Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure.

FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30-40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30-50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.

Autologous Stem Cell Transplantation in Multiple Myeloma: Where Are We and Where Do We Want to Go?

The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based response-adjusted trials that will define, in particular, the role of consolidation and maintenance therapies. In this review, we will provide an overview of the most recent evidence and the future prospects of ASCT in MM patients.

Conditioning Regimens for Frail Patients with Acute Leukemia Undergoing Allogeneic Stem Cell Transplant: How to Strike Gently.

Despite the recent dramatic progress in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) therapy, allogeneic transplant remains a mainstay of treatment for patients with acute leukemia. The availability of novel compounds and low intensity chemotherapy regimens made it possible for a significant proportion of elderly and comorbid patients with AML or ALL to undergo curative treatment protocols. In addition, the expansion of donor availability and the recent dramatic progress in haploidentical stem cell transplant, allow the identification of an available donor for nearly every patient. Therefore, an increasing number of transplants are currently performed in elderly and frail patients with AML or ALL. However, allo-Hematopoietic stem cell transplant (HSCT) in this delicate setting represents an important challenge, especially regarding the selection of the conditioning protocol. Ideally, conditioning intensity should be reduced as much as possible; however, in patients with acute leukemia relapse remains the major cause of transplant failure. In this article we present modern tools to assess the patient health status before transplant, review the available data on the outcome of frail AML an ALL patients undergoing allo-HSCT, and discuss how preparatory regimens can be optimized in this setting.

Gastrointestinal Complications after Allogeneic Hematopoietic Stem Cell Transplant: A Multidisciplinary Approach with Early Endoscopic Evaluation.

Gastrointestinal complications (GICs) represent the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Differential diagnosis of GICs is of paramount importance since early and reliable identification of graft-versus-host disease (GVHD) is essential for a correct management of the patients. The aim of the present retrospective study was to evaluate the occurrence of GICs after allo-HSCT and to assess the diagnostic performance of a quick endoscopic and histological assessment in the differential diagnosis between GVHD and other GI conditions. Between January 2015 and August 2019, 122 consecutive patients receiving an allo-HSCT were managed by an interdisciplinary team, supported by a dedicated endoscopic service. Clinical, therapeutic, endoscopic and histological data were analyzed for each patient. Collectively, 94 of the patients developed GICs (77%). A moderate-severe mucositis was the most frequent complication, occurring in 79 patients (84%). Acute GI-GVHD was diagnosed in 35 patients (37% of whom with GICs) and 19 of them with a moderate-severe grade. Infective acute colitis developed in eight patients, mainly due to Clostridium difficile (CD) and Cytomegalovirus infections (8.5%). Rectal biopsy showed the highest sensitivity and specificity (80% and 100%, respectively). However, when biopsy procedures were guided by symptoms and performed on apparently intact mucosa, upper histology also provided a high negative predictive value (80%). Our multidisciplinary approach with a quick endoscopic/histologic investigation in the patients receiving an allo-HSCT and who suffered GICs could improve diagnostic and therapeutic management in this challenging setting.

Anticoagulation and Vessel Recanalization in Cirrhotic Patients with Splanchnic Vein Thrombosis: A Multidisciplinary "Real Life" Experience.

BACKGROUND AND AIM: Splanchnic vein thrombosis (SVT) is a potentially life-threatening complication of liver cirrhosis. This study aimed to evaluate the impact of a multi-disciplinary approach and early anticoagulation therapy (AT) on bleeding/thrombotic events, recanalization rates and outcome of cirrhotic patients with SVT. METHODS: This is a single-center, registry-based cohort study. Over 17 years, 149 SVT patients were enrolled and prospectively evaluated. Regarding cirrhotic-SVT, a pre-specified algorithm, guiding initial posology of AT and follow-up visits schedule, was performed. Major bleeding (MB), thrombotic events, functional liver scores and all cause-mortality were investigated. Efficacy of AT was evaluated by radiological imaging. RESULTS: In cirrhotic-SVT, the incidence rate of MB was 8.4 per 100 patient-year (95% CI, 3.83-15.97), while the incidence rate of thrombosis was 5.6 per 100 patient-year (95% CI, 2.05-12.2). In incidental SVT treated with AT, MB incidence was 6.5 per 100 patient-year (95% CI: 2.8-12.82), while in symptomatic SVT was 2.2 per 100 patient-year (95% CI: 0.25-8.02). All thrombotic recurrences occurred in incidental SVT (7.7 per 100 patient-years; 95% CI, 3.71-14.26). Overall survival was significantly higher in patients who had at least a partial recanalization (p < 0.01) and partial/total recanalization was independently associated with improved MELD score at multivariate analysis (HR 2.62, 95% CI 1.1-6.47, p = 0.03). CONCLUSION: In cirrhotic SVT patients, partial or total resolution of thrombosis ameliorates liver function and is associated with higher overall survival. A multidisciplinary approach together with radiological follow-up at pre-fixed time improves patient selection and monitoring.

