Charting a path forward: Promising outcomes of convalescent plasma therapy in the care of severely B-cell depleted patients with persistent COVID-19.

BACKGROUND: Patients with severe B-cell depletion related to hematological malignancies or B-cell targeted therapy suffer from impaired antibody responses to SARS-CoV-2 and are at risk for prolonged COVID-19. In this population, COVID-19 convalescent plasma (CCP) may provide passive immunity, enhance immune response, and promote virus neutralization. This study evaluated outcomes of B-cell depleted patients with persistent COVID-19 treated with CCP. STUDY DESIGN AND METHODS: This analysis included all consecutive severely B-cell depleted patients with persistent COVID-19, receiving CCP at Rambam between 01.2022-02.2023. Persistent COVID-19 was defined as the presence of symptoms for ≥14 days in patients with negative SARS-CoV-2 nucleocapsid antibody test results. RESULTS: Twenty patients met inclusion criteria, 17 of whom had hematological malignancies, two suffered from rheumatoid arthritis and one had both. Twelve patients received anti-CD-20 treatment, one - CAR-T cells and three underwent stem cell transplantation. The median duration of COVID-19 symptoms was 27.5 days (range 14-97); 12 patients had mild-to-moderate COVID-19 and 8 had severe infection. Sixteen patients required hospitalization. The majority of patients received other COVID-19 therapies before CCP. Within a median of two days (range 1-16) post-infusion, 19/20 patients clinically improved. No CCP-associated adverse events were documented. COVID-19 symptoms recurred in 3 of the improved patients. Two patients died from COVID-19 on days 1 and 90 following the first CCP infusion. DISCUSSION: In severely B-cell depleted patients with persistent COVID-19, CCP is safe and associated with rapid clinical improvement. This subset of immunocompromised patients could particularly benefit from CCP administration.

Modified Citrus Pectin Treatment in Non-Metastatic Biochemically Relapsed Prostate Cancer: Long-Term Results of a Prospective Phase II Study.

The optimal therapy for patients with non-metastatic biochemically relapsed prostate cancer (BRPC-M0) after local therapy is elusive. Thus, the evaluation of new non-toxic compounds in BRPC-M0 patients is warranted. PectaSol®-Modified citrus pectin (P-MCP) is a food supplement categorized as GRAS (Generally Recognized As Safe) by the FDA. It is a competitive inhibitor of the galectin-3 protein, which is involved in cancer pathogenesis. In an early report of the present phase 2 study, P-MCP treatment for 6 months led to prostate-specific antigen doubling time (PSADT) improvement in 75% of patients with BRPC-M0. Herein, we report the second long-term treatment phase of an additional 12 months of P-MCP therapy (4.8 g × 3/day orally) in patients without disease progression after the initial 6 months of therapy. Of the 46 patients that entered the second treatment phase, 7 patients withdrew consent and decided to continue therapy out of pocket, and 39 initiated the second treatment phase. After a total of 18 months of P-MCP treatment, 85% (n = 33) had a durable long-term response, with 62% (n = 24) showing decreased/stable PSA, 90% (n = 35) PSADT improvement, and all with negative scans. No patient had grade 3/4 toxicity. In conclusion, P-MCP may have long-term durable efficacy and is safe in BRPC-M0.

External Validity of a Randomized Controlled Trial on Duration of Antibiotics for the Treatment of Gram-Negative Bacteremia.

INTRODUCTION: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial. METHODS: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017. In a concomitant observational study, RCT participants were compared with patients who fulfilled the inclusion criteria but were not included in the trial due to participation in other trials, discharge before approached by researchers, refusal to participate, or unwillingness of the treating physician to allow participants' recruitment. RESULTS: Six hundred and four RCT patients were compared with 613 nonincluded patients. Almost 50% of nonincluded patients (288/613) were dependent on others for activities of daily living at baseline compared to 37.7% of RCT participants (228/604). Dementia was nearly 2-fold more frequent in nonincluded patients than those included (5.9% [36/613] versus 3.6% [22/604], p = 0.07). Patients who were not included in the RCT were more likely to acquire their infection in the hospital (53.3% [327/613] versus 29.1% [176/604], p < 0.001). The primary composite outcome of mortality, clinical failure, readmissions, or extended hospitalization at 90 days occurred in 353 of 613 nonincluded patients (57.6%) compared to 299 of 604 RCT participants (49.6%), p = 0.005. However, on multivariate analysis noninclusion in the RCT was not an independent risk factor for clinical failure and mortality. CONCLUSIONS: RCTs, even with broad eligibility criteria, do not represent the whole spectrum of patients and leave out a population with more severe illness for whom the evidence is lacking.

