; HR =0.5573, 95% CI: 0.4969-0.6251 for PEM), thus confirming the results of the original trials. The indirect comparison of PEM plus chemotherapy vs. TIS plus chemotherapy showed a substantial equivalence between these two regimens (HR =0.952; 95% CI: 0.775-1.168; 90% CI: 0.801-1.130) suggesting an acceptable degree of equivalence according to regulatory criteria. Medians were 8.89 months for PEM combination, 7.97 months for TIS combination, and 5.69 for the controls. CONCLUSIONS: The PFS of TIS combined with chemotherapy was similar to that of PEM combined with chemotherapy. Based on the HR with 90% CI, these two agents met an equivalence criterion for PEM vs. TIS ranging from -19.9% to +13.0%.

Best Possible Medication History Collection by Clinical Pharmacist in a Preoperative Setting: An Observational Prospective Study.

BACKGROUND: A Best Possible Medication History (BPMH) collected by clinical pharmacists is crucial for effective medication review, but, in Italy, it is often left to the nursing staff. This study aims to compare the quality and accuracy of a clinical pharmacist-documented BPMH with the current standard practice of ward staff-collected BPMH in an Italian preoperative surgical setting. METHODS: A 20-week prospective observational non-profit study was conducted in a major university hospital. The study comprised three phases: a feasibility, an observational, and an interventional phase. During the feasibility phase, 10 items for obtaining a correct BPMH were identified. The control group consisted of retrospectively analyzed BPMHs collected by the ward staff during the observational phase, while interventions included BPMHs collected by the clinical pharmacist during the third phase. Omissions between the two groups were compared. RESULTS: 14 (2.0%) omissions were found in the intervention group, compared with 400 (57.4%) found in the controls (p < 0.05); data collection was more complete when collected by pharmacists compared to the current modality (98.0% of completed information for the intervention versus 42.6%; p < 0.05). CONCLUSIONS: The involvement of a pharmacist significantly reduced the number of omissions in preoperative surgical-collected BPMHs. This intervention holds the potential to decrease the risk of medication errors associated with inaccurate or incomplete BPMHs prior to surgical hospitalization.

Alternative Antimicrobial Irrigation Strategies for the Treatment of Infections in Children: A Review of the Existing Literature.

As a synergistic treatment approach with systemic antimicrobial therapy or a systemic antibiotic-sparing strategy, the local administration of antimicrobial agents has been proposed as an alternative route for complicated infections. With the rationale of concentrating the active principle in the desired target site, avoiding potentially toxic systemic levels and bypassing anatomical and physiological barriers, local irrigation or infusion of antibiotics may effectively shorten the antimicrobial therapy course and reduce both infection-related and systemic therapy-related complications. Although evidence from the adult population supports its use in selected patients with an acceptable safety profile, data specifically focused on the pediatric population are limited. To provide a rapid and easily accessible tool for clinical practice, we synthesized the most relevant evidence on the use of local antimicrobial agents in common severe infections in children: meningitis, mediastinitis, pleural infections, recurrent urinary infections, and peritonitis. A literature search was performed using predefined combined keywords through an electronic research database (PubMed). Described molecules, dosages, routes, treated age groups, and related efficacy have been summarized for prompt application to clinical practice. It should, however, be noted that the evidence for the pediatric population remains limited, and the local administration of several molecules remains off-label. A careful multidisciplinary and patient-tailored evaluation, as well as a rational use of available guidelines, should always be the basis of clinical decision making in settings where local administration of antibiotics may be considered.

Real-Life Experience on Dolutegravir and Lamivudine as Initial or Switch Therapy in a Silver Population Living with HIV.

