Giorgio Minotti
@unicampus.it
Department of Medicine
Università Campus Bio-Medico e Fondazione Policlinico Campus
RESEARCH INTERESTS
Cancer drugs
Cardiovascular toxicities
Cardio-Oncology
Oxidative stress
Scopus Publications
Scopus Publications
Massimiliano Camilli, Marcello Viscovo, Tamara Felici, Luca Maggio, Federico Ballacci, Giacomo Carella, Alice Bonanni, Priscilla Lamendola, Lorenzo Tinti, Antonio Di Renzo,et al.
Springer Science and Business Media LLC
Abstract Aims Chimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy. Methods Patients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers. Results Incidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01). Conclusions There is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised. Graphical Abstract
Nabil V Sayour, Ágnes M Paál, Pietro Ameri, Wouter C Meijers, Giorgio Minotti, Ioanna Andreadou, Antonella Lombardo, Massimiliano Camilli, Heinz Drexel, Erik Lerkevang Grove,et al.
Oxford University Press (OUP)
Abstract Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.
Massimiliano Camilli, Antonella Lombardo, Filippo Crea, and Giorgio Minotti
Oxford University Press (OUP)
Giorgio Minotti and Massimiliano Camilli
American Society for Pharmacology & Experimental Therapeutics (ASPET)
Massimiliano Camilli, Federico Ballacci, Federica Giordano, and Giorgio Minotti
Ovid Technologies (Wolters Kluwer Health)
ABSTRACT
Sodium-glucose cotransporter 2 (SGLT2) inhibitors represent one of the most important pharmacological innovations in the field of Cardiology of the last decades, having shown significant outcome improvement in all the heart failure (HF) spectrum. However, cost-effectiveness considerations should be made. This editorial discusses results of a cost-effectiveness study coming from China and focusing on patients affected by HF with reduced ejection fraction.
Giorgio Minotti, Emanuela Salvatorelli, and Pierantonio Menna
Ovid Technologies (Wolters Kluwer Health)
Massimiliano Camilli, Juan Guido Chiabrando, Marco Lombardi, Marco Giuseppe Del Buono, Rocco Antonio Montone, Antonella Lombardo, Filippo Crea, and Giorgio Minotti
Springer Science and Business Media LLC
Abstract Background Several cohort studies aimed at demonstrating an increased risk of cancer incidence and mortality in patients with a pre-existing diagnosis of heart failure (HF); however, conflicting results have been reported that call for systematic review and meta-analysis. Methods We conducted a systematic search of multiple databases from their inception through July 2022 and retrieved only papers reporting hazard ratios (HR). Random and fixed-effects models were fit for the study duration. Results The analysis included nine cohort studies for a total of 515′041 HF cases and 1′365’452 controls without HF. Although high heterogeneity among studies was observed, the HR for incident cancer in HF patients was statistically significant (1.45, 95% CI 1.31–1.61, p < 0.0001), which was confirmed by sensitivity analyses; however, by analyzing the few papers reporting HRs for cancer mortality, no significant difference between HF and non-HF patients could be detected (HR 2.03, 95% CI [0.93–4.43], p = 0.0736). Further scrutiny of studies with adjusted HRs, when available, confirmed that cancer incidence was significantly increased in patients with HF, as was cancer mortality as well. Conclusions This meta-analysis shows that HF patients are at an increased risk of incident cancer. Increased mortality could not be firmly demonstrated by the available data. Our results call for inclusion of cancer-related endpoints in HF trials to adequately address this important clinical issue.
Pierantonio Menna, Francesco Marchesi, Chiara Cattaneo, Anna Candoni, Mario Delia, Gianpaolo Nadali, Alessandra Vatteroni, Crescenza Pasciolla, Salvatore Perrone, Luisa Verga,et al.
Wiley
AbstractMidostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3‐mutated acute myeloid leukemia. Chemotherapy‐induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin‐related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real‐life study to evaluate (i) how often concerns around PCZ‐midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ‐midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ‐midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (Cmin) was greater than three times higher than reported; moreover, midostaurin Cmin, maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin‐related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin‐treated patient.