Outcomes of Refractory Cytomegalovirus Infection in the First Year after Allogeneic Hematopoietic Cell Transplantation.

Outcomes of refractory (Rf) cytomegalovirus (CMV) infection (CMVi) after hematopoietic cell transplantation (HCT) are poor owing to limited treatment options and treatment related toxicities. Maribavir, an orally bioavailable CMV antiviral, was recently approved for treatment of Rf-CMVi. Real-world studies quantifying the burden of Rf-CMVi prior to maribavir provide a benchmark for evaluating the net value of novel treatments. Here we report the incidence, clinical outcomes, and healthcare resource utilization (HRU) associated with Rf-CMVi in the first year post-HCT in a cohort of CMV-seropositive HCT recipients (R+) who underwent HCT between January 1, 2014, and December 31, 2017, at Memorial Sloan Kettering Cancer Center and were managed exclusively by preemptive therapy. CMVi was defined as CMV viremia treated preemptively. Rf-CMVi was defined as a <1 log10 decrease and CMV viral load >1000 U/mL after ≥14 days of appropriately dosed therapy. Welldays were defined as alive days not hospitalized and off CMV antivirals by 1 year post-HCT. The impact of Rf-CMVi on mortality and HRU was examined in multivariable models. Of the 286 R+ patients, 145 (50.7%) developed CMVi (99 no Rf-CMVi and 46 Rf-CMVi). Compared with the no Rf-CMVi group, the Rf-CMVi group had higher rates of CMV EOD (23.9% versus 10.1%; P = .030), CMV-related mortality (9.5% versus .0%; P = .002), and all-cause mortality (33.3% versus 15.6%; adjusted P = .049). Rf-CMVi was an independent predictor for readmission (adjusted odds ratio [aOR], 3.24; 95% confidence interval [CI], 2.19 to 4.87; P < .0001); CMV-related readmission (aOR, 9.48; 95% CI, 5.83 to 15.80; P < .0001), and decreased well days (adjusted arithmetic mean ratio, .72; 95% CI, .58 to .89; P = .001) in the first year post-HCT. Rf-CMVi is associated with increased mortality and increased HRU at 1 year after HCT. Improved therapies for Rf-CMVi have the potential of improving HCT outcomes and reducing HRU.

COVID-19 in Patients with Hematologic Malignancies: Clinical Manifestations, Persistence, and Immune Response.

BACKGROUND: The clinical presentation of coronavirus disease 19 (COVID-19) is the result of intricate interactions between the novel coronavirus and the immune system. In patients with hematologic malignancies (HM), these interactions dramatically change the clinical course and outcomes of COVID-19. SUMMARY: Patients with HM and COVID-19 are at an increased risk for prolonged viral shedding, more protracted and severe presentation, and death, even when compared to other immunocompromised hosts. HM (e.g., multiple myeloma, chronic lymphocytic leukemia) and anticancer treatments (e.g., anti-CD20 agents) that impair humoral immunity markedly increase the risk of severe COVID-19 as well as protracted viral shedding and possibly longer infectivity. Cytokine release syndrome (CRS) is an important player in the pathophysiology of severe and fatal COVID-19. Treatments targeting specific cytokines involved in CRS such as interleukin-6 and Janus kinase have proven beneficial in COVID-19 patients but were not assessed specifically in HM patients. Although neutropenia (as well as neutrophilia) was associated with increased COVID-19 mortality, granulocyte colony-stimulating factors were not beneficial in patients with COVID-19 and may have been associated with worse outcomes. Decreased levels of T lymphocytes and especially decreased CD4+ counts, and depletion of CD8+ lymphocytes, are a hallmark of severe COVID-19, and even more so among patients with HM, underlying the important role of T-helper dysfunction in severe COVID-19. In HM patients with intact cellular immunity, robust T-cell responses may compensate for an impaired humoral immune system. Further prospective studies are needed to evaluate the mechanisms of severe COVID-19 among patients with HM and assess the efficacy of new immunomodulating COVID-19 treatments in this population. KEY MESSAGES: Understanding the immunopathology of COVID-19 has greatly benefited from the previous research in patients with HM. So far, no COVID-19 treatments were properly evaluated in patients with HM. Patients with HM should be included in future RCTs assessing treatments for COVID-19.

