Combination of sepsis biomarkers may indicate an invasive fungal infection in haematological patients.

Background: Invasive fungal infections are a major threat to a large cohort of immunocompromised patients, including patients with chemotherapy-associated neutropenia. Early differential diagnosis with bacterial infections is often complicated, which leads to a delay in empirical antifungal therapy and increases risk for adverse outcome. Accessibility and performance of specific fungal antigen and PCR-tests are still limited, while sepsis biomarkers are more broadly used in most settings currently. Methods: Haematological patients hospitalized to receive chemotherapy with proven or probable invasive fungal infection or microbiologically proven bacterial bloodstream infection were included in the study. C-reactive protein was assessed daily during the profound neutropenia period, while procalcitonin or presepsin were measured during the first 48 hours after the onset of febrile episode. Results: There were totally 64 patients included in the study, 53 with bacterial bloodstream infections and 11 with invasive fungal infections. Combination of CRP >120 with PCT <1.25 or presepsin <170 was shown to be a possible combined biomarker for invasive fungal infections in immunocompromised patients, with areas under the ROC-curves: 0.962 (95% CI 0.868 to 0.995) for PCT-based combination and 0.907 (95% CI 0.692 to 0.990) for presepsin-based combination.

Mesenchymal stem cells transplantation in hematological patients with acute graft-versus-host disease: characteristics and risk factors for infectious complications.

The role of MSCs in infection prevention and treatment is still discussed in transplant and hematological patients. The spectrum and risk factors for infections after MSCs transplantation in patients with acute GVHD have not been studied before. To determine the risk factors and spectrum of infectious complications in patients received mesenchymal stem cell transplantation as a treatment for acute GVHD. A prospective observational study was performed to evaluate the risk factors and characteristics of infectious complications after MSCs transplantation in adult patients having acute GVHD. Thirty-four episodes of MSCs transplantation in patients with acute GVHD after allogeneic HSCT were enrolled in the study. MSCs were given at a median dose of 1.32 (interquartile range 0.87-2.16) mln cells/kg per infusion at 91 days (interquartile range 31-131 days) after HSCT. Data relating to age, gender, date, and type of transplantation, characteristics of MSCs, infectious agents, and antimicrobial therapy and prevention regimens were prospectively collected in all of the enrolled patients. The episode of proven infectious complication was set as a primary outcome. There were totally 68 patients with acute GVHD in the study; among them there were 34 cases of MSCs transplantation performed. Among the registered infectious episodes were viral infections (CMV-associated disease, EBV-associated disease), invasive pulmonary aspergillosis, bacterial bloodstream infections, and pneumonia. MSCs transplantation has shown no statistically significant association with risk of infectious complications in patients with acute GVHD in a performed multivariate analysis. Among the most frequent infections in acute GVHD, we have described CMV, invasive aspergillosis, and bacterial infections (bloodstream infections or pneumonia). Among risk factors for infectious complications in patients with acute GVHD with/without MSCs transplantation are progression of main disease and neutropenia below 500 cells/mm3 (for aspergillosis) and unrelated HSCT in the past history and progression of main disease (for bacterial bloodstream infections and pneumonia).

Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial.

OBJECTIVES: PALG CLL4 is the first, randomized, phase IIIb study with rituximab, cladribine, and cyclophosphamide (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients. METHODS: The induction treatment consisted of 6 RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm. RESULTS: In the intention-to-treat population, 97 patients completed the induction phase with an overall response rate (ORR) of 73.2% (CR 22.7%, PR 50.5%). Subsequently, 66 patients were randomized into the rituximab maintenance arm (n = 33) or the observational arm (n = 33). CR rates were 57.1% in the maintenance group vs 50% in the observational group. PFS was significantly longer in the rituximab maintenance vs the observational arm (P = .028). The multivariate Cox model indicated that del17p (P = .006) and elevated beta-2-microglobulin (P = .015) significantly increased the hazard ratio (HR) of progression, whereas the presence of CD38 (P = .013) significantly decreased it; maintenance therapy with rituximab (P < .0001) significantly decreased the HR of disease progression. CONCLUSIONS: The study confirmed the high efficacy and acceptable safety profile of induction therapy with RCC and maintenance therapy with rituximab in previously untreated patients with CLL.