Emanuela Salvatorelli, Giorgio Minotti, and Pierantonio Menna
S. Karger AG
ABSTRACT Background Acute myeloid leukemia (AML) is a life-threatening disease whose treatment is made difficult by a number of mutations or receptor overexpression in the proliferating cellular clones. Life expectancy of patients diagnosed with new, relapsed-refractory or secondary AML has been improved by drugs targeted at such moieties. Regrettably, however, clinical use of new AML drugs is complicated by pharmacokinetic interactions with other drugs the patient is exposed to. Summary The most relevant drug-drug interactions (DDI) with clinical implications build on competition for or induction/inhibition of CYP3A4, which is a versatile metabolizer of a plethora of pharmacological agents. Here we review DDI between AML drugs and the agents used to prevent or treat invasive fungal infections (IFI). The pathophysiology of AML, characterized by functionally defective white blood cells and neutropenic/immunosoppressive effects of concomitant induction chemotherapy, can in fact increase the risk of infectious complications, with IFI causing high rates of morbidity and mortality. Triazole antifungals, such as posaconazole, are strong inhibitors of CYP3A4 and may thus cause patient’s overexposure to AML drugs that are metabolized by CYP3A4. We describe potential strategies to minimize the consequences of DDI between triazole antifungals and targeted therapies for acute myeloid leukemia and the role that collaboration between clinical pharmacologists, hematologists and clinical or laboratory microbiologists may have in these settings. Key Messages Therapeutic drug monitoring and clinical pharmacology stewardship could represent two strategies that best express multidisciplinary collaboration for improving patient management.
Giorgio Minotti
American Society for Pharmacology & Experimental Therapeutics (ASPET)
Giorgio Minotti
American Society for Pharmacology & Experimental Therapeutics (ASPET)
Giuseppe Boriani, Pierantonio Menna, Riccardo Morgagni, Giorgio Minotti, and Marco Vitolo
S. Karger AG
Background: The natural history of chronic lymphocytic leukemia (CLL) was dramatically improved by the introduction of ibrutinib, a Bruton’s kinase (BTK) inhibitor. In this review we aimed to summarize and critically evaluate the association between first and second generation BTK inhibitors and the risk of atrial fibrillation (AF) and ventricular arrhythmias (VA). Summary: Since the first clinical experience, the development of AF was observed as the result of off-target effects that likely combined with patient’s predisposing risk factors and concomitant cardiac morbidities. More recently both ibrutinib dose reduction and arrhythmia management allowed long-term treatment, with positive effects on progression-free survival and reduced all-cause mortality as well. Second-generation BTK inhibitors, acalabrutinib and zanubrutinib have been tested and validated in CLL. A lower occurrence of AF as compared with ibrutinib has been found, although AF has always been a secondary endpoint of all studies that probed these agents. Key Messages: For this reason, caution should be exercised before concluding that second-generation BTK inhibitors are safer than ibrutinib. Recent data on the effectiveness of ibrutinib over a follow-up of 8 years show a remarkable benefit on all-cause mortality, which is of great value also for interpreting the clinical impact of the few cases of VA and sudden cardiac death (SCD) reported for ibrutinib, independently of QT lengthening. Since a risk of VA and SCD has been recently reported also during treatment with second-generation BTK inhibitors, it appears that this risk, usually reaching its maximum size effect at long-term follow-up, likely denotes a class effect of BTK-inhibitors.
Massimiliano Camilli, Roderick Skinner, Giulia Iannaccone, Giulia La Vecchia, Rocco Antonio Montone, Gaetano Antonio Lanza, Luigi Natale, Filippo Crea, Matteo Cameli, Marco Giuseppe Del Buono,et al.
