THERAPY-RELATED MYELOID NEOPLASMS: CONSIDERATIONS FOR PATIENTS’ CLINICAL EVALUATION

Therapy-related myeloid neoplasms (t-MNs) encompass a specific sub-group of myeloid malignancies arising after exposure to radio/cytotoxic agents for the treatment of unrelated diseases. Such malignancies present unique features, including advanced age, high comorbidities burden, and unfavorable genetic profiles. All these features justify the need for a specific diagnostic work-up and dedicated treatment algorithms. However, as new classification systems recognize the unique clinical characteristics exhibited by t-MN patients, how to assess fitness status in this clinical setting is largely unexplored. Optimizing fitness assessment would be crucial in the management of t-MN patients, considering that factors usually contributing to a worse or better outcome (like age, comorbidities, and treatment history) are patient-specific.In the absence of specific tools for fitness assessment in this peculiar category of AML, the aim of this review is to describe all those factors related to patient, treatment, and disease that allow planning treatments with an optimal risk/benefit ratio

Time for Dynamic Assessment of Fitness in Acute Myeloid Leukemia

Informed treatment decision-making in acute myeloid leukemia (AML) requires a comprehensive evaluation of all clinical and biological features that may affect the outcome with any given type or intensity of therapy [...

Effects of growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure.

BACKGROUND: Because GH exerted beneficial effects in various experimental models of heart failure, we investigated the effects of GH on physical exercise capacity and cardiopulmonary performance in patients with dilated cardiomyopathy and chronic heart failure (CHF). METHODS: Twenty-two patients with CHF (New York Heart Association functional class II-III) underwent spirometry and a symptom-limited, cardiopulmonary exercise testing before and after 3 months of GH (n = 11; seven males; seven idiopathic; 57 +/- 11 yr; 4 IU sc every other day) or placebo (n = 11; eight males; six idiopathic; 54 +/- 10 yr) administration, in a randomized, double-blind trial. Background CHF therapy remained unchanged. RESULTS: GH, but not placebo, increased IGF-I serum concentration (from 144 +/- 35 to 293 +/- 58 ng/ml; P < 0.005) and improved New York Heart Association functional class (from 2.4 +/- 0.5 to 1.8 +/- 0.4; P < 0.005), exercise duration (from 831 +/- 273 to 925 +/- 266 sec; P < 0.005), peak power output (from 245 +/- 127 to 280 +/- 132 W; P < 0.05), peak minute ventilation (from 52.5 +/- 16.1 to 61.3 +/- 17.3 liters/min; P < 0.05), peak oxygen consumption (from 19.8 +/- 5.6 to 25.1 +/- 5.6 ml/kg.min; P < 0.005), and anaerobic threshold (from 14.9 +/- 4.8 to 20.0 +/- 4.5 ml/kg.min; P < 0.005) without affecting lung function parameters. Furthermore, the slope of the relationship between minute ventilation and pulmonary carbon dioxide production (ventilatory efficiency) decreased from 34.7 +/- 5.1 to 31.7 +/- 5.3 (P < 0.005), whereas the slope of the relation between percent predicted heart rate reserve used and percent observed metabolic reserve used (chronotropic index) rose from 0.57 +/- 0.20 to 0.69 +/- 0.18 (P < 0.005). CONCLUSION: Given the predictive value of physical exercise capacity and cardiopulmonary performance in CHF progression, these data provide additional insights into the mechanisms by which GH may potentially benefit CHF patients

Clinical outcomes and safety of patients treated with NAb-Paclitaxel plus Gemcitabine in metastatic pancreatic cancer:the NAPA study

BACKGROUND: The phase III MPACT trial demonstrated the superiority of gemcitabine (Gem) combined with Nab-paclitaxel (Nab-P) versus gemcitabine alone in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to evaluate the effect of Gem/Nab-P in routine clinical practice.METHODS: From January 2015 to December 2018, patients with metastatic PDAC receiving first-line treatment with a combination of gemcitabine and Nab-paclitaxel were included in a multicentre retrospective observational study. Exploratory analyses of efficacy, and prognostic and predictive markers, were performed.RESULTS: The cohort comprised 115 patients (median age 65 [range 50-84] years) with good performance status (ECOG PS 0-1). The median overall survival (OS) was 11 months (95 % CI; 9-13) and the median progression free survival (PFS) was 6 months (95 % CI 5-7). Partial response and stable disease were achieved in 44 and 30 patients respectively, yielding an overall disease control rate (DCR) of 64.3%. Grade 3-4 haematological toxicity frequency was 22.61% for neutropenia, 5.22% for anaemia and 3.48% for thrombocytopenia. Grade 3 asthenia was recorded in 2.61% of patients. No grade 4 nonhaematological events were reported. Dose reduction was necessary in 51.3 % of the patients.CONCLUSIONS: Our results confirm the efficacy and safety of a first line regimen comprising gemcitabine and Nab-paclitaxel in metastatic PDAC in a real-life population.</p