Clinical efficacy of pneumococcal vaccination in multiple myeloma patients on novel agents: Results of a prospective clinical study.

INTRODUCTION: Among the high risk groups, patients with multiple myeloma (MM) have one of the highest incidence of invasive pneumococcal disease, mainly pneumonias. Recent changes in MM treatment have now led to an increase of survival, while the infection-related mortality remains high. The question of efficacy of pneumococcal vaccination in patients receiving novel target agents has not been clinically investigated before. PATIENTS AND METHODS: We have introduced the 3-dose vaccination regimen by 13-valent pneumococcal conjugate (PCV13) vaccine between the treatment courses with novel target agents (bortezomib, lenalidomide, ixazomib) with a minimum of 1 month interval. The incidence of pneumonias during the one-year observation period was taken as a primary outcome in this registered clinical trial. RESULTS: From 2017 to 2020, we have prospectively included 18 adult patients who were vaccinated by PCV13 along with 18 patients of a control matched group. No adverse effects of vaccination were registered in the study. We have observed an independent effect of PCV13 vaccination on the incidence of pneumonias. The absolute risk reduction of pneumonias in patients received PCV13 vaccination was 33.3%. Number needed to treat for PCV13 vaccination in multiple myeloma patients receiving novel agents was 3.0; (95% CI 1.61-22.1; p = 0.0571). CONCLUSION: Therefore, we have shown the clinical effectiveness of PCV13 vaccination schedule based on 3 doses given with a minimum 1 month interval between the courses of novel agents in multiple myeloma patients, despite the expected decrease in immunological response to vaccination during target and immunotherapy. ClinicalTrials.gov Identifier: NCT03619252.

Decolonization of Intestinal Carriage of MDR/XDR Gram-Negative Bacteria with Oral Colistin in Patients with Hematological Malignancies: Results of a Randomized Controlled Trial.

BACKGROUND: Intestinal colonization by MDR/XDR gram-negative bacteria leads to an increased risk of subsequent bloodstream infections (BSI) in patients receiving chemotherapy as a treatment for hematologic malignancies. OBJECTIVES: The objective of this study was to evaluate the efficacy of oral colistin in eradicating the intestinal carriage of MDR/XDR Gram-negative bacteria in patients with hematological malignancies. METHODS: In a tertiary hematology center, adult patients with intestinal colonization by MDR/XDR Gram-negative bacteria were included in a randomized controlled trial (RCT) during a period from November 2016 to October 2017. Patients were treated with oral colistin for 14 days or observed with the primary outcome set as decolonization on day 21 post-treatment. Secondary outcomes included treatment safety and changes in MICs of isolated microorganisms. ClinicalTrials.gov Identifier: NCT02966457. RESULTS: Short-time positive effect (61.3% vs 32.3%; OR 3.32; 95% CI 1.17-9.44; p=0.0241) was demonstrated on the day 14 of colistin treatment, without any statistical difference on day 21 post-treatment. The incidence of BSI in decolonization group was lower in the first 30 days after the intervention (3.2% vs. 12.9%), but overall in the 90-day observation period, it did not show any advantages comparing to control group (log-rank test; p=0.4721). No serious adverse effects or increase in resistance to colistin was observed. CONCLUSIONS: This study suggests that in hematological patients the strategy of selective intestinal decolonization by colistin may be beneficial to decrease the rate of MDR/XDR Gram-negative intestinal colonization and the risk of BSI in the short-term period, having no long-term sustainable effects.

Diagnostic value of sepsis biomarkers in hematopoietic stem cell transplant recipients in a condition of high prevalence of gram-negative pathogens.

OBJECTIVE/BACKGROUND: A decision about the need for antimicrobial therapy in a patient with febrile neutropenia after hematopoietic stem cell transplantation (HSCT) is often complicated because of the low frequency of culture isolation and reduced clinical manifestation of infection. Usefulness and choice of sepsis biomarkers to distinguish bloodstream infection (BSI) from other causes of febrile episode is still argued in HSCT recipients in modern epidemiological situations characterized by the emergence of highly resistant gram-negative microorganisms. In this study a comparative analysis of diagnostic values of presepsin, procalcitonin (PCT), and C-reactive protein (CRP) was performed as sepsis biomarkers in adult patients after HSCT in a condition of high prevalence of gram-negative pathogens. METHODS: A prospective observational clinical study was performed at the Center of Hematology and Bone Marrow Transplantation in Minsk, Republic of Belarus. The biomarkers (presepsin, PCT, and CRP) were assessed in a 4-hour period after the onset of febrile neutropenia episode in adult patients after HSCT. Microbiologically-confirmed BSI caused by a gram-negative pathogen was set as a primary outcome. RESULTS: Clinical and laboratory data were analyzed in 52 neutropenic patients after HSCT aged 18-79years. Out of the biomarkers assessed, the best diagnostic value was shown in presepsin (area under the curve [AUC]: 0.889, 95% confidence interval [CI]: 0.644-0.987, p<.0001) with 75% sensitivity and 100% specificity, then in PCT (AUC: 0.741, 95% CI: 0.573-0.869, p=.0037) with 62% sensitivity and 88% specificity. The optimal cut-off value for CRP was set as 165mg/L, while it had an average diagnostic value (AUC: 0.707, 95% CI: 0.564-0.825, p=.0049) with low sensitivity (40%) and should not be routinely recommended as a biomarker in adult patients with suspected BSI after HSCT. CONCLUSION: Presepsin may be recommended in adult patients with suspected gram-negative BSI after HSCT as a possible additional supplementary test with a cut-off value of 218pg/mL. PCT is inferior to presepsin in terms of sensitivity and specificity, but still shows a good quality of diagnostic value with an optimal cut-off value of 1.5ng/mL. CRP showed an average diagnostic value with low sensitivity (40%) and should not be routinely recommended as a biomarker in adult patients with suspected BSI after HSCT in a condition of high prevalence of gram-negative pathogens.

Risk factors for mortality in patients with bloodstream infections during the pre-engraftment period after hematopoietic stem cell transplantation.

BACKGROUND: Bloodstream infections (BSI) remain a frequent complication during the pre-engraftment period after hematopoietic stem cell transplantation (HSCT), resulting in high mortality rates. This study evaluated risk factors for mortality in hematopoietic stem cell transplant recipients with BSI in the pre-engraftment period. METHODS: This prospective case control study was performed at the Center of Hematology and Bone Marrow Transplantation in Minsk, Republic of Belarus. Data relating to patient age and gender, date and type of transplantation, conditioning chemotherapy regimen, microorganisms isolated from blood, and antibacterial therapy were prospectively collected from all hematopoietic stem cell recipients with microbiologically proven cases of BSI in the pre-engraftment period. The primary outcome was all-cause 30-day mortality after onset of febrile neutropenia. RESULTS: A total of 135 adult patients with microbiologically proven BSI after HSCT were studied, with 65.2% of cases caused by gram-negative microorganisms and 21.5% by non-fermenting bacteria. Inadequate empiric antibacterial therapy and isolation of carbapenem-resistant non-fermenting gram-negative bacteria (Acinetobacter baumannii and Pseudomonas aeruginosa) were independently associated with increased all-cause 30-day mortality in these patients. CONCLUSION: The risk factors for mortality in adult patients with BSI in the pre-engraftment period after HSCT were inadequacy of empirical antibacterial therapy and isolation of carbapenem-resistant A. baumannii or P. aeruginosa.