Elsevier BV
Giorgio Minotti, Emanuela Salvatorelli, Giorgio Reggiardo, Fabio Mangiacapra, Massimiliano Camilli, and Pierantonio Menna
American Society for Pharmacology & Experimental Therapeutics (ASPET)
Diastolic dysfunction (DD) was reported to precede heart failure (HF) in patients with cancer who were treated with chemotherapy. We aimed at defining risk versus dose relationships and risk predictors in patients with cancer treated mainly with anthracyclines. Data from 67 patients without comorbidities (60 treated with anthracyclines, 7 with nonanthracycline chemotherapy) were retrospectively incorporated in a mathematical function that correlated DD risk with experimental indices of anthracycline accumulation in human myocardium. Risk was calculated for all patients and for subgroups stratified by intertreatment levels of the endogenous cardiac relaxant agent, B-type natriuretic peptide (BNP). Grade I DD (impaired relaxation) occurred in 14 of 67 patients, and 5% risk doses were much lower for DD than HF (mg of anthracycline/m2: 210 vs. 470 or 190 vs. 450 for all patients or anthracycline-treated patients in isolation, respectively; P ≤ 0.01 for DD vs. HF). Patients with transient BNP elevations showed the lowest 5% risk dose (150 mg/m2), whereas patients with persistent elevations showed the highest risk dose (280 mg/m2; P < 0.05). Patients with or without DD were similar for systemic and cardiac exposure to anthracyclines; however, high-risk patients with transient BNP elevations and DD were older and presented at baseline with lower indices of transmitral flow. In conclusion, DD risk develops after lower anthracycline doses than HF and intertreatment levels of BNP help to identify patients with high or low DD risk. These findings are of potential value to monitor or treat the patient with cancer at risk of DD. SIGNIFICANCE STATEMENT DD is an early manifestation of cardiotoxicity from anthracyclines and nonanthracycline chemotherapeutics. We show that merging preclinical characterization of cardiac anthracycline accumulation with clinical data from patients treated primarily with anthracyclines identifies DD risk from very low anthracycline doses. DD risk is associated with older age, baseline diastolic indices toward the lower limit of normal, and transient intertreatment elevations of the endogenous cardiac relaxant agent, BNP. These findings have numerous pharmacological implications.
Massimiliano Camilli, Marco Lombardi, Juan G. Chiabrando, Andrea Zito, Marco G. Del Buono, Rocco Vergallo, Nadia Aspromonte, Antonella Lombardo, Rocco A. Montone, Giampaolo Niccoli,et al.
Ovid Technologies (Wolters Kluwer Health)
Supplemental Digital Content is Available in the Text. Background: Recent trials demonstrated the clinical efficacy of sodium–glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure (HF), regardless of the presence or absence of type 2 diabetes. These data may allow the use of this innovative drug class in clinical routine for treating these patients. Study Question: We aimed at further clarifying the role of SGLT2i in patients with diagnosis of HF, capitalizing on pooled sample size and heightened power for clinically relevant safety and efficacy outcomes. Data Sources: We conducted a systematic search of PubMed, reference lists of relevant articles, and Medline database from inception until March 1, 2021. Study Design: This meta-analysis was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched for randomized trials that evaluated the cardiovascular effects of SGLT2i in patients with HF. Three investigators independently assessed study eligibility, extracted the data, and assessed risk of bias. Hazard ratios and 95% confidence intervals (CIs) were pooled and meta-analyzed using a random-effect model. Numbers needed to treat (NNT) with the relative 95% CIs were also calculated. The primary outcome was a composite of HF hospitalization or an urgent visit for worsening HF and cardiovascular death. Results: Three trials were included in the study. Overall, treatment with SGLT2i was associated with a lower risk of the primary composite outcome [hazard ratios 0.73, 95% CI (0.67–0.80), NNT = 11.3]. Similarly, there was a significantly reduced risk of cardiovascular death, all-cause death, HF hospitalization and need for urgent treatment for HF, and HF hospitalization. Conclusions: Therefore, the available evidence supports the routine use of these drugs as standard-of-care, also given the highly favorable NNTs.
Giorgio Minotti, Giorgio Reggiardo, Massimiliano Camilli, Emanuela Salvatorelli, and Pierantonio Menna
Elsevier BV
Joerg Herrmann, Daniel Lenihan, Saro Armenian, Ana Barac, Anne Blaes, Daniela Cardinale, Joseph Carver, Susan Dent, Bonnie Ky, Alexander R Lyon,et al.
Oxford University Press (OUP)
Abstract The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.
