Advances in the pharmacological management of acute myeloid leukemia in adults.

INTRODUCTION: With advances in molecular medicine and precision approaches, there has been significant improvement in the treatment of acute myeloid leukemia (AML) in recent years. This reflects better understanding of molecular and metabolic pathways in leukemia cells, including BCL2 upregulation that prevents apoptosis, FLT3 tyrosine kinase activating mutations that allow uncontrolled proliferation, and IDH mutations that result in differentiation block. AREAS COVERED: We performed a compressive review of important pre-clinical studies in AML that involve major molecular and metabolic pathways in AML, and we discussed standard therapeutic modalities and ongoing clinical trials for patients with AML, as well as an overall update of recent efforts in this area. EXPERT OPINION: Targeting these pathways has resulted in improvement in the overall survival of some groups of AML patients. Secondary AML and TP53 mutated AML remain challenging subtypes of AML with limited treatment options and represent areas of unmet research need. Ongoing work with menin inhibitors in MLL rearranged leukemia, which comprise a large portion of secondary AML cases, the development of CAR T cell products and targeting the CD47 receptor on macrophages in myeloid neoplasms including in TP53 mutated AML have provided hope for these challenging subtypes of AML.

Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors.

Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.

Innate Immune Mechanisms and Immunotherapy of Myeloid Malignancies.

Similar to other cancers, myeloid malignancies are thought to subvert the immune system during their development. This subversion occurs via both malignant cell-autonomous and non-autonomous mechanisms and involves manipulation of the innate and adaptive immune systems. Multiple strategies are being studied to rejuvenate, redirect, or re-enforce the immune system in order to fight off myeloid malignancies. So far, the most successful strategies include interferon treatment and antibody-based therapies, though chimeric antigen receptor (CAR) cells and immune checkpoint inhibitors are also promising therapies. In this review, we discuss the inherent immune mechanisms of defense against myeloid malignancies, currently-approved agents, and agents under investigation. Overall, we evaluate the efficacy and potential of immuno-oncology in the treatment of myeloid malignancies.

Genetically Informed Prostate Cancer Treatment for Metastatic Disease.

Germline testing should be performed to support treatment selection for patients with metastatic prostate cancer, and should be identified in patients with high-risk localized disease. Patients with germline BRCA1/2 mutations should be educated regarding additional personal cancer risk, and risk for family members. Guidelines recommend that all men with metastatic prostate cancer should also undergo somatic tissue and germline testing for priority genes BRCA1/2, PALB2, ATM, and MSH2/6. The advent of high throughput sequencing enables patients to be tested for a more comprehensive panel of germline and somatic mutations.

Operator-Controlled Comparison Between 5 French and 6 French Guiding Catheters for Percutaneous Intervention Using Transradial Approach.

Objective To compare 5 French (Fr) and 6 Fr guiding catheters regarding the volume of contrast administered, fluoroscopy time, and total procedure time during transradial percutaneous coronary intervention (PCI). Background Previous studies had compared 5 Fr and 6 Fr catheters and deemed 5 Fr catheters safe and effective. In this study, we retrospectively compared the 5 Fr catheter to 6 Fr catheter with an attempt to eliminate the effect of inter-operator skill level variability. Methods In a single-center, retrospective cohort study, we randomly selected patients who had received PCI through transradial access using 5 Fr or 6 Fr catheters. The study involved two groups of 100 patients each. These groups were comprised of an equal number of cases from each operator. The primary endpoint was contrast medium volume. Secondary endpoints were fluoroscopy time and procedure time. Results Less contrast was used in the 5 Fr group vs. 6 Fr catheter group (140.2 ± 45.7 mL vs. 158.2 ± 66.7 mL, p=0.004). PCI using 5 Fr catheters was associated with shorter fluoroscopy time (13.7 ± 7.3 mins vs. 15.2 ± 8.2 mins, p=0.584) and shorter procedure time (43.7 ± 22.2 mins vs. 46.5 ± 19.7 mins, p=0.890), but this was not statistically significant. Conclusion Transradial PCI using 5 Fr guiding catheters was associated with less contrast medium usage, but there was no advantage regarding procedure time or fluoroscopy time when compared to 6 Fr catheters. Similar to 6 Fr catheters, 5 Fr catheters achieved high PCI success rates through radial access when compared in the treatment of coronary lesions with the same level of complexity.

Comparison of Transradial and Transfemoral Approaches for Coronary Angiography and Percutaneous Intervention in Patients with Coronary Bypass Grafts.