Implementing Lean Techniques to Increase the Efficiency of a Rural Primary Care Clinic: A Prospective Controlled Study.

BACKGROUND: Lean, a management approach focused on identifying and eliminating waste, has been proposed as a solution for shortages in health care. Many studies implementing Lean in health care have lacked adequately designed controls. METHODS: This was a prospective, block randomized, controlled study conducted in a single primary care clinic comprising three primary care providers. A multidisciplinary team constructed a value stream, proposing foci of waste and possible solutions. These were implemented during three consecutive eight-week blocks. A sample was taken of 40 random visits for each physician during each block, and one physician was randomized to implement the interventions while the other two served as controls. RESULTS: Intervention blocks were significantly shorter compared to control blocks, with a mean difference (MD) of -1,190 seconds (s) (95% confidence interval = 1,039-1,342, p < 0.001). This was primarily the result of four interventions: (1) relocating the printer to the front desk (MD -378 s, p < 0.001), (2) adding another parallel working station (MD -258 s uploading the patient's file and MD -138 s uploading the history, p < 0.001 for both), (3) documenting in plain typing (MD -229 s, p < 0.001), and (4) rerouting delayed patients to the next available physician (MD -195 s, p = 0.004). Two steps were modestly lengthened: anamnesis (MD 24 s, p < 0.001) and explaining the diagnosis and treatment plan (MD 11 s, p = 0.001). Average productivity was increased by 1.65 appointments per hour (p < 0.001). Burnout scores decreased from an average of 74 points during control blocks to 63.8 on intervention (p < 0.01). No clinically or statistically significant difference was noted in quality of care, definitivity of treatment, or patient satisfaction (p = 0.83, 0.55, and 0.77, respectively). CONCLUSION: Intrinsically led, multidisciplinary Lean implementation in a rural primary care clinic dramatically shortened the value stream duration, while requiring no extrinsic resources. Widening Lean implementation and research in primary care, particularly in rural settings, may increase the availability and effectiveness of primary care.

Impact of Letermovir Primary Cytomegalovirus Prophylaxis on 1-Year Mortality After Allogeneic Hematopoietic Cell Transplantation: A Retrospective Cohort Study.

BACKGROUND: Cytomegalovirus (CMV)-seropositive (R+) hematopoietic cell transplant (HCT) recipients have a survival disparity compared with CMV-seronegative recipient/donor (R-D-) pairs. We hypothesized that primary letermovir prophylaxis (LET) may abrogate this disparity. We investigated the relationship between LET and mortality at 1 year post-HCT. METHODS: In this retrospective cohort study, we included adult R-D- or R+ patients who received HCT pre-LET (between 1 January 2013 through 15 December 2017) and post-LET (between 16 December 2017 through December 2019). R+ were categorized by LET receipt as R+/LET or R+/no-LET. Cox proportional hazard models were used to estimate the association of LET with all-cause mortality at 1 year after transplantation. RESULTS: Of 848 patients analyzed, 305 were R-D-, 364 R+/no-LET, and 160 R+/LET. Because of similar mortality (adjusted hazard ratio [aHR], 1.29 [95% confidence interval {CI}, .76-2.18]; P = .353]) between pre-LET/R-D- and post-LET/R-D-, R-D- were combined into 1 group. Compared with R-D-, the aHR for mortality was 1.40 (95% CI, 1.01-1.93) for R+/no-LET and 0.89 (95% CI, .57-1.41) for R+/LET. Among R+, LET was associated with decreased risk of death (aHR, 0.62 [95% CI, .40-.98]); when conventional HCT and T-cell depleted HCT were analyzed separately, the aHR was 0.86 (95% CI, .51-1.43) and 0.21 (95% CI, .07-.65), respectively. CONCLUSIONS: At 1 year post-HCT, LET was associated with closing the mortality disparity between R-D- and R+. Among all R+, LET was associated with decreased mortality, driven by 79% reduced incidence of death in T-cell depleted HCT.

Omitting Ciprofloxacin Prophylaxis in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation and Its Impact on Clinical Outcomes and Microbiome Structure.

Fluoroquinolone prophylaxis during allogeneic hematopoietic stem cell transplantation (allo-HSCT) reduces bloodstream infections. However, this practice affects the gut microbiome and potentially increases dysbiosis, which is closely related to transplantation outcomes, and lower gastrointestinal (GI) tract acute graft-versus-host disease (GVHD). This study assessed the impact of omitting ciprofloxacin prophylaxis on GI GVHD, clinical outcomes, and microbiome composition in patients undergoing allo-HSCT. In this single-center, retrospective study comprising recipients of allo-HSCT performed between 2018 and 2020, routine ciprofloxacin prophylaxis (the exposure variable) was stopped in December 2018. The primary outcome was acute lower GI GVHD within 100 days post-transplantation; secondary outcomes were 1-year overall survival, nonrelapse mortality, relapse, and overall acute GVHD. Outcomes were compared using univariate and multivariate analyses and Kaplan-Meier/competing-risk analyses. Sequential stool samples were collected prospectively from a subpopulation of recipients, and the microbiome composition was analyzed. Seventy-five of the 129 patients (58.1%) received prophylactic ciprofloxacin treatment. Baseline characteristics did not differ between the 2 study groups: patients with ciprofloxacin prophylaxis and those without ciprofloxacin prophylaxis. The rate of lower GI GVHD also did not differ between the 2 groups (24% versus 18.5%; P = .597). None of the secondary outcomes was significantly different between the 2 groups in univariate, multivariate, and time-to-event analyses. In addition, microbiome analysis in a subpopulation of 22 patients did not reveal any significant between-group difference in alpha or beta diversity. Omitting prophylactic ciprofloxacin during allo-HSCT did not affect microbiome composition, lower GI-GVHD rate, or other significant clinical outcomes. The use of prophylactic antibiotics in this setting should be evaluated further.

Immune reconstitution inflammatory syndrome (IRIS) in a patient with neuro pulmonary nocardiosis following hematopoietic cells transplantation (HCT).

Immune reconstitution inflammatory syndrome (IRIS) is increasingly reported in various HIV negative patients with immunosuppression, but the relationship with hematopoietic cell transplantation (HCT) is not well defined. We report a case of IRIS in a patient infected with pulmonary and CNS Nocardiosis following HCT due to primary myelofibrosis.

Risk factors for functional decline among survivors of Gram-negative bloodstream infection: A prospective cohort study.

OBJECTIVE: To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia. PATIENTS AND METHODS: A prospective cohort study based on a randomized controlled trial conducted between January 1, 2013 and August 31, 2017 in Israel and Italy. Hospitalized patients with Gram-negative bacteremia who survived until day 90 and were not bedridden at baseline were included. The primary end point was functional decline at 90 days. RESULTS: Five hundred and nine patients were included. The median age of the cohort was 71 years (interquartile range [IQR], 60-80 years), 46.4% (236/509) were male and 352 of 509 (69%) patients were independent at baseline. Functional decline at 90 days occurred in 24.4% of patients (124/509). In multivariable analysis; older age (odds ratio [OR], 1.03; for an one-year increment, 95% confidence interval [CI] 1.01-1.05), functional dependence in instrumental activities of daily living at baseline (OR, 4.64; 95% CI 2.5-8.6), low Norton score (OR, 0.87; 95% CI 0.79-0.96) and underlying comorbidities: cancer (OR, 2.01; 95% CI 1.14-3.55) and chronic pulmonary disease (OR, 2.23 95% CI 1.12-4.42) and longer length of hospital stay (OR 1.09; for one-day increment, 95% CI 1.04-1.15) were associated with functional decline. Appropriate empirical antibiotic treatment was associated with lower rates of functional decline within 90 days (OR, 0.4; 95% CI 0.21-0.78). CONCLUSIONS: Patients surviving bloodstream infections have poor long term trajectories after clinical recovery and hospital discharge. This has vast implications for patients, their family members and health policy makers.

Safety and efficacy of intravenously administered cidofovir in adult haematopoietic cell transplant recipients: a retrospective multicentre cohort study.

OBJECTIVES: To evaluate the safety and efficacy of cidofovir for the treatment of double-stranded DNA (dsDNA) viral infections following allogeneic haematopoietic cell transplant (HCT). METHODS: This was a retrospective multicentre cohort study including adult HCT recipients who received ≥1 dose of IV-administered cidofovir for any dsDNA viral infection from 2006 to 2019. The objectives were to describe the rate of and risk factors for nephrotoxicity and virological response by the end of treatment (EOT). RESULTS: We included 165 patients from nine centres. Cidofovir was administered at 5 mg/kg/week (N = 115; 69.7%), 1 mg/kg/week (18; 10.9%), 3 mg/kg/week (12; 7.3%) or 1 mg/kg three times/week (11; 6.7%). Cidofovir was administered for adenovirus, cytomegalovirus (CMV) and BK virus infection in 75 (45.5%), 64 (38.8%) and 51 (30.9%) patients, respectively. Among 158 patients with renal function data at baseline and EOT, 40 (25.3%) developed nephrotoxicity. In multivariable analyses, age (OR 1.04; P = 0.05), weight (OR 1.05; P = 0.01), CMV infection (OR 3.6; P = 0.02), liposomal amphotericin B (OR 8.06; P = 0.05) and IV voriconazole/posaconazole (OR 13.0; P = 0.003) were predictors of nephrotoxicity. Creatinine concentration was significantly higher at EOT (1.16 ±â€Š0.95 mg/dL) compared with baseline (0.91 ±â€Š0.39 mg/dL; P < 0.001), but improved by 2 weeks (0.91 ±â€Š0.84 mg/dL; P = 0.007) and 4 weeks (0.96 ±â€Š0.89 mg/dL; P = 0.03) post-EOT. Median viral load significantly declined for patients with adenovirus DNAaemia by EOT (P < 0.0001) and for patients with CMV DNAaemia by EOT + 4 weeks (P = 0.003), but not for patients with BK virus DNAaemia. CONCLUSIONS: One in four HCT recipients treated with IV cidofovir developed largely reversible nephrotoxicity. Careful selection of patients and close follow-up of renal function may minimize toxicity.

Multidrug-resistant, gram-negative infections in high-risk haematologic patients: an update on epidemiology, diagnosis and treatment.

PURPOSE OF REVIEW: Multidrug-resistant Gram-negative bacilli (MDR-GNB) infections are a significant cause of morbidity and mortality in high-risk hematologic patients. Early diagnosis and management of antibiotic treatment in these patients is a challenge for physicians. This review focuses on the latest literature reports that concern the epidemiology, diagnosis and treatment of MDR-GNB infections in this population. RECENT FINDINGS: High-risk haematological patients have several risk factors that make them particularly susceptible to MDR-GNB infections. Few studies have examined the implementation of rapid diagnostic methods for multidrug resistance, and their impact on management in this population. Inappropriate empiric antibiotic treatment in these patients has been described frequently and is associated with poor outcomes. SUMMARY: Knowledge of the local epidemiology of MDR-GNB is a basic requirement to guide empiric antibiotic treatments in each centre. New diagnosic tests might help in faster identification of MDR-GNB infections. Appropriate empiric antibiotic treatment is crucial for improving patients' prognosis. Important strategies to reduce inadequate antibiotic treatment include better risk stratification for MDR-GNB infection and the introduction of new, more broad-spectrum antibiotic therapies.

Efficacy and safety of isavuconazole compared with voriconazole as primary antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients.

Voriconazole is frequently discontinued prematurely as primary antifungal prophylaxis (AFP) in allogeneic hematopoietic cell transplant (HCT) recipients due to adverse events. Limited data exists for isavuconazole as AFP. We analyzed adult HCT recipients who received voriconazole or isavuconazole AFP to estimate rate of premature AFP discontinuation, identify risk factors for premature AFP discontinuation, and compare incidence of invasive fungal infection (IFI) and survival at day + 180 post-HCT between patients who received voriconazole/isavuconazole-AFP. This was a propensity score matched cohort analysis of 210 HCT-recipients who received voriconazole-AFP (9/1/2014-12/31/2016; voriconazole-cohort), and 95 HCT-recipients who received isavuconazole-AFP (5/1/2017-10/31/2018; isavuconazole-cohort). AFP discontinuation for any reason prior to completion was defined as "premature". Median (interquartile range, IQR) duration of AFP was longer in the isavuconazole-cohort (94 days, 87-100) vs. the voriconazole-cohort (76 days, 23-94; P-value < 0.0001). Premature AFP discontinuation was more frequent in the voriconazole-cohort (92/210, 43.8%) vs. the isavuconazole-cohort (14/95, 14.7%; P-value < 0.0001). The most common reason for premature discontinuation was biochemical hepatotoxicity (voriconazole-cohort: 48/210, 22.8% vs. isavuconazole-cohort: 5/95, 5.26%; P-value = 0.0002). Transaminase values between baseline and end-of-treatment (EOT) and up to 14 days post-EOT significantly increased in the voriconazole-cohort, but remained unchanged in the isavuconazole-cohort. The incidence of IFI at day + 180 was 2.9% (6/210) and 3.2% (3/95) in the voriconazole-cohort and isavuconazole-cohort, respectively (P-value = 0.881). All-cause mortality at day + 180 was 2.4% (5/210) and 6.3% (6/95) in the voriconazole-cohort and isavuconazole-cohort, respectively (P-value = 0.089). When compared to voriconazole, isavuconazole was a safer and as effective primary AFP during the first 3 months after HCT. LAY SUMMARY: When compared to voriconazole, isavuconazole is a safer and as effective primary antifungal prophylaxis during the first 3 months after allogeneic hematopoietic cell transplant, with lower rates of hepatotoxicity, and similar rates of fungal infections and all-cause mortality.