BACKGROUND: Clinical trials and real-life studies have granted the efficacy and safety of dolutegravir and lamivudine (DTG/3TC) in naïve and experienced people living with HIV (PLWH), but there are no long-term data in elderly people. We herein describe our real-life cohort of PLWH who were ≥65 years of age (PLWH ≥ 65) who started or were switched to DTG/3TC, single-tablet regimen, or DTG plus 3TC. METHODS: We considered laboratory/clinical parameter changes from the baseline to the last follow-up time point available for each person by the paired Wilcoxon test and analyzed factors associated with virological failure (VF) and discontinuation. RESULTS: We included 112 PLWH with a median age of 66 (IQR: 65-70) years, 77.6% males; 84.8% of people had multimorbidity, 34.8% were on polypharmacy, and only 5.4% were naïve to treatment. Reasons to be switched to DTG/3TC were: abacavir removal (38.7%), treatment simplification (33.1%), and PI discontinuation (28.2%). The median treatment durability was 6 (IQR: 5.4-7) years. No significant changes were detected in metabolic, renal, immunological, or cardiovascular biomarkers during follow-up. HIV RNA undetectability was maintained in 104 (92.8%) individuals for whom follow-up evaluation was available. We observed eight discontinuations (two deaths, two VFs, two early intolerances, one significant weight gain, and one switch to long-acting therapy). No factors were significantly associated with VF or discontinuation. CONCLUSIONS: This is the first study on DTG/3TC in PLWH ≥ 65 with a follow-up longer than 5 years. DTG/3TC was found to be safe and effective, neutral on metabolic parameters, and with a low discontinuation rate for toxicity or VF.

Cefiderocol-Based versus Colistin-Based Regimens for Severe Carbapenem-Resistant Acinetobacter baumannii Infections: A Propensity Score-Weighted, Retrospective Cohort Study during the First Two Years of the COVID-19 Pandemic.

BACKGROUND: A large increase in multi-drug-resistant Acinetobacter baumannii, especially carbapenem-resistant strains, occurred during the first two years of the COVID-19 pandemic, posing important challenges in its treatment. Cefiderocol appeared to be a good option for the treatment of Carbapenem-resistant Acinetobacter baumannii (CR-Ab), but to date, the guidelines and evidence available are conflicting. METHODS: We retrospectively included a group of patients with CR-Ab infections (treated with colistin- or cefiderocol-based regimens) at Padua University Hospital (August 2020-July 2022) and assessed predictors of 30-day mortality, and differences in microbiological and clinical treatment. To evaluate the difference in outcomes, accounting for the imbalance in antibiotic treatment allocation, a propensity score weighting (PSW) approach was adopted. RESULTS: We included 111 patients, 68% males, with a median age of 69 years (IQR: 59-78). The median duration of antibiotic treatment was 13 days (IQR:11-16). In total, 60 (54.1%) and 51 (45.9%) patients received cefiderocol- and colistin-based therapy, respectively. Notably, 53 (47.7%) patients had bloodstream infections, while 58 (52.3%) had pneumonia. Colistin was combined in 96.1%, 80.4%, and 5.8% of cases with tigecycline, meropenem, and fosfomycin, respectively. Cefiderocol was combined in 13.3%, 30%, and 18.3% of cases with fosfomycin, tigecycline, and meropenem, respectively. At the baseline, the two treatment groups significantly differed in age (patients treated with colistin were significantly older), the prevalence of diabetes and obesity (more frequent in the group treated with colistin), length of stay (longer in the group receiving cefiderocol), and type of infection (BSI were more frequent in the group receiving cefiderocol). The proportion of patients who developed acute kidney injury was significantly higher in the colistin group. By using PSW, no statistically significant differences emerged for mortality or clinical and microbiological cure between the two groups. No independent predictors were detected for hospital mortality or clinical cure, while for the length of stay, the only selected predictor was age, with a non-linear effect (p-value 0.025 for non-linearity) on the prolongation of hospital stay of 0.25 days (95% CI 0.10-0.39) at increasing ages (calculated over the IQR). CONCLUSIONS: Cefiderocol treatment did not differ in terms of main outcomes and safety profile from colistin-based regimens. More prospective studies with a larger number of patients are required to confirm our results.

Progression-Free and Overall Survival of First-Line Treatments for Advanced Renal Cell Carcinoma: Indirect Comparison of Six Combination Regimens.

BACKGROUND: Recently, numerous combination therapies based on immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors have been proposed as first-line treatments for advanced renal cell carcinoma (aRCC). Our study aimed to compare the efficacy of these combination regimens by the application of an innovative method that reconstructs individual patient data. METHODS: Six phase III studies describing different combination regimens for aRCC were selected. Individual patient data were reconstructed from Kaplan-Meier (KM) curves through the "Shiny method". Overall survival (OS) and progression-free survival (PFS) were compared among combination treatments and sunitinib. Results were summarized as multi-treatment KM curves. Standard statistical testing was used, including hazard ratio and likelihood ratio tests for heterogeneity. RESULTS: In the overall population of aRCC patients, pembrolizumab + lenvatinib showed the longest median PFS and was expected to determine the longest OS. Pembrolizumab + axitinib, nivolumab + cabozantinib and nivolumab + ipilimumab were similar in terms of PFS, but pembrolizumab + axitinib also demonstrated a better OS. Our subgroup analysis showed that sunitinib is still a valuable option, whereas, in intermediate-poor risk patients, pembrolizumab + axitinib and nivolumab + ipilimumab significantly improve OS compared to sunitinib. CONCLUSION: The Shiny method allowed us to perform all head-to-head indirect comparisons between these agents in a context in which "real" comparative trials have not been performed.

Risk of hospitalization and sequelae in patients with COVID-19 treated with 3-day early remdesivir vs. controls in the vaccine and Omicron era: A real-life cohort study.

Recently, a benefit from administration of a 3-day course of early remdesivir (ER) in the outpatients' setting was reported. However, real-life data on its use is scarce. Therefore, we explored the ER clinical outcome in our outpatients' s cohort, compared to untreated controls. We included all patients who were prescribed ER from February to May 2022 and followed them up for 3 months and compared patients who received treatment with untreated controls. In the two groups the following outcomes were investigated: hospitalization and mortality rate, time of negativization and symptom's resolution, and postacute coronavirus disease 19 (COVID-19) syndrome prevalence. Overall, 681 patients were analyzed, mostly females (53.6%), and with a median age of 66 years (interquartile range: 54-77), 316 (46.4%) patients received ER, and 365 (53.6%) did not receive antiviral treatment (control group). Overall, 8.5% patients eventually required oxygen support, 8.7% were hospitalized for COVID-19, and 1.5% died. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization and ER (adjusted odds ratio [aOR]: 0.049 [0.015; 0.16], p < 0.001) independently reduced hospitalization risk. ER was significantly associated with a shorter duration of SARS-CoV-2 positivity at nasopharyngeal swabs (aß -8.15 [-9.21; -7.09], p < 0.001) and of symptoms (aß -5.11 [-5.82; -4.39], p < 0.001), and with lower rate of COVID-19 sequelae compared to control group (aOR: 0.18 [0.10; 0.31], p < 0.001). Even in the SARS-CoV-2 vaccination and Omicron era, in patients at high risk of developing severe disease, ER demonstrated to have a good safety profile and to significantly reduce the risk of disease progression and COVID-19 sequelae compared to untreated controls.

Application of the IPDfromKM-Shiny Method to Compare the Efficacy of Novel Treatments Aimed at the Same Disease Condition: A Report of 14 Analyses.

In the area of evidence-based medicine, the IPDfromKM-Shiny method is an innovative method of survival analysis, midway between artificial intelligence and advanced statistics. Its main characteristic is that an original software investigates the Kaplan-Meier graphs of trials so that individual-patient data are reconstructed. These reconstructed patients represent a new form of original clinical material. The typical objective of investigations based on this method is to analyze the available evidence, especially in oncology, to perform indirect comparisons, and determine the place in therapy of individual agents. This review examined the most recent applications of the IPDfromKM-Shiny method, in which a new web-based software-published in 2021-was used. Reported here are 14 analyses, mostly focused on oncological treatments. Indirect comparisons were based on overall survival or progression free survival. Each of these analyses provided original information to compare treatments with one another and select the most appropriate depending on patient characteristics. These analyses can also be useful to assess equivalence from a regulatory viewpoint. All investigations stressed the importance of heterogeneity to better interpret the evidence generated by IPDfromKM-Shiny investigations. In conclusion, these investigations showed that the reconstruction of individual patient data through this online tool is a promising new method for analyzing trials based on survival endpoints. This new approach deserves further investigation, particularly in the area of indirect comparisons.