OBJECTIVE: We sought to compare the transradial and transfemoral approaches for coronary angiography and percutaneous intervention in patients with coronary artery bypass grafts in terms of volume of radiographic contrast administered during cardiac catheterization, fluoroscopy time, and total procedure time. BACKGROUND: The transradial access has been increasingly used as an alternative to transfemoral. Several studies demonstrated that such access is associated with lower rates of vascular and bleeding complications. Although coronary artery bypass graft patients comprise a significant portion of the coronary artery disease population, this subpopulation was often excluded or underrepresented in transradial access studies. METHODS: Single center, retrospective cohort study. In the study period, all patients who had previously undergone coronary artery bypass graft surgery and had received cardiac catheterization at our institution were included in the study population. RESULTS: A total of 2153 patients were included in the study. From these, 1937 were performed by femoral artery and 216 by transradial approach. Compared to the transfemoral approach, transradial access was associated with lower contrast use (136.3 ±â€¯74.4 ml vs. 122.8 ±â€¯59.1 ml, p = 0.035) and longer fluoroscopy time (13.9 ±â€¯25.6 min vs. 15.9 ±â€¯14.3 min, p < 0.001). CONCLUSION: Diagnostic and interventional catheterization through the transradial approach in patients with previous coronary artery bypass graft surgery was associated with less contrast amount used and longer fluoroscopy time compared to the transfemoral approach. The transradial approach was also associated with lower crossover rates and less vascular complications.

Ammonia vs. Lactic Acid in Predicting Positivity of Microbial Culture in Sepsis: The ALPS Pilot Study.

OBJECTIVE: The use of serum ammonia as a novel marker for sepsis compared to lactic acid levels in intensive care unit (ICU) patients. DESIGN AND INTERVENTIONS: Single arm, prospective clinical trial to collect arterial blood samples from patients with sepsis. Serial ammonia and lactic acid levels were sent every six hours for a total of three days. MEASUREMENTS AND RESULTS: Compare mean levels of ammonia and lactic acid in terms of diagnosing sepsis and patient outcome, including length of stay and mortality. A total of 30 patients were enrolled in the pilot study. On admission, mean ammonia level was 35.7 µmol/L and lactic acid was 3.06 mmole/L. Ammonia levels checked at the end of day 2 (ammonia 2-4) and the beginning of day 3 (ammonia 3-1) were higher in patients who had a microbial culture-proven sepsis (p-values 0.029 and 0.002, respectively) compared to those without culture-positive sepsis. Ammonia levels did predict a longer hospital stay; ammonia level of more than 40 µmol/L had a mean hospital stay of 17.6 days vs. patients with normal levels who had a mean hospital stay of 9.62 days (p-value 0.0082). CONCLUSION: Elevated ammonia level can be a novel biomarker for sepsis, comparable to conventional markers. Ammonia levels have a prognostic utility as elevated levels were associated with longer hospital stay.

Candida krusei Empyema Thoracis: A Community-Acquired Infection Requiring a High Index of Suspicion.

Empyema thoracis is a serious condition characterized by the accumulation of purulent fluid in the pleural cavity, typically following a pneumonia, subdiaphragmatic abscess, or esophageal rupture. Fungal empyema thoracis is a rare form of this condition with especially high mortality, in which the most frequently isolated fungus is Candida spp. This article presents a 74-year-old female with Candida krusei pneumonia and a complicated hospital course, initially presenting with nausea, vomiting, and dysphagia. She was initially suspected to have community-acquired pneumonia and was started on azithromycin and ceftriaxone. Worsening respiratory function led to the diagnosis of hydropneumothorax. Pleural fluid and an independent sample of pus and pleural tissue grew Candida krusei, giving the diagnosis of fungal empyema. With further respiratory deterioration, the patient was intubated and switched to piperacillin/tazobactam and micafungin. Decortication with extensive pleural peel and removal of foul-smelling pus and food particles within the chest was performed. This further lead to confirmation of esophageal perforation, and she was started on voriconazole and meropenem. After developing septic shock, the patient was managed with phenylephrine and vasopressin. Finally, after improving she was weaned off pressors and extubated, followed by an esophagogastroduodenoscopy (EDG) with pneumatic balloon dilation and WallFlex stent placement. This patient's case demonstrated an example of empyema thoracis, which required a high index of suspicion since the presentation was with a community-acquired infection. Candida empyema thoracis may be a complication of operation, gastroesophageal fistula, and spontaneous esophageal rupture. On the other hand, the course of this patient's hospital stay progressed from esophageal perforation to Candida krusei pneumonia, empyema, and pneumothorax. Thus, community-acquired fungal empyema should be considered in patients with respiratory symptoms and suspected esophageal perforation; nevertheless, after a diagnosis of fungal empyema, esophageal perforation should also be ruled out in addition to other causes like pneumonia, subphrenic abscess, and hematogenous spread. Improved communication between clinicians and microbiologists can lead to early diagnosis and a reduction in the morbidity and mortality of this condition.

Clonal Emergence of Invasive Multidrug-Resistant Staphylococcus epidermidis Deconvoluted via a Combination of Whole-Genome Sequencing and Microbiome Analyses.