Cytomegalovirus Viral Load Kinetics Predict Cytomegalovirus End-Organ Disease and Mortality After Hematopoietic Cell Transplant.

BACKGROUND: We investigatedthe association between time-averaged area under the curve (AAUC) of cytomegalovirus (CMV) viral load (VL) by day 100 and overall survival (OS) at 1-year after hematopoietic cell transplantation (HCT). METHODS: In a retrospective cohort study, including patients receiving HCT between June 2010 and December 2017 from Memorial Sloan Kettering Cancer Center, AAUC was calculated for patients with detected VL. Patients were categorized into non-controllers (Q4) and controllers (Q1-Q3) using the highest AAUC quartile as cutoff. Cox models were used to estimate the association between AAUC and OS. Patients with non-detected CMV VL were categorized into elite-controllers (recipient+ [R+] or R-/donor+ [D+]) and R-/D-. RESULTS: The study (N = 952) included 282 controllers, 93 non-controllers, 275 elite-controllers, and 302 R-/D-. OS was 80.1% and 58.1% for controllers and non-controllers, respectively. In multivariable models, non-controllers had worse OS versus controllers (adjusted hazard ratio [HR] = 2.65; 95% confidence interval [CI], 1.71-4.12). In landmark analyses, controllers had similar OS as elite-controllers (HR = 1.26; 95% CI, .83-1.91) or R-/D- (HR = 0.98; 95% CI, .64-1.5). CONCLUSIONS: Non-controllers had worse OS 1-year post-HCT. Controllers had similar OS as elite-controllers or R-/D-. Future studies are needed to validate our AAUC cutoff across different cohorts and CMV management strategies.

Impact of Preemptive Therapy for Cytomegalovirus on Hospitalizations and Cost after Hematopoietic Stem Cell Transplantation.

Cytomegalovirus (CMV) viremia occurs in 40% to 80% of CMV-seropositive (R+) recipients of allogeneic hematopoietic cell transplantation (HCT). The preemptive therapy (PET) strategy has reduced the risk of CMV end-organ disease (EOD) and associated mortality but may lead to substantial healthcare resource utilization (HCRU) and costs. Real-world data on the economic impact of PET is relevant for the evaluation of alternative strategies for CMV management. We examined the impact of clinically significant CMV treated with PET on inpatient length of stay (LOS), number of readmissions, and associated costs from day 0 through day 180 post-HCT. This was a retrospective study of R+ adults who underwent peripheral blood or marrow allogeneic HCT at Memorial Sloan Kettering Cancer Center between March 2013 and December 2017. Patients were routinely screened for CMV by qPCR and received PET according to institutional standards of care. Data were extracted from electronic medical records and hospital databases. Itemized cost data per patient were obtained from the Vizient database, adjusted to 2017 dollars using inflation indices. Study outcomes included HCRU evaluated by inpatient LOS and inpatient cost in patients who received PET for clinically significant CMV (PET group) compared with those who did not receive PET (no PET group) and the frequency and cost of CMV-related readmissions compared with non CMV-related readmissions. We used generalized linear models to examine the incremental HCRU and costs associated with PET controlling for other potential factors. Of 357 patients, PET was initiated in 208 (58.3%), at a median of 35 days after HCT. By day 180, 23 patients (6.4%) had developed CMV EOD and 3 (.8%) had died of CMV. Compared with the no PET group, the PET group had a longer LOS for HCT admission (P = .0276), longer total LOS by day 180 (P = .0001), a higher number of readmissions (P = .0001), a higher mean inpatient cost for HCT admission ($189,389 versus $151,646; P = .0133), and a higher total inpatient cost ($297,563 versus $205,815; P < .0001). Among PET recipients, CMV-related readmissions were associated with higher mean cost per episode compared with non CMV-related readmissions ($165,455 versus $89,419; P = .005). CMV-related readmissions comprised 40.6% of total all-cause readmissions and incurred 55.9% of total all-cause readmission costs in PET recipients. Our data show that patients treated with currently available PET had greater inpatient HCRU and cost, by day 180 compared with patients who did not receive PET. The cost of CMV-related readmissions accounted for 56% of total readmission cost among PET recipients. Future studies are needed to examine the cost-effectiveness of alternative strategies for CMV management.