The Time Has Come for Targeted Therapies for AML: Lights and Shadows.

Acute myeloid leukemia (AML) is a complex disease characterized by genetic and clinical heterogeneity and high mortality. After 40 years during which the standard of care for patients evolved very little, the therapeutic landscape has recently seen rapid changes, with the approval of eight new drugs by the Food and Drug Administration (FDA) within the last 2 years, providing new opportunities, as well as new challenges, for treating clinicians. These therapies include FLT3 inhibitors midostaurin and gilteritinib, CPX-351 (liposomal cytarabine and daunorubicin), gemtuzumab ozogamicin (GO, anti-CD33 monoclonal antibody conjugated with calicheamicin), IDH1/IDH2 inhibitors ivosidenib and enasidenib, Hedgehog inhibitor glasdegib, and BCL-2 inhibitor venetoclax. In this review, we summarize currently available data on these new drugs and discuss the rapidly evolving therapeutic armamentarium for AML, focusing on targeted therapies.

SARS-CoV-2 infection in kidney transplant recipients: Experience of the italian marche region.

BACKGROUND: Infection related to Coronavirus-19 (CoV-2) is pandemic affecting more than 4 million people in 187 countries worldwide. By May 10, 2020, it caused more than 280 000 deaths all over the world. Preliminary data reported a high prevalence of CoV-2 infection and mortality due to severe acute respiratory syndrome related CoV-2 (SARS-CoV-2) in kidney-transplanted patients (KTRs). Nevertheless, the outcomes and the best treatments for SARS-CoV-2-affected KTRs remain unclear. METHODS: In this report, we describe the clinical data, the treatments, and the outcomes of 5 KTRs with SARS-CoV-2 admitted to our hospital in Ancona, Marche region, Italy, from March 17 to present. Due to the severity of SARS-CoV-2, immunosuppression with calcineurin inhibitors, antimetabolites, and mTOR-inhibitors were stopped at the admission. All KTRs were treated with low-dose steroids. 4/5 KTRs were treated with hydroxychloroquine. All KTRs received tocilizumab up to one dose. RESULTS: Overall, the incidence of SARS-CoV-2 in KTRs in the Marche region was 0.85%. 3/5 were admitted in ICU and intubated. One developed AKI with the need of CRRT with Cytosorb. At present, two patients died, two patients were discharged, and one is still inpatient in ICU. CONCLUSIONS: The critical evaluation of all cases suggests that the timing of the administration of tocilizumab, an interleukin-6 receptor antagonist, could be associated with a better efficacy when administered in concomitance to the drop of the oxygen saturation. Thus, in SARS-CoV-2-affected KTRs, a close biochemical and clinical monitoring should be set up to allow physicians to hit the virus in the right moment such as a sudden reduction of the oxygen saturation and/or a significant increase in the laboratory values such as D-dimer.

Feasibility and Outcome of a Phase II Study of Intensive Induction Chemotherapy in 91 Elderly Patients with AML Evaluated Using a Simplified Multidimensional Geriatric Assessment.

INTRODUCTION: We prospectively tested in a phase II study high-dose aracytin and idarubicin plus amifostine as induction regimen in 149 patients with acute myeloid leukaemia (AML) aged ≥ 60 years, evaluated by a simplified multidimensional geriatric assessment (MGA). METHODS: Ninety-one fully or partially fit patients (61%) were allocated to intensive chemotherapy and 58 (39%) frail patients to best supportive care (BSC). Intensively treated patients, showing early death and complete response (CR) rate respectively of 5.5% and 73.6%, received 61 consolidations, followed by autologous transplant (ASCT), stem cell transplantation (SCT) or gemtuzumab ozogamicin, depending on mobilization outcome and donor availability. RESULTS: The 8-year overall survival (OS) of these patients was 20.4%, with median duration of 11.4 months significantly superior to the 1.5 months of BSC arm (p < 0.001). Hyperleukocytosis and cytogenetics were predictors of survival with a relative risk of 1.8 in patients with poor karyotype without hyperleukocytosis (p = 0.02) and 3 in those with hyperleukocytosis (≥ 50,000/µl) (p = 0.002). CONCLUSION: MGA allowed tailored post-consolidation in 53.8% of patients after high-dose aracytin induction, with long-term survival doubling that reported in the literature after standard-dose cytarabine regimens. TRIAL REGISTRATION: The study was registered with the Umin Clinical Trial Registry (www.umin.ac.jp/ctr), number R000014052.