Pulmonary function testing for fitness assessment in asymptomatic adults with newly diagnosed acute myeloid leukemia

Not available

The Addition of Venetoclax to Induction Chemotherapy in No Low-Risk AML Patients: A Propensity Score-Matched Analysis of the Gimema AML1718 and AML1310 Trials

Venetoclax combined with intensive chemotherapy proved to be safe with promising activity in fit patients with no-low-risk newly diagnosed acute myeloid leukemia (AML), as demonstrated also by an intermediate analysis of the GIMEMA AML1718 trial (NCT03455504). The latter trial, still ongoing, is based on the administration of venetoclax-FLAI to intermediate/high-risk ELN2017 AML and produced a complete remission (CR) rate of 84%, a minimal residual disease (MRD)-negativity rate of 74% and a 12-month Overall Survival (OS) and disease-free survival (DFS) of 75.7% (95%CI: 64.1%, 89.5%) and 80.7% (95%CI: 67.9%, 95.9%), respectively. In order to evaluate the actual advantage of the addition of venetoclax to chemotherapy, the GIMEMA AML1718 was matched to AML1310, which entailed a "3+7"-like induction and a risk-adapted, MRD-directed post-remission transplant allocation (NCT01452646, Venditti et al - Blood 2019). To generate a reliable comparison, AML1718 and AML1310 were matched by using a propensity score and then compared in terms of CR achievement, MRD-negativity and survival outcomes. Patient-level data from GIMEMA AML1718 (n=57) and AML1310 (N=445) with ELN2017 risk classification available were used to conduct a propensity score matching analysis, widely used for reducing the effects of confounding when estimating the effects of treatment on outcomes. Conditional on the propensity score, the distribution of measured variables is expected to be the same in treated (i.e. AML1718) and control (i.e. AML1310) subjects. In the present propensity score model, we included the following variables: age at diagnosis, gender, ELN2017 risk classification and transplant. Different methods for matching were attempted, including 1:1 nearest neighbor, full-matching, optimal matching (1:2, 1:3 and 1:4) and 1:2 genetic matching. The methods employed for assessing balancing were: i) Standardized Mean Difference - Love plot, ii) Empirical cumulative density function, iii) Variance ratio, iv) Empirical QQ-plot. Weights were calculated with probit or logit regression models according to the propensity score method used. Weights obtained from full-matching were used to adjust outcomes (CR, MRD negativity and survival outcomes). No patients were dropped in the full-matching process. A standardized bias score less than 0.25 was used as a criterion for adequate balancing. We used balance tables and Love plots to assess for covariate balance before and after matching. Survival curves were compared by Log-rank test and Restricted Mean Survival Time (RMST) at 12 months. AML1718 and AML1310 cohorts differed in terms of age (median: 54 vs 49 years, p=0.003) and risk category (p&lt; .0001) - since the low risk was not represented in AML1718 trial - and female sex (35% vs 48%, p=0.069), though to a lesser extent. Contrariwise, the percentage of transplanted patients was comparable before matching (49% vs 49%, p=0.96). Being more recent, AML1718 median follow-up was shorter than AML1310 (10.5 vs 75.8 months). Full-matching, 1:2 optimal matching and 1:2 genetic matching produced the best balancing. Table 1 shows the results of the analysis for the unmatched and matched data. After balancing, according to all matching methods, the CR rate observed in the AML1718 was significantly higher than AML1310, as well as MRD-negativity rate. Comparing survival outcomes at 12 months, emerged that, upon matching, OS and DFS estimates of the AML1718 were higher than those of AML1310, though a slight statistical significance was reached only with the optimal matching on DFS (p=0.042). This result was confirmed by a statistically significant difference between the two RMST at 12 months (p=0.036). Despite this, a longer AML1718 follow-up is needed to provide a robust comparison between the two protocols. Our propensity-score analysis showed that combining venetoclax with chemotherapy in newly diagnosed AML patients resulted in improved outcomes in terms of CR rate and MRD-negativity: these achievements are crucial to allow transition to allogenic transplantation in first remission. With regards to survival outcomes, a solid conclusion will be drawn when a longer AML1718 follow-up is available. These preliminary results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy and paves the way to novel combination regimens based on venetoclax

Measurable Residual Disease (MRD) as a Surrogate Efficacy-Response Biomarker in AML