Changing patterns and clinical outcomes of hospitalized patients with COVID-19 severe pneumonia treated with remdesivir according to vaccination status: results from a real-world retrospective study.

Since the beginning of Coronavirus Disease 2019 (COVID-19) pandemic, many drugs have been purposed for the treatment of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Remdesivir emerged as an encouraging antiviral drug for patients with documented severe COVID-19-related pneumonia. Although several studies about remdesivir effectiveness exist, no study investigated the effect of the combination of remdesivir with the vaccination status. The aim of this study was to assess whether the administration of remdesivir could show some differences in terms of clinical outcomes in patients vaccinated against SARS-CoV-2 versus those who were not. The primary outcome was the in-hospital mortality. The secondary outcomes were 30-days mortality, the need for ICU admission and for oxygen supplementation. This is a retrospective cohort study including all consecutive adult patients hospitalized for severe COVID-19 at the Padua University Hospital (Italy), between September 1st, 2020, and January 31st, 2022, and who received a 5-days course of remdesivir. A total of 708 patients were included, 467 (66%) were male, and the median age was 67 (IQR: 56-79) years. To better estimate the outcomes of interest, a propensity score weighted approach was implemented for vaccination status. A total of 605/708 patients (85.4%) did not complete the vaccination schedule. In-hospital mortality rate was 5.1% (n = 36), with no statistically significant difference between the unvaccinated (n=29, 4.8%) and vaccinated (n=7, 6.8%; p=0.4) patients. After propensity score matching, mortality between the two groups remained similar. However, both the need for ICU and oxygen supplementation were significantly lower in the vaccinated group. Our finding suggests that a complete vaccination course could have an impact in reducing the need for transfer in ICU and for high-flow therapy in moderate-to-severe COVID-19 patients treated with remdesivir.

Therapeutic Options and Outcomes for the Treatment of Children with Gram-Positive Bacteria with Resistances of Concern: A Systematic Review.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci (MR-CoNS), and vancomycin-resistant Enterococci (VRE) are increasing worldwide and represent a threat for the limited treatment options in pediatric patients and neonates compared to adults. Recommendations in pediatrics are mainly extrapolated from adults' studies. METHODS: A literature search for the treatment of these pathogens in children (<18 years old) was conducted in Embase, MEDLINE, and Cochrane Library. Studies reporting data on single-patient-level outcomes related to a specific antibiotic treatment for multidrug resistant (MDR) Gram-positive bacterial infection in children were included. Studies reporting data from adults and children were included if single-pediatric-level information could be identified (PROSPERO registration: CRD42022383867). RESULTS: The search identified 11,740 studies (since January 2000), of which 48 fulfilled both the inclusion and the exclusion criteria and were included in the analysis: 29 for MRSA, 20 for VRE, and seven for MR-CoNS. Most studies were retrospective studies. Vancomycin was mainly used as a comparator, while linezolid and daptomycin were the most studied antimicrobials showing good efficacy. CONCLUSIONS: Linezolid showed a safety and efficacy profile in a neonatal setting; daptomycin is increasingly used for MRSA, but the evidence is scarce for VRE.

Molnupiravir and Nirmatrelvir/Ritonavir: Tolerability, Safety, and Adherence in a Retrospective Cohort Study.

