CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program

Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT

Ultrasound-assessed visceral fat and associations with glucose homeostasis and cardiovascular risk in clinical practice

Despite the lack of evidence that assessing the global cardiovascular risk leads to a decreased incidence of cardiovascular events, accurate patient profiling is paramount in preventive medicine. An excess of visceral fat (VF) is associated with an enhanced cardiovascular risk; importantly, VF is quantifiable rapidly, cheaply and safely by ultrasound, which makes it suitable for use in clinical practice. In the present study, we aimed to evaluate if US-measured VF (USVF) could be a better predictor of glucose homeostasis and cardiovascular risk than simple anthropometric measures

Antiviral treatment of hepatitis C improves glucose metabolism along the entire spectrum from normal glucose tolerance to diabetes

Background and Aims: Insulin resistance (IR) complicates frequently chronic hepatitis C virus (HCV) infection, leading to an increased incidence of type 2 diabetes mellitus among infected patients. Indeed, it is well known that diabetes control of these patients benefits of successful treatment with either interferon-based regimens or direct antivirals (DAA). Whether the same applies to more subtle alterations of glucose metabolism is unknown. We aimed to fill this gap. Method: The study population included 82 HCV RNA positive patients (48 males, median age 66 years, 73 with advanced fibrosis, 41 HCV-1b), attending the liver clinic of an academic hospital, not previously known to be diabetics. A standard oral glucose tolerance test (OGTT) was performed in all patients before starting DAA treatment and after its conclusion. OGTT results were interpreted according to the American Diabetes Association guidelines. Results: Based on the results of the baseline OGTT, the majority of patients had evidence of abnormal glucose metabolism (N=45,54%; impaired fasting glucose (IFG) 10%, impaired glucose tolerance (IGT) 16%, IFG+IGT 12%, while 17% were diabetics). Conversely, only a minority of them(N=37,45%)were normally glucose tolerant. At the end of treatment, HCV RNA quantification was below the detection threshold (HCV RNA <12 UI/ml), for all the subjects enrolled. A significant decrease in glucose and insulin plasma concentrations was evident both at fasting and after 60 and 120 minutes, leading to a significant reduction in the Homeostasis model assessment (HOMA) IR (from 3.42 [2.66\u20135.38] to 2.80 [1.78\u20133.95]); p<0.001 and a corresponding increase in insulin sensitivity (ISI Belfiore from 0.49 [0.26\u20130.75] to 0.64 [0.42\u20130.91]; p<0.001) despite a significant reduction in insulin secretion (EFP Stumvoll from 1363.0 [959.2\u2013 1730.0] to 1264.0 [975.8\u20131588.0]; p=0,027). Moreover, a significant decrease in glycated hemoglobin was observed (p=0.008), and two patients, formerly categorized as diabetics, did not satisfy criteria OGTT for diabetes anymore. The number of patients with normal glucose tolerance increased from 37 (45.1%)to 53 (64.6%); p=0.013), which was paralleled by a reduced number of those satisfying criteria for prediabetic conditions (31 (37.9%) vs.17 (20.8%); p=0.025). Conclusion: After treatment with DAA, glucose metabolism parameters of HCV infected patients improve early and affect the entire pathophysiologic spectrum of glucose metabolism

Sequential Treatment with Ipilimumab and BRAF Inhibitors in Patients With Metastatic Melanoma: Data From the Italian Cohort of the Ipilimumab Expanded Access Program

Of 93 patients with pretreated, BRAFV600 mutation-positive advanced melanoma who received vemurafenib or dabrafenib before (n = 45) or after (n = 48) treatment with ipilimumab 3 mg/kg, median overall survival (mOS) from first treatment was 9.9 and 14.5 months, respectively. Among patients treated with a BRAF inhibitor first, mOS from the end of BRAF inhibition was 1.2 months for those who did not complete ipilimumab treatment as per protocol, compared with 12.7 months for those who did (p &lt; .001). Prospective, randomized studies are required to determine the optimal sequencing of ipilimumab and BRAF inhibitors in patients with BRAF-mutated metastatic melanoma. Copyright © 2014 Informa Healthcare USA, Inc

Sequential Treatment with Ipilimumab and BRAF Inhibitors in Patients With Metastatic Melanoma: Data From the Italian Cohort of the Ipilimumab Expanded Access Program

Of 93 patients with pretreated, BRAFV600 mutation-positive advanced melanoma who received vemurafenib or dabrafenib before (n = 45) or after (n = 48) treatment with ipilimumab 3 mg/kg, median overall survival (mOS) from first treatment was 9.9 and 14.5 months, respectively. Among patients treated with a BRAF inhibitor first, mOS from the end of BRAF inhibition was 1.2 months for those who did not complete ipilimumab treatment as per protocol, compared with 12.7 months for those who did (p &lt; .001). Prospective, randomized studies are required to determine the optimal sequencing of ipilimumab and BRAF inhibitors in patients with BRAF-mutated metastatic melanoma. Copyright © 2014 Informa Healthcare USA, Inc

CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program

Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT

The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors

Background: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. Methods: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. Results: Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068). Conclusions: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways