Invasive fusariosis.

Invasive fusariosis is a serious invasive fungal disease, affecting immunocompetent and, more frequently, immunocompromised patients. Localized disease is the typical clinical form in immunocompetent patients. Immunocompromised hosts at elevated risk of developing invasive fusariosis are patients with acute leukemia receiving chemotherapeutic regimens for remission induction, and those undergoing allogeneic hematopoietic cell transplant. In this setting, the infection is usually disseminated with positive blood cultures, multiple painful metastatic skin lesions, and lung involvement. Currently available antifungal agents have poor in vitro activity against Fusarium species, but a clear-cut correlation between in vitro activity and clinical effectiveness does not exist. The outcome of invasive fusariosis is largely dependent on the resolution of immunosuppression, especially neutrophil recovery in neutropenic patients.

Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group.

Infection remains the leading cause of morbidity and mortality in patients with multiple myeloma because of the cumulative effect of disease, treatment, and host-related factors. Given that infectious risk is cumulative through the course of the disease, preventing infections is paramount. Optimal preventive strategies include vaccination against common pathogens, antimicrobial prophylaxis, infection control measures, and immunoglobulin replacement in a small subset of patients; however, there are no universally accepted guidelines for infection prevention. This Review provides a consensus statement from a panel of 36 experts with global representation, which was convened by The International Myeloma Society to review existing literature and current guidelines, address issues associated with the risk of infection and prevention of infectious complications in multiple myeloma in the context of emerging therapies, and offer recommendations for preventing these complications.

Invasive Fusariosis in Patients with Hematologic Diseases.

Fusarium species are filamentous fungi widely encountered in nature, and may cause invasive disease in patients with hematologic conditions. Patients at higher risk are those with acute leukemia receiving induction remission chemotherapy or allogeneic hematopoietic cell transplant recipients. In these hosts, invasive fusariosis presents typically with disseminated disease, fever, metastatic skin lesions, pneumonia, and positive blood cultures. The prognosis is poor and the outcome is largely dependent on the immune status of the host, with virtually a 100% death rate in persistently neutropenic patients, despite monotherapy or combination antifungal therapy. In this paper, we will review the epidemiology, clinical manifestations, diagnosis, and management of invasive fusariosis affecting patients with hematologic diseases.

Healthcare utilization and cost of cancer-related care prior to allogeneic hematopoietic cell transplantation for hematologic malignancies in the US: a retrospective real-world analysis.

BACKGROUND: Hematopoietic cell transplantation (HCT) is a potentially curative therapy as well as a costly procedure. Published studies have examined the cost of HCT in the US and the complications that follow but little is known about the cancer-related healthcare costs and resource utilization prior to the procedure and none of the studies have examined the variability in cost based on the type of hematologic malignancy involved. The aim of this study was to estimate mean cancer-related costs and resources incurred before the HCT is performed from the time the hematologic malignancy first develops. METHODS: The IBM® MarketScan® Research Databases were used to identify adult patients ≥18 years of age with commercial or Medicare supplemental insurance who had undergone allogeneic HCT for hematologic malignancies from January 1, 2008 to December 31, 2017. Healthcare utilization and costs were assessed during the 6 months prior to diagnosis (pre-diagnostic period) and the follow-up period from diagnosis just prior to the HCT (pre-HCT period). Multivariable regression models were constructed to estimate total all-cause costs and cancer-related costs as well as healthcare utilization by type in each time period. RESULTS: A total of 2663 commercially insured patients and 266 with Medicare supplemental insurance were included in the study population. The mean-adjusted incremental cancer-related costs for commercially insured patients was $399,011 in the overall observation period including the pre-diagnostic and pre-HCT periods combined, 9% of which was incurred in the pre-diagnostic period. The corresponding mean-adjusted incremental cancer-related costs for Medicare supplemental patients was $195,575 for the same time period but the patterns of healthcare utilization were similar to the commercially insured population. Inpatient care accounted for approximately one-half the cost in both patient populations. By type of hematologic malignancy, costs were lowest for myeloproliferative disorders ($211,561) and highest for acute lymphocytic leukemia ($462,072) in the commercially insured population. CONCLUSION: This study demonstrates that overall patients with hematologic malignancies requiring HCT have considerable cancer-related healthcare resource utilization and costs leading up to HCT compared to the period of time prior to developing cancer.

Serum 1,3-beta-D-glucan as a noninvasive test to predict histologic activity in patients with inflammatory bowel disease.

BACKGROUND: 1,3-beta-D-glucan (BG) is a ubiquitous cell wall component of gut micro-organisms. We hypothesized that the serum levels of BG could reflect active intestinal inflammation in patients with inflammatory bowel disease. AIM: To determine whether the serum BG concentrations correlate with intestinal inflammation. METHODS: A prospective observational study was performed in a tertiary referral center, from 2016 to 2019, in which serum BG was determined in 115 patients with Crohn's disease (CD), 51 with ulcerative colitis (UC), and 82 controls using a photometric detection kit. Inflammatory activity was determined by ileocolonoscopy, histopathology, magnetic resonance enterography, and biomarkers, including fecal calprotectin (FC), C-reactive protein, and a panel of cytokines. The ability of BG to detect active vs inactive disease was assessed using the area under the receiver operating characteristic curve. In subgroup analysis, serial BG was used to assess the response to therapeutic interventions. RESULTS: The serum BG levels were higher in CD patients than in controls (P = 0.0001). The BG levels paralleled the endoscopic activity in CD patients and histologic activity and combined endoscopic and histologic activity in both CD and UC patients. The area under the curve (AUC) in receiver operating characteristic analysis to predict endoscopic activity was 0.694 [95% confidence interval (CI): 0.60-0.79; P = 0.001] in CD, and 0.662 (95%CI: 0.51-0.81; P = 0.066) in UC patients. The AUC in receiver operating characteristic analysis to predict histologic activity was 0.860 (95%CI: 0.77-0.95; P < 0.001) in CD, and 0.786 (95%CI: 0.57-0.99; P = 0.015) in UC patients. The cut-off values of BG for both endoscopic and histologic activity were 60 µg/mL in CD, and 40 µg/mL in UC patients. Performance analysis showed that the results based on BG of 40 and 60 µg/mL were more specific for predicting endoscopic activity (71.8% and 87.2% for CD; and 87.5% and 87.5% for UC, respectively) than FC (53.3% and 66.7% for CD; and 20% and 80% for UC, respectively); and also histologic activity (60.5% and 76.3% for CD; and 90.0% and 95.0% for UC, respectively) than FC (41.7% and 50.0% for CD; and 25% and 50% for UC, respectively). Regarding the clinical, endoscopic, and histologic activities, the BG levels were reduced following therapeutic intervention in patients with CD (P < 0.0001) and UC (P = 0.003). Compared with endoscopic (AUC: 0.693; P = 0.002) and histologic (AUC: 0.868; P < 0.001) activity, no significant correlation was found between serum BG and transmural healing based on magnetic resonance enterography (AUC: 0.576; P = 0.192). Positive correlations were detected between BG and IL-17 in the CD (r: 0.737; P = 0.001) and the UC group (r: 0.574; P = 0.005), and between BG and interferon-gamma in the CD group (r: 0.597; P = 0.015). CONCLUSION: Serum BG may represent an important novel noninvasive approach for detecting mucosal inflammation and therapeutically monitoring inflammatory bowel diseases, particularly in CD.

Time of catheter removal in candidemia and mortality.

BACKGROUND: The impact of central venous catheter (CVC) removal on the outcome of patients with candidemia is controversial, with studies reporting discrepant results depending on the time of CVC removal (early or any time during the course of candidemia). OBJECTIVE: Evaluate the effect of time to CVC removal, early (within 48h from the diagnosis of candidemia) vs. removal at any time during the course of candidemia, on the 30-day mortality. METHODS: Retrospective cohort study of 285 patients with candidemia analyzing CVC removal within 48h (first analysis) or at any time (second analysis). RESULTS: A CVC was in place in 212 patients and was removed in 148 (69.8%), either early (88 patients, 41.5%) or late (60 patients, 28.3%). Overall, the median time to CVC removal was one day (range 1-28) but was six days (range 3-28) for those removed later. In the first analysis, APACHE II score (odds ratio [OR] 1.111, 95% confidence interval [95% CI] 1.066-1.158), removal at any time (OR 0.079, 95% CI 0.021-0.298) and Candida parapsilosis infection (OR 0.291, 95% CI 0.133-0.638) were predictors of 30-day mortality. Early removal was not significant. In the second analysis APACHE II score (OR 1.122, 95% CI 1.071-1.175) and C. parapsilosis infection (OR 0.247, 95% CI 0.103-0.590) retained significance. CONCLUSIONS: The impact of CVC removal is dependent on whether the optimal analysis strategy is deployed and should be taken into consideration in future analyses.

Time of catheter removal in candidemia and mortality

ABSTRACT Background: The impact of central venous catheter (CVC) removal on the outcome of patients with candidemia is controversial, with studies reporting discrepant results depending on the time of CVC removal (early or any time during the course of candidemia). Objective: Evaluate the effect of time to CVC removal, early (within 48 h from the diagnosis of candidemia) vs. removal at any time during the course of candidemia, on the 30-day mortality. Methods: Retrospective cohort study of 285 patients with candidemia analyzing CVC removal within 48 h (first analysis) or at any time (second analysis). Results: A CVC was in place in 212 patients and was removed in 148 (69.8%), either early (88 patients, 41.5%) or late (60 patients, 28.3%). Overall, the median time to CVC removal was one day (range 1-28) but was six days (range 3-28) for those removed later. In the first analysis, APACHE II score (odds ratio [OR] 1.111, 95% confidence interval [95% CI] 1.066-1.158), removal at any time (OR 0.079, 95% CI 0.021-0.298) and Candida parapsilosis infection (OR 0.291, 95% CI 0.133-0.638) were predictors of 30-day mortality. Early removal was not significant. In the second analysis APACHE II score (OR 1.122, 95% CI 1.071-1.175) and C. parapsilosis infection (OR 0.247, 95% CI 0.103-0.590) retained significance. Conclusions: The impact of CVC removal is dependent on whether the optimal analysis strategy is deployed and should be taken into consideration in future analyses.

Population Pharmacokinetics and Optimal Sampling Strategy for Model-Based Precision Dosing of Melphalan in Patients Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity. OBJECTIVE: The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy. METHODS: A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m2 by intravenous infusion. The determinant-optimal sampling strategy was explored with PopED software. Individual area under the curve estimates were generated by Bayesian estimation using full and the proposed sparse sampling data. The predictive performance of the optimal sampling strategy was evaluated based on bias and precision estimates. The feasibility of the optimal sampling strategy was tested using pharmacokinetic data from five pediatric patients. RESULTS: A two-compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33-0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R 2 = 0.98; p < 0.01) with a mean bias of -2.2% and precision of 9.4%. A similar relationship was observed in children (R 2 = 0.99; p < 0.01). CONCLUSIONS: The developed pharmacokinetic model-based sparse sampling strategy promises to achieve the target area under the curve as part of precision dosing.

Fusariosis.

Fusarium species are frequent agents of onychomycosis and fungal keratitis, and occasional agents of invasive disease. The clinical spectrum of fusariosis in the lungs includes allergic disease (allergic bronchopulmonary fusariosis), hypersensitivity pneumonitis, colonization of a preexisting cavity, and pneumonia. Fusarial pneumonia occurs almost exclusively in severely immunocompromised patients, especially acute leukemia patients and recipients of allogeneic cell transplantation. In such patients, invasive fusariosis is usually disseminated, and pneumonia occurs in almost 50% of cases. The radiologic picture is similar to invasive aspergillosis, with alveolar infiltrates, nodules with or without halo sign, ground-glass infiltrates, and pleural effusions. Different from aspergillosis is the frequent occurrence of disseminated nodular and papular skin lesions and positive blood cultures. The drug of choice for the treatment of invasive fusariosis is either voriconazole or liposomal amphotericin B. The outcome is usually poor, and largely dependent on the recovery of the immune status of the host, particularly neutropenia.

Distinguishing the Causes of Pulmonary Infiltrates in Patients With Acute Leukemia.

Pulmonary infiltrates are commonly observed in patients with acute leukemia (AL), particularly acute myeloid leukemia, who undergo remission induction therapy. The mortality rate is unacceptably high and depends on 3 factors: the host (performance status, comorbidities, and frailty), the etiology of the infiltrates and the type of response to antileukemic therapy. The approach to the diagnosis of pulmonary infiltrates in patients with AL includes a medical history, thorough physical examination, radiologic pattern of the infiltrates (focal vs. diffuse), and timing of their appearance in relation to the start of antileukemic therapy (early, ie, within the first 2 weeks or late). Localized infiltrates are most commonly caused by bacterial (early) and fungal infections (late). Diffuse early infiltrates might be caused by leukemic infiltration of the lungs, pulmonary hemorrhage and/or edema, diffuse alveolar damage, viral pneumonia, and rarely transfusion-related acute lung injury (TRALI) or the differentiation syndrome. Similar to the early phase, pulmonary edema, viral pneumonia, and rarely TRALI might cause diffuse infiltrates during the late phase, in addition to immune reconstitution and pneumocystosis, particularly among patients with acute lymphoblastic leukemia. Diagnostic tests, invasive and noninvasive, can be particularly useful to establish the diagnosis. Early intervention is critical and is based on the most likely diagnosis with modification when the etiology is confirmed.

Tackling antibiotic resistance in febrile neutropenia: current challenges with and recommendations for managing infections with resistant Gram-negative organisms.

Multidrug resistant (MDR) Gram-negative bacteria (GNB) have emerged as important pathogens and a serious challenge in the management of neutropenic patients worldwide. The great majority of infections are caused by the Enterobacteriaceae (especially Escherichia coli and Klebsiella spp.) and Pseudomonas aeruginosa, and less frequently Acinetobacter spp. and Stenotrophomonas maltophilia. A broader-spectrum empiric antibiotic regimen is usually recommended in patients with a history of prior bloodstream infection caused by a MDR GNB, in those colonized by a MDR GNB, and if MDR GNBs are frequently isolated in the initial blood cultures. In any situation, de-escalation to standard empiric regimen is advised if infection with MDR GNB is not documented.

GWAS of 972 autologous stem cell recipients with multiple myeloma identifies 11 genetic variants associated with chemotherapy-induced oral mucositis.

PURPOSE: High-dose chemotherapy and autologous stem cell transplant (ASCT) to treat multiple myeloma (MM) and other cancers carries the risk of oral mucositis (OM) with sequelae including impaired nutritional and fluid intake, pain, and infectious complications. As a result of these problems, cancer treatment may have to be interrupted or delayed. In this study, we looked beyond OM's known risk factors of renal function and melphalan dose with a genome-wide association study (GWAS) to evaluate whether genetic variants in conjunction with clinical risk factors influence predisposition for OM. METHODS: Genotyping was performed using Illumina HumanOmni1-Quad v1.0 BeadChip and further assessed for data quality. We tested 892,589 germline single-nucleotide polymorphisms (SNPs) for association with OM among 972 Caucasian patients treated with high-dose melphalan and ASCT in Total Therapy clinical trials (TT2, TT3, TT4) for newly diagnosed MM. Statistical analyses included t tests, stepwise regression modeling, and logistic regression modeling to find baseline clinical factors and genotypes associated with OM. RESULTS: We found that 353 (36.3 %) patients had grades 2-4 OM. Type of treatment protocol, baseline estimated glomerular filtration rate, and melphalan dose along with baseline serum albumin and female gender predicted 43.6 % of grades 2-4 OM cases. Eleven SNPs located in or near matrix metalloproteinase 13, JPH3, DHRS7C, CEP192, CPEB1/LINC00692, FBN2, ALDH1A1, and DMRTA1/FLJ35282 were associated with grades 2-4 OM. The addition of these SNPs increased sensitivity in detecting grades 2-4 OM cases to 52 %. CONCLUSIONS: These SNPs may be important for their roles in inflammatory pathways, epithelial healing, and chemotherapy detoxification.