Impact of Preemptive Therapy for Cytomegalovirus on Toxicities after Allogeneic Hematopoietic Cell Transplantation in Clinical Practice: A Retrospective Single-Center Cohort Study.

(Val)ganciclovir (vGCV) or foscarnet (FCN) as preemptive therapy (PET) for cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT) is associated with myelosuppression and nephrotoxicity, respectively. We analyzed a cohort of CMV-seropositive (R+) HCT recipients managed preemptively at a single center. The objectives of our study were to (1) quantify the frequencies of neutropenia and acute kidney injury (AKI) through day +100 (D100) post-HCT and at PET discontinuation and (2) assess the impact of PET on neutropenia and AKI in multivariate models. This was a retrospective cohort study of adult CMV R+ recipients who underwent allo-HCT at Memorial Sloan Kettering Cancer Center from March 18, 2013, through December 31, 2017, and were managed with PET. Patients were grouped by receipt of PET (PET and no PET). Neutropenia and AKI were defined by Common Terminology Criteria for Adverse Events version 4. Frequencies of toxicities by D100 were compared between relevant groups. The impact of PET on toxicities was examined in univariate and multivariate Poisson/negative binomial regression models. Of 368 CMV R+ HCT recipients, 208 (56.5%) received PET. Neutropenia by D100 occurred in 41.8% and 28.6% patients in PET and no PET, respectively (P = .0009). PET increased the risk of neutropenia (adjusted relative risk = 1.81; 95% confidence interval [CI], 1.48 to 2.21; P < .0001) in multivariate analyses. AKI by D100 occurred in 12.0% and 7.8% patients in PET and no PET, respectively (P = .19). PET increased the risk of AKI by 2.75-fold (95% CI, 1.71 to 4.42; P < .0001). When PET recipients were grouped by first antiviral, neutropenia by D100 occurred in 34.8% and 48.9% of vGCV and FCN recipients, respectively, (P = .08), and AKI occurred in 13.0% and 34.0% of vGCV and FCN recipients, respectively (P = .001). At discontinuation of vGCV or FCN, neutropenia was present in 11.2% versus 2.1% patients, respectively (P = .08), and AKI was present in 1.9% of versus 12.8% patients respectively (P = .005). Preemptive therapy for CMV increased the risk of neutropenia and AKI in the first 100 days post-HCT by 1.8-fold and 2.8-fold, respectively. Our results underscore the need for safer antivirals for CMV management in HCT recipients.

Baseline Chest Computed Tomography as Standard of Care in High-Risk Hematology Patients.

Baseline chest computed tomography (BCT) in high-risk hematology patients allows for the early diagnosis of invasive pulmonary aspergillosis (IPA). The distribution of BCT implementation in hematology departments and impact on outcome is unknown. A web-based questionnaire was designed. International scientific bodies were invited. The estimated numbers of annually treated hematology patients, chest imaging timepoints and techniques, IPA rates, and follow-up imaging were assessed. In total, 142 physicians from 43 countries participated. The specialties included infectious diseases (n = 69; 49%), hematology (n = 68; 48%), and others (n = 41; 29%). BCT was performed in 57% (n = 54) of 92 hospitals. Upon the diagnosis of malignancy or admission, 48% and 24% performed BCT, respectively, and X-ray was performed in 48% and 69%, respectively. BCT was more often used in hematopoietic cell transplantation and in relapsed acute leukemia. European centers performed BCT in 59% and non-European centers in 53%. Median estimated IPA rate was 8% and did not differ between BCT (9%; IQR 5-15%) and non-BCT centers (7%; IQR 5-10%) (p = 0.69). Follow-up computed tomography (CT) for IPA was performed in 98% (n = 90) of centers. In high-risk hematology patients, baseline CT is becoming a standard-of-care. Chest X-ray, while inferior, is still widely used. Randomized, controlled trials are needed to investigate the impact of BCT on patient outcome.