Background: Pathobionts, bacteria that are typically human commensals but can cause disease, contribute significantly to antimicrobial resistance. Staphylococcus epidermidis is a prototypical pathobiont as it is a ubiquitous human commensal but also a leading cause of healthcare-associated bacteremia. We sought to determine the etiology of a recent increase in invasive S. epidermidis isolates resistant to linezolid. Methods: Whole-genome sequencing (WGS) was performed on 176 S. epidermidis bloodstream isolates collected at the MD Anderson Cancer Center in Houston, Texas, between 2013 and 2016. Molecular relationships were assessed via complementary phylogenomic approaches. Abundance of the linezolid resistance determinant cfr was determined in stool samples via reverse-transcription quantitative polymerase chain reaction. Results: Thirty-nine of the 176 strains were linezolid resistant (22%). Thirty-one of the 39 linezolid-resistant S. epidermidis infections were caused by a particular clone resistant to multiple antimicrobials that spread among leukemia patients and carried cfr on a 49-kb plasmid (herein called pMB151a). The 6 kb of pMB151a surrounding the cfr gene was nearly 100% identical to a cfr-containing plasmid isolated from livestock-associated staphylococci in China. Analysis of serial stool samples from leukemia patients revealed progressive staphylococcal domination of the intestinal microflora and an increase in cfr abundance following linezolid use. Conclusions: The combination of linezolid use plus transmission of a multidrug-resistant clone drove expansion of invasive, linezolid-resistant S. epidermidis. Our results lend support to the notion that a combination of antibiotic stewardship plus infection control measures may help to control the spread of a multidrug-resistant pathobiont.

Comparing the safety and efficacy of voriconazole versus posaconazole in the prevention of invasive fungal infections in high-risk patients with hematological malignancies.

Invasive fungal infection (IFI) is a leading cause of morbidity and mortality in immunocompromised cancer patients. New triazole-based antifungal agents have been recommended for IFI prophylaxis in these patients. This retrospective study compared the safety and efficacy of voriconazole and posaconazole as prophylaxis in patients with hematological malignancies (HM), who were admitted to The University of Texas MD Anderson Cancer Center between January 2014 and August 2015, and who were started on single antifungal prophylaxis consisting of either voriconazole or posaconazole. A total of 200 patients with hematological malignancy were evaluated, the majority of whom had acute myeloid leukemia (AML) (67%). Baseline characteristics, including malignancy status and neutropenia status, were comparable in the two groups. The duration of prophylaxis was similar in the two groups, with medians of 46 days for voriconazole and 48 days for posaconazole. There was no significant difference in breakthrough IFIs between the two groups (3% vs. 0%, P = 0.25). Adverse events occurred in 65% of the voriconazole group vs. 78% of the posaconazole group (P = 0.08). Symptomatic adverse events were more common for voriconazole than for posaconazole (6% vs. 0%, P = 0.03). Eleven patients discontinued voriconazole and seven patients discontinued posaconazole due to adverse events. All-cause mortality was similar in the two groups. Both agents were effective in preventing IFI in hematological malignancy, with comparable all-cause mortality rates. Symptomatic adverse events were significantly more common in the voriconazole group, whereas liver function test abnormality was more common in the posaconazole group.

A Novel Nonantibiotic Nitroglycerin-Based Catheter Lock Solution for Prevention of Intraluminal Central Venous Catheter Infections in Cancer Patients.

For long-term central lines (CL), the lumen is the major source of central line-associated bloodstream infections (CLABSI). The current standard of care for maintaining catheter patency includes flushing the CL with saline or heparin. Neither agent has any antimicrobial activity. Furthermore, heparin may enhance staphylococcal biofilm formation. We evaluated the safety and efficacy of a novel nonantibiotic catheter lock solution for the prevention of CLABSI. Between November 2015 and February 2016, we enrolled 60 patients with hematologic malignancies who had peripherally inserted central catheters (PICC) to receive the study lock solution. The study lock consisted of 15 or 30 µg/ml of nitroglycerin in combination with 4% sodium citrate and 22% ethanol. Each lumen was locked for at least 2 h once daily prior to being flushed. After enrollment of 10 patients at the lower nitroglycerin dose without evidence of toxicity, the dose was escalated to the higher dose (30 µg/ml). There were no serious related adverse events or episodes of hypotension with lock administration. Two patients experienced mild transient adverse events (one headache and one rash) possibly related to the lock and that resolved without residual effect. The CLABSI rate was 0 on lock days versus 1.6/1,000 catheter days (CD) off lock prophylaxis, compared with a rate of 1.9/1,000 CD at the institution in the same patient population. In conclusion, the nitroglycerin-based lock prophylaxis is safe and well tolerated. It may prevent CLABSI when given daily to cancer patients. Large, prospective, randomized clinical trials are needed to validate these findings. (This study has been registered at ClinicalTrials.gov under identifier NCT02577718.).