How we treat invasive fungal diseases in patients with acute leukemia: the importance of an individualized approach.

Invasive fungal diseases (IFDs) represent an important cause of treatment failure in adults with acute leukemia. Because of leukemia's heterogeneity, the risk for IFDs is highly variable. We therefore apply a risk-adapted antifungal strategy with strong emphasis on pretreatment and day-15 posttreatment to allow earlier and more individualized interventions. We determine pretreatment risks for IFDs based on 4 factors: (1) host fitness for standard therapy (ie, fit, unfit, or frail); (2) leukemia resistance (high vs low probability of achieving complete remission [CR]); (3) anticipated treatment-related toxicity such as neutropenia, mucositis, and steroid-induced immunosuppression; and (4) patient exposure to opportunistic fungi. Accordingly, we stratify patients as high, intermediate, or low risk for IFDs and apply risk-adapted antifungal strategies, including primary or secondary prophylaxis and diagnostic-based preemptive or empiric therapy. Prevention of IFDs also relies on optimizing organ function, decreasing exposure to opportunistic fungi, and improving net state of immunosuppression with use of better-tolerated and investigational agents for unfit patients and those with adverse leukemia biology. Novel targeted and safe therapies that can achieve higher rates of sustained CR among patients with adverse genetics offer the best promise for reducing the burden of IFDs in these patients.

Future directions in the clinical management of amyloid light-chain amyloidosis.

Amyloid light-chain (AL) amyloidosis results from extracellular deposition of fibril-forming monoclonal immunoglobulin light chains (LCs) usually secreted by a plasma cell (PC) clone. Misfolded LCs deposit as unique fibrils leading to organ failure and eventually death. Survival for untreated patients remains poor, and restrictive cardiomyopathy, nephrotic syndrome or hepatic failure greatly worsen outcome. Conventional chemotherapy and novel therapy with immunomodulatory drugs or proteasome inhibitors (PIs) eradicate PCs but generate adverse toxicities, and sustained responses are limited. Moreover, only 20% of patients with AL amyloidosis are eligible for stem cell transplant. The molecular events deregulated in AL amyloidosis remain undefined, and effective therapies based upon the biology of the disease are lacking. Impressive hematologic response rates obtained with bortezomib provide practice-changing data to advocate their introduction early in the treatment course. Bortezomib and the emerging second-generation PIs alone or combined with dexamethasone and alkylating agents may enhance hematologic and organ responses in AL amyloidosis.

Comparison of an assumption-free Bayesian approach with Optimal Sampling Schedule to a maximum a posteriori Approach for Personalizing Cyclophosphamide Dosing.

STUDY OBJECTIVE: Variable metabolism, dose-dependent efficacy, and a narrow therapeutic target of cyclophosphamide (CY) suggest that dosing based on individual pharmacokinetics (PK) will improve efficacy and minimize toxicity. Real-time individualized CY dose adjustment was previously explored using a maximum a posteriori (MAP) approach based on a five serum-PK sampling in patients with hematologic malignancy undergoing stem cell transplantation. The MAP approach resulted in an improved toxicity profile without sacrificing efficacy. However, extensive PK sampling is costly and not generally applicable in the clinic. We hypothesize that the assumption-free Bayesian approach (AFBA) can reduce sampling requirements, while improving the accuracy of results. DESIGN: Retrospective analysis of previously published CY PK data from 20 patients undergoing stem cell transplantation. In that study, Bayesian estimation based on the MAP approach of individual PK parameters was accomplished to predict individualized day-2 doses of CY. Based on these data, we used the AFBA to select the optimal sampling schedule and compare the projected probability of achieving the therapeutic end points. MEASUREMENTS AND MAIN RESULTS: By optimizing the sampling schedule with the AFBA, an effective individualized PK characterization can be obtained with only two blood draws at 4 and 16 hours after administration on day 1. The second-day doses selected with the AFBA were significantly different than the MAP approach and averaged 37% higher probability of attaining the therapeutic targets. CONCLUSIONS: The AFBA, based on cutting-edge statistical and mathematical tools, allows an accurate individualized dosing of CY, with simplified PK sampling. This highly accessible approach holds great promise for improving efficacy, reducing toxicities, and lowering treatment costs.