Locally acquired hepatitis E virus in Marche Italy: Clinical/laboratory features and outcome.

BACKGROUND AND AIMS: Hepatitis E Virus is endemic in Europe with increasing numbers of cases in recent years, also in Italy where this phenomenon has hitherto been modest. The aim of this study was to document the clinical features/natural history of locally acquired hepatitis E in our territory and explore factors which determine adverse outcome. METHODS: Retrospective study of patients with locally-acquired HEV (hepatitis E virus) in Marche, Italy (2011-2019). RESULTS: 1189 patients were tested for HEV with 89 confirmed cases. 81 (6.8%) had locally acquired infection; 54 (66%) were male (mean age 55.5 years) and 32 (39.5%) had active co-morbidities. 41 cases were viraemic (all HEV-3 (HEV genotype 1,2,3,4)); acute infection was found in 79 and chronic infection in 2. Forty-five cases (55%) required admission to hospital, for a total of 785 days. 4 patients developed acute on-chronic liver failure, 6 developed acute kidney injury and 8 died: all had active comorbidities. Univariate analysis showed that bilirubin, INR, immunosuppression, cirrhosis and diabetes were associated with death. On multivariant analysis the only predictor of death was the presence of diabetes (p = 0.04). CONCLUSIONS: Hepatitis E in Marche Italy is mostly locally acquired and caused by HEV-3 that impacts on the morbidity and mortality particularly for fragile patients.

Functional correlates of TSH, fT3 and fT4 in Alzheimer disease: a F-18 FDG PET/CT study.

The present study was aimed to investigate the relationships between thyroid stimulating hormone (TSH), freeT3 (fT3) and freeT4 (fT4) and brain glucose consumption as detectable by means of 2-deoxy-2-(F-18) fluoro-D-glucose (F-18 FDG) Positron Emission Tomography/Computed Tomography (PET/CT) in a selected population with Alzheimer disease (AD). We evaluated 87 subjects (37 males and 50 females, mean age 70 (±6) years old) with AD. All of them were subjected to TSH, fT3 and fT4 assay and to cerebrospinal fluid amyloid (Aß1-42) and tau [phosphorylated-tau (p-tau) and total-tau (t-tau)] assay prior PET/CT examination. Values for TSH, fT3 and fT4 were in the normal range. The relationships were evaluated by means of statistical parametric mapping (SPM8) using age, sex, MMSE, scholarship and CSF values of amyloid and tau as covariates. We found a significant positive correlation between TSH values and cortical glucose consumption in a wide portion of the anterior cingulate cortex bilaterally (BA32) and left frontal lobe (BA25) (p FWE-corr <0.001; p FDRcorr <0.000; cluster extent 66950). No significant relationships were found between cortical F-18 FDG uptake and T3 and T4 serum levels. The results of our study suggest that a cortical dysfunction in anterior cingulate and frontal lobes may affect serum values of TSH in AD patients.

PET Probe-Guided Surgery in Patients with Breast Cancer: Proposal for a Methodological Approach.

BACKGROUND: Although it is valuable for detecting distant metastases, identifying recurrence, and evaluating responses to chemotherapy, the role of 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) in assessing locoregional nodal status for initial staging of breast cancer has not yet been well-defined in clinical practice. In the current report, we describe a new PET probe-based clinical approach, with evaluation of the technical performance of a handheld high-energy gamma probe for intraoperative localization of breast carcinomas, and evaluation of lymph node metastases during radio-guided oncological surgery. PATIENTS AND METHODS: Three patients underwent a PET/CT scan immediately prior to surgery following the standard clinical protocol. Intraoperatively, tumors were localized and resected with the assistance of a hand-held gamma probe. PET-guided assessment of the presence or absence of regional nodal spread of malignancy was compared with the reference standard of histopathological examination. RESULTS: In all three cases, perioperative 18F-FDG PET/CT imaging and intraoperative gamma probe detection verified complete resection of the hypermetabolic lesions and demonstrated no additional suspicious occult disease. CONCLUSION: This innovative approach demonstrates great promise for providing real-time access to metabolic and morphological tumor information that may lead to an optimal disease-tailored approach. In carefully selected indications, a PET probe can be a useful adjunct in surgical practice, but further trials with a larger number of patients need to be performed to verify these findings.