In acute myeloid leukemia (AML) many patients experience relapse, despite the achievement of morphological complete remission; therefore, conventional morphologic criteria are currently considered inadequate for assessing the quality of the response after treatment. Quantification of measurable residual disease (MRD) has been established as a strong prognostic marker in AML and patients that test MRD negative have lower relapse rates and better survival than those who test positive. Different techniques, varying in their sensitivity and applicability to patients, are available for the measurement of MRD and their use as a guide for selecting the most optimal postremission therapy is an area of active investigation. Although still controversial, MRD prognostic value promises to support drug development serving as a surrogate biomarker, potentially useful for accelerating the regulatory approval of new agents. In this review, we will critically examine the methods used to detect MRD and its potential role as a study endpoint

Case report: A Saprochaete clavata (Magnusiomyces clavatus) severe infection effectively treated with granulocyte transfusion in a young patient with myeloid sarcoma

Myeloid sarcoma is a hematologic malignancy consisting of extramedullary tissue involvement by myeloid blasts, usually considered as acute myeloid leukemia and treated accordingly. The disease itself, together with chemotherapy and disease-associated factors, may have an impact in increasing the risk of developing severe and frequently life-threatening infections. Herein, we describe the case of a patient with a right breast skin lesion, histologically diagnosed myeloid sarcoma, who developed a severe disseminated fungal infection by Saprochaete clavata (Magnusiomyces clavatus), during the first consolidation course of chemotherapy. Despite maximum antifungal therapy, the infection progressed and the fungus continued to be isolated until granulocyte transfusion therapy was initiated. Our experience suggests that patients with profound and long-lasting neutropenia could benefit from granulocyte transfusions as additional therapy in severe fungal infections resistant to broad-spectrum antimicrobial therapy

Sex differences in the efficacy and safety of SARS-CoV-2 vaccination in residents of long-term care facilities: insights from the GeroCovid Vax study

Despite the reported sex-related variations in the immune response to vaccination, whether the effects of SARS-CoV-2 vaccination differ by sex is still under debate, especially considering old vulnerable individuals, such as long-term care facilities (LTCFs) residents. This study aimed to evaluate COVID-19 infections, adverse events, and humoral response after vaccination in a sample of LTCF residents. A total of 3259 LTCF residents (71% females; mean age: 83.4 +/- 9.2 years) were enrolled in the Italian-based multicenter GeroCovid Vax study. We recorded the adverse effects occurring during the 7 days after vaccine doses and COVID-19 cases over 12 months post-vaccination. In a subsample of 524 residents (69% females), pre- and post-vaccination SARS-CoV-2 trimeric S immunoglobulin G (Anti-S-IgG) were measured through chemiluminescent assays at different time points. Only 12.1% of vaccinated residents got COVID-19 during the follow-up, without any sex differences. Female residents were more likely to have local adverse effects after the first dose (13.3% vs. 10.2%, p = 0.018). No other sex differences in systemic adverse effects and for the following doses were recorded, as well as in anti-S-IgG titer over time. Among the factors modifying the 12-month anti-S-IgG titers, mobility limitations and depressive disorder were more likely to be associated with higher and lower levels in the antibody response, respectively; a significantly lower antibody titer was observed in males with cardiovascular diseases and in females with diabetes or cognitive disorders. The study suggests that, among LTCF residents, SARS-CoV-2 vaccination was effective regardless of sex, yet sex-specific comorbidities influenced the antibody response. Local adverse reactions were more common in females

Predictors of Early Thrombotic Events in Adult Patients with Acute Myeloid Leukemia: A Real-World Experience

Information regarding the incidence and the prognostic impact of thrombotic events (TE) in non-promyelocytic acute myeloid leukemia (AML) is sparse. Although several risk factors associated with an increased risk of TE development have been recognized, we still lack universally approved guidelines for identification and management of these complications. We retrospectively analyzed 300 consecutive patients with newly diagnosed AML. Reporting the incidence of venous TE (VTE) and arterial TE (ATE) was the primary endpoint. Secondarily, we evaluated baseline patient- and disease-related characteristics with a possible influence of VTE-occurrence probability. Finally, we evaluated the impact of TE on survival. Overall, the VTE incidence was 12.3% and ATE incidence was 2.3%. We identified three independent predictors associated with early-VTE: comorbidities (p = 0.006), platelets count &gt;50x10e9/L (p = 0.006), and a previous history of VTE (p = 0.003). Assigning 1 point to each variable, we observed an overall cumulative incidence of VTE of 18.4% in the high-risk group (&gt;2 points) versus 6.4% in the low-risk group (0–1 point), log-rank = 0.002. Overall, ATE, but not VTE, was associated with poor prognosis (p &lt; 0.001). In conclusion, TE incidence in AML patients is not negligible. We proposed an early-VTE risk score that could be useful for a proper management of VTE prophylaxis