BACKGROUND: Molnupiravir (MOL) and nirmatrelvir/ritonavir (NIR) were recently approved for the early treatment of COVID-19, but real-life data on tolerability, safety, and adverse events (AEs) are still scarce. METHODS: We conducted a retrospective cohort study including all patients who were prescribed MOL and NIR at the Infectious Diseases Unit of Padua University Hospital, between January and May 2022. Demographic, clinical, and safety variables were recorded. RESULTS: We included 909 patients, 48.3% males and 95.2% vaccinated against SARS-CoV-2. The median age was 73 (IQR: 62-82) years. MOL and NIR were prescribed in 407 (44.8%) and 502 (55.2%) patients, respectively. Overall, 124/909 (13.6%) patients experienced any AEs following antivirals intake: 98/124 (79%) patients reporting adverse events presented grade 1 AEs, 23/124 (18.5%) grade 2 AEs and 3 (2.5%) grade 3 AEs. Treatment discontinuation was recorded in 4.8% of patients. AEs were significantly higher in women, in patients treated with NIR compared to MOL and in people who were not vaccinated. CONCLUSIONS: In our real-life setting, AEs were higher than those reported by clinical trials, and were particularly associated with NIR use and with not being vaccinated. Further analyses are needed to better assess safety of oral antivirals and to define which patient's profile may benefit most from MOL and NIR.

Factors influencing the acceptability of different devices for subcutaneous drug delivery: a cross-sectional observational study from the patient's point of view.

BACKGROUND: In recent years, an increasing number of patient-reported outcome assessment tools (PROs) have been developed specifically to ascertain patients' perceptions of different drug treatments. Among them, the injection process has been analysed, especially in patients chronically treated with chronic biological therapies. One of the main advantages of most current biological therapies is the possibility to self-administer medication at home through the use of a variety of devices, including prefilled syringes (PFS) and prefilled pens (PFP). OBJECTIVES: The aim of this study was to conduct qualitative research to assess the degree of preference between the different pharmaceutical forms PFS and PFP. METHODS: We performed a cross-sectional observational study in patients on biological drug therapy through the compilation of a web-based questionnaire at the time of routine delivery of biological therapy. Questions regarding primary diagnosis, adherence to therapy, the preferred pharmaceutical form and the main reason for preference among five possibilities already reported in the scientific literature were included. RESULTS: During the study period, data were collected from 111 patients and 68 (58%) indicated PFP as their preference. From the analysis of reasons that led a patient to choose one device over another, PFSs are chosen mainly out of habit (n=13 (28.3%) PFS vs n=2 (3.1%) PFP) while PFPs are chosen to avoid needle vision (n=15 (23.1%) PFP vs n=1 (2.2%) PFS). Both differences were found to be statistically significant (p<0.001). CONCLUSION: As biological subcutaneous drugs are increasingly prescribed for a wide variety of long-term therapies, further research focused on identifying patient factors which may enhance adherence to treatment will become even more valuable.

Early Treatments of Fragile Children with COVID-19-Results of CLEVER (Children COVID Early Treatment), a Retrospective, Observational Study.

(1) Background: SARS-CoV-2 infection is notably mild in children, though comorbidities may increase the risk of hospitalization and may represent a risk for increased disease severity. There is an urgent need for targeted therapies with an acceptable efficacy and safety profile. To date, most of the medicines for COVID-19-specific treatment are prescribed off-label for children due to a lack of clinical trials and consequent evidence in this population. (2) Methods: This was a retrospective, observational study investigating the safety of treatments for the prevention of severe COVID-19 in fragile pediatric patients who received monoclonal antibodies and antivirals for mild-to-moderate symptoms between December 2021 and July 2022. (3) Results: Thirty-two patients were included. Monoclonal antibodies were prescribed to 62%, intravenous antivirals to 22%, and oral antivirals to 16% of children. Sotrovimab was the most frequently prescribed drug among monoclonal antibodies and overall (59%). The second most prescribed drug was remdesivir (22%). No severe adverse drug reaction was reported. There was no progression to severe disease and no death cases due to COVID-19 or drug administration. At drug-type stratification, resolution of symptoms and swab positivity time showed no difference between the two groups at 7 and 28 days. Off-label prescriptions were 84% overall, and in similar proportions between the two groups. (4) Conclusions: in this small sample, antivirals seemed safe and showed no differences in efficacy as compared to MAbs for the early treatment of COVID-19 in fragile children, thus representing a valuable choice, even when administered off-label.