Evaluation of recurrent disease in the re-staging of colorectal cancer by 18F-FDG PET/CT: Use of CEA and CA 19-9 in patient selection.

The aim of the present retrospective study was to evaluate the sensitivity and specificity of fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing the recurrence of colorectal cancer (CRC) with regard to carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). 18F-FDG PET/CT was performed in 100 patients for the re-staging of CRC. Therapy was discontinued prior to the examination. The mean (± standard deviation) CEA value (measured ~30 days prior to PET/CT examination) was 23.71 (±107) ng/ml, whereas the CA 19-9 value was 72 (±190.3) U/ml. Differences in CEA and CA 19-9 values in patients with scans that were positive or negative for recurrence were analyzed by means of a receiver operating characteristic (ROC) curve. ROC curves were used for the calculation of the sensitivity and specificity of 18F-FDG PET/CT for the CEA and CA 19-9 levels. The results of the 18F-FDG PET/CT were found to be associated with the CEA level (P=0.001), but not with the CA 19-9 level (P=0.43). PET/CT was positive for recurrence in 60 patients (60.0%), whose mean CEA and CA 19-9 values were 33.07±136.7 ng/ml and 75.24±192.3 U/ml, respectively. PET/CT was negative for recurrence in 40 patients (40.0%), whose mean CEA and CA 19-9 values were 10.15±30 ng/ml and 67.76±190 U/ml, respectively. On the basis of ROC curve analysis, the best compromise between sensitivity and specificity was achieved for CEA levels of 3.5 ng/ml [sensitivity, 80%; 95% confidence interval (CI), 67-89%; and specificity, 60%; 95% CI, 45-78%]. The study concluded that the detection of recurrence by 18F-FDG PET/CT in patients treated for CRC is associated with CEA, but not CA 19-9 serum levels. Moreover, 18F-FDG PET/CT should be recommended in patients with suspected CRC recurrence even when they present with CEA levels below the normal cut-off.

Carbapenem-Resistant Klebsiella pneumoniae influences the outcome of early infections in liver transplant recipients.

BACKGROUND: Infections remain a leading cause of morbidity and mortality among liver transplant (LT) recipients. The aim of our study was to define the factors associated with outcome of early bacterial and fungal infections in a cohort of patients who underwent LT at the University Hospital of Ancona over a nine year period. METHODS: All consecutive patients who underwent LT in our center were considered. An early infection was defined as occurring in the first month post-transplantation. RESULTS: Among 330 patients who underwent LT from August 2005 to October 2014, 88 (27 %) had at least one infection documented within 30 days after transplantation. In 54 cases only one site was involved, in 34 cases ≥2 sites. There were 43 (30 %) pneumonia, 40 (27 %) surgical site infections, 31 (22 %) blood stream infections, and 30 (21 %) urinary tract infections. Gram-negative bacteria accounted for 64 % of the culture-positive cases, followed by Gram-positive bacteria (30 %) and fungi (6 %). A high proportion of drug-resistant strains was found within either Gram-negative (79 %) or Gram-positive (81 %) bacteria. There were 27 out 88 patients (31 %) who died within 180 days from the transplant. Factors independently associated with a higher risk of mortality were: renal replacement therapy (HR 11.797 [CI95 % 3.082-45.152], p < 0.0001), multisite infections (HR 4.865 [CI95 % 1.417-16.700], p = 0.012) and being infected with carbapenem-resistant Klebsiella pneumoniae (CRKP; HR 5.562 [CI95 % 1.186-26.088], p = 0.030). CONCLUSIONS: Overall, these data indicate that early infections in LT patients are characterized by significant mortality. In particular, an early infection caused by CRKP has an adverse impact on survival in these patients suggesting an urgent need for adopting preventive measures to avoiding this complication.

Is cerebral glucose metabolism related to blood-brain barrier dysfunction and intrathecal IgG synthesis in Alzheimer disease?: A 18F-FDG PET/CT study.

The aim of this study was to investigate the relationships between blood-brain barrier (BBB) dysfunction, intrathecal IgG synthesis, and brain glucose consumption as detectable by means of serum/cerebrospinal fluid (CSF) albumin index (Qalb) and IgG index [(CSF IgG/serum IgG) × Serum albumin/CSF albumin)] and 2-deoxy-2-(F) fluoro-D-glucose (F-FDG) positron emission tomography/computed tomography (PET/CT) in a selected population affected by Alzheimer disease (AD). The study included 134 newly diagnosed AD patients according to the NINCDS-ADRDA criteria. The mean (±SD) age of the patients was 70 (±6) years; 60 were male and 64 were female. Mini mental State Examination was equal to 18.9 (±7.2). All patients underwent a CSF assay and magnetic resonance before F-FDG PET scanning. The relationships were evaluated by means of statistical parametric mapping (SPM8). We found a significant negative correlation between the increase of Qalb and F-FDG uptake in the Brodmann Area 42 and 22 that corresponds to the left superior temporal gyrus, with higher Qalb values being related to a reduced glucose consumption in these areas. No significant relationships have been found between brain glucose consumption and IgG index. The results of our study suggest that BBB dysfunction is related to reduction of cortical activity in the left temporal cortex in AD subjects.