Steady-state pharmacokinetics of oral voriconazole and its primary metabolite, N-oxide voriconazole, pre- and post-autologous peripheral stem cell transplantation.

Voriconazole (VCZ) is frequently utilized for prevention and treatment of invasive fungal infections in peripheral stem cell transplant (PSCT) patients. We performed an open-label pharmacokinetic study to compare VCZ and N-oxide voriconazole (N-oxide VCZ) pharmacokinetics in patients pre- and post-PSCT. Ten patients completed both sampling periods. The pharmacokinetics of VCZ were unchanged; however, those of N-oxide VCZ were significantly different pre- and post-PSCT.

Waldenström's macroglobulinemia associated with serum amyloid A protein amyloidosis: pitfalls in diagnosis and successful treatment with melphalan-based autologous stem cell transplant.

Waldenström's macroglobulinemia (WM) is increasingly being associated with amyloidosis particularly of the amyloid light-chain variety. We report on one of the few cases of WM associated with serum amyloid A protein (AA) amyloidosis. Autologous stem cell transplant (ASCT) is now being increasingly used for the treatment of amyloidosis, but most studies are small case series. Traditionally AA amyloid is associated with connective tissue disorders and periodic fever syndromes and has been treated by addressing the underlying condition. We present the first case of serum amyloid A being treated with melphalan-based ASCT to deal with the underlying WM and thereby control the amyloid, thus demonstrating the viability of this novel approach for the treatment of this disorder.

Validation of a novel approach for dose individualization in pharmacotherapy using gabapentin in a proof of principles study.

STUDY OBJECTIVE: To demonstrate the premise of individualized dosing charts (IDCs) as a clinical-bedside decision-support tool to individualize dosage regimens for drugs in which the interpatient variability is controlled by the pharmacokinetic (PK) behavior of the patient, to calculate the optimal sampling schedule (OSS), which minimizes the number of blood samples per patient. The approach is illustrated with available PK data for gabapentin. DESIGN: Retrospective proof of principles study using gabapentin PK data from a published clinical trial. PATIENTS: Nineteen subjects in a trial designed to uncover the importance of the genetic contributions to variability in gabapentin absorption, renal elimination, and transport; subjects were monitored for 36 hours after administration of a single dose of gabapentin 400 mg, and plasma concentrations were determined at 14 time points. MEASUREMENTS AND MAIN RESULTS: When the PK profiles were different between subjects, the IDCs are dramatically different from each other and from the IDC for an "average" patient representing the patient population. The dose amount and dosing interval must be adjusted to maximize the probability of staying within the target concentration range. An optimal sampling methodology based on the assumption-free Bayesian approach is used to distinguish the PK profile of an individual patient from the patient population. In the case of gabapentin, only two optimally selected test blood samples, at 1.5 and 6 hours after administration of a single doses, were necessary. The average sensitivity and the average specificity of the OSS was 99% and 96%, respectively. CONCLUSION: IDCs display the risk of a patient violating the target concentration range for any dosage regimen. They can be used as a clinical-bedside decision-support tool in a patient-physician partnership to decide on a dose amount and dosing interval that are medically acceptable while practical and convenient to ensure compliance. By using the assumption-free Bayesian approach and the OSS, the number of samples required from a new patient to individualize the dosage regimen can be reduced significantly while preserving high levels of sensitivity and specificity. Prospective studies are being planned to validate the encouraging results. This approach can be extended to any drug if PK data and a target concentration range are available for either therapeutic drug monitoring or target concentration intervention.