Giorgio Minotti, Pierantonio Menna, Massimiliano Camilli, Emanuela Salvatorelli, and Roberto Levi
Elsevier
Pier Luigi Zinzani and Giorgio Minotti
Springer Science and Business Media LLC
Abstract Purpose CD19 is a cell surface protein that is found on both healthy and malignant B cells. Accordingly, it has become an important target for novel treatments for non-Hodgkin lymphomas and B-cell leukaemia. Three anti-CD19 monoclonal antibodies with distinct mechanisms of action have been developed for the treatment of B-cell malignancies. Methods We reviewed the preclinical and clinical data on the development of the newly approved anti-CD19 monoclonal antibodies blinatumomab, tafasitamab and loncastuximab tesirine, and consider their place in the treatment of relapsed or refractory B-cell malignancies. Results Blinatumomab is a bispecific T-cell engager that binds to both CD19 on B cells and CD3 on T cells, facilitating antibody-dependent cytotoxicity. Blinatumomab significantly prolongs overall survival in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, although cytokine release syndrome and severe neurotoxicity may necessitate discontinuation. Tafasitamab, which has modified anti-CD19 Fab and Fc regions, has significantly enhanced affinity for both CD19 and effector cell receptors compared with unmodified anti-CD19. In L-MIND, tafasitamab plus lenalidomide provided an overall response rate (ORR) of 57.5% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients non-transplant eligible. Loncastuximab tesirine is an antibody–drug conjugate that has been studied as monotherapy and in combination with ibrutinib in 3L + relapsed or refractory DLBCL. The ORR was 48.3% in a phase II trial of loncastuximab tesirine. The optimal place of anti-CD19 monoclonal antibodies in therapy has yet to be determined, but the prospect of improved outcomes for at least some patients with treatment-resistant B-cell malignancies appears likely, particularly in those with limited therapeutic options and poor prognosis.
Giorgio Minotti and Massimiliano Camilli
Elsevier BV
Robert S. Benjamin and Giorgio Minotti
American Association for Cancer Research (AACR)
Abstract Doxorubicin cardiac toxicity is widely misunderstood, largely preventable, and starts with the first dose. This article reviews the history of doxorubicin cardiac toxicity and strategies for minimizing it. Dexrazoxane cardioprotection can safely be initiated on day 1 without compromising antitumor activity, allowing doxorubicin administration beyond the reported maximum lifetime dose. See related articles by Van Tine et al., p. 3854 and Jones et al., p. 3861
Massimiliano Camilli, Marco Lombardi, Juan Guido Chiabrando, Marco Giuseppe Del Buono, Rocco Antonio Montone, Giuseppe Biondi-Zoccai, Filippo Crea, and Giorgio Minotti
Oxford University Press (OUP)
Giorgio Minotti
S. Karger AG
Pierantonio Menna, Emanuela Salvatorelli, Maria Ilaria Del Principe, Salvatore Perrone, Livio Pagano, Francesco Marchesi, and Giorgio Minotti
S. Karger AG
<b><i>Introduction:</i></b> Patients treated with midostaurin and chemotherapy are at risk of invasive fungal disease. Prophylactic posaconazole is recommended for these patients, but posaconazole strongly inhibits the CYP3A4 isozyme that metabolizes midostaurin. Posaconazole therefore introduces a risk of patient’s overexposure to midostaurin. <b><i>Methods:</i></b> Blood samples were obtained from 4 patients treated with midostaurin for newly diagnosed FLT3-<i>mut</i>AML. Patients had received a concomitant treatment with posaconazole, isavuconazole, or micafungin, respectively. All blood samples were drawn before daily dose administration of midostaurin. <b><i>Results:</i></b> Posaconazole caused a ≥8-fold increase of midostaurin plasma levels at through, which was accompanied by a decreased plasma exposure to O-demethylated or hydroxylated midostaurin metabolites. We also show that hematologists react to risk perception by replacing posaconazole with antifungals like micafungin or isavuconazole, which lack a strong inhibition of CYP3A4 and fail to modify midostaurin pharmacokinetics but are not formally recommended in these settings. <b><i>Discussion:</i></b> In real-life scenarios, concerns about CYP3A4 inhibition may outweigh compliance with recommendations. Large studies are needed to survey the risk:benefit of hematologist’s decision to replace posaconazole with other antifungals.
Pierantonio Menna, Emanuela Salvatorelli, and Giorgio Minotti
S. Karger AG