Factors affecting ¹8F FDOPA standardized uptake value in patients with primary brain tumors after treatment.

AIM: To investigate the factors affecting (18)F FDOPA uptake in patients with primary brain tumors (PBT) after treatment. MATERIALS AND METHODS: 97 patients with PBT (6 were grade I, 40 were grade II, 29 were grade III and 22 were grade IV) underwent (18)F FDOPA positron emission tomography/computed tomography (PET/CT) after treatment. Intervals from surgery, chemotherapy (CHT) and radiotherapy (RT) were 41.48 (±42.27), 16.04 (±29.08) and 28.62 (±34.49) months respectively. RESULTS: (18)F FDOPA uptake in the site of recurrence was not related to the interval from surgery and CHT while a significant relationship has been found with the interval from RT and tumor grade. CONCLUSIONS: The results of our study show that the interval from RT and the grade of PBT should be considered carefully when evaluating brain PET/CT scans since these factors could directly affect (18)F FDOPA uptake.

Invasive aspergillosis in liver transplant recipients: epidemiology, clinical characteristics, treatment, and outcomes in 116 cases.

Invasive aspergillosis (IA) in liver transplant recipients is associated with grave outcomes. We reviewed 116 individual cases reported in the literature from 1985 to 2013. IA was diagnosed after a median of 25 days after transplantation and involved a single organ in 51% of the cases, whereas in the remaining cases, multiple sites were involved. The most common infecting Aspergillus species were Aspergillus fumigatus (73%), Aspergillus flavus (14%), and Aspergillus terreus (8%). Amphotericin B was the drug most frequently used, and it was followed by voriconazole and itraconazole. Combination regimens were used in 51% of the cases. The overall 1-year cumulative survival probability was 35% [95% confidence interval (CI) = 24.6%-49.6%]. Survival was significantly higher for patients reported from the year 2000 and thereafter (P < 0.001), for those diagnosed with IA more than 30 days after transplantation versus those diagnosed earlier (P = 0.019), and for patients without renal failure (P = 0.020). Additionally, the use of voriconazole was significantly associated with a higher probability of survival (P < 0.001). Cox regression analysis showed that subjects with the involvement of multiple sites had a 2.52 times higher risk of a negative outcome (95% CI = 1.08-5.87) than those with the involvement of a single site. Thus, IA causes life-threatening infections in liver transplant recipients. Predictors associated with poor outcomes may help clinicians to optimize the management of this infection.

Do CSF levels of t-Tau, p-Tau and ß1₋42 amyloid correlate with dopaminergic system impairment in patients with a clinical diagnosis of Parkinson disease? A ¹²³I-FP-CIT study in the early stages of the disease.

PURPOSE: To investigate the relationships among cerebrospinal fluid (CSF) levels of t-Tau, p-Tau and Aß1₋42 amyloid peptide and (123)I-FP-CIT uptake. METHODS: The study included 58 subjects (31 men and 27 women, age 67 ± 9 years) with a clinical diagnosis of Parkinson disease diagnosed according to the United Kingdom Parkinson Disease Society Brain Bank criteria. All subjects underwent a CSF assay 28 ± 3 days before (123)I-FP-CIT SPECT scanning. The relationships were evaluated by means of linear regression analysis and Pearson correlation. RESULTS: Striatal (123)I-FP-CIT was positively related to both t-Tau and p-Tau CSF values with low levels of t-Tau and p-Tau being related to a low uptake of (123)I-FP-CIT. In particular, differences with higher statistical significance were found for the striatum that is contralateral to theside mainly affected on clinical examination (P<0.001) [corrected].No significant relationships were found between Aß1₋42 amyloid peptide and (123)I-FP-CIT binding. CONCLUSION: The results of our study suggest that the presynaptic dopaminergic system is more involved in Parkinson disease patients with lower t-Tau and p-Tau CSF values while values of Aß1₋42 amyloid peptide seems not to be related to nigrostriatal degeneration in our series.