A Single-Center, Open-Label Trial of Isavuconazole Prophylaxis against Invasive Fungal Infection in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation.

Isavuconazole is a broad-spectrum triazole approved for treatment of invasive fungal infections (IFIs). In this open-label, single-arm study, we evaluated isavuconazole for antifungal prophylaxis after allogeneic hematopoietic cell transplantation (HCT). Adult patients admitted for first HCT received micafungin 150 mg i.v. daily from admission through day +7 (D+7) post-transplantation (±2 days) followed by isavuconazole prophylaxis (i.v./p.o. 372 mg every 8 hours for 6 doses and then 372 mg daily) through maximum D+98 post-HCT. Patients were followed through D+182. The primary endpoint was prophylaxis failure, defined as discontinuation of prophylaxis for proven/probable IFI; systemic antifungal therapy for >14 days for suspected IFI; toxicity leading to discontinuation; or an adverse event. Between June 2017 and October 2018, 99 patients were enrolled in the study, of whom 95 were included in our analysis. The median patient age was 57 years (interquartile range [IQR], 50 to 66 years). Sixty-four (67%) patients received peripheral blood, 17(18%) received bone marrow, and 14 (15%) received a cord blood allograft for acute leukemia (55%), lymphoma (17%), myelodysplastic syndrome (16%), or another hematologic disease (14%). One-third (n = 31; 33%) of patients underwent CD34+-selected HCT. Isavuconazole prophylaxis was given for a median of 90 days (IQR, 87 to 91 days). Ten patients (10.7%) met the primary endpoint. Candidemia occurred in 3 patients (3.1%), 1 of whom had grade III skin acute graft-versus-host disease (GVHD). Toxicity leading to discontinuation occurred in 7 patients (7.4%). The most common toxicity was liver function abnormalities in 5 patients, including grade 1 transaminitis in 2 patients and grade 3 hyperbilirubinemia in 3 patients. Four patients (4.2%) had early discontinuation of isavuconazole for reasons not meeting the primary study endpoint. Six patients died during the study period, including 3 during prophylaxis and 3 during follow-up. No deaths were attributed to isavuconazole. The majority (85%) of allogeneic HCT recipients completed isavuconazole prophylaxis according to protocol. The rate of breakthrough candidemia was 3.1%, and there were no invasive mold infections. Our data support the utility of isavuconazole for antifungal prophylaxis after HCT.

CMV Prevention and Treatment in Transplantation: What's New in 2019.

PURPOSE OF REVIEW: Transplant recipients are at risk for cytomegalovirus (CMV) infection and associated morbidity and mortality. We summarize recently introduced or currently investigated modalities for prevention and treatment of CMV infection in hematopoietic cell (HCT) and solid organ transplant (SOT) recipients. RECENT FINDINGS: Letermovir was recently approved for CMV prevention in HCT recipients. Data from real world studies support its role to improve outcomes in this population. Letermovir is currently under investigation for broader patient populations and indications. Maribavir is in late stages of development for CMV treatment and may provide a safer alternative to currently available anti-CMV drugs. Promising CMV vaccine candidates and adoptive cell therapy approaches are under evaluation. CMV immune monitoring assays are predicted to play a more central role in our clinical decision making. In recent years, major advances have been made in CMV prevention and treatment in transplant recipients. Rigorous research is ongoing and is anticipated to further impact our ability to improve outcomes in this population.

Baseline Chest Computed Tomography for Early Diagnosis of Invasive Pulmonary Aspergillosis in Hemato-oncological Patients: A Prospective Cohort Study.

Invasive pulmonary aspergillosis (IPA) has dire consequences in hemato-oncological patients. We report our experience with performing routine baseline chest computed tomography for early diagnosis of IPA. We found high rates of proven or probable IPA diagnosed on admission among patients with newly diagnosed acute myeloid leukemia.