Hematologic Stem Cell Transplantation Research Articles

Comment on: Pneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients.

Pneumocystis jirovecii can cause life-threatening pneumonia following treatment for haematological malignancies or after HSCT. The mortality rate of P. jirovecii pneumonia (PCP) in these patients is 30%-60%, especially after HSCT. The clinical presentation of PCP in haematology differs from that associated with HIV infection, with the disease being acute and more often severe, having a lower fungal burden and being more frequently linked to treatment with corticosteroids. Most cases occur in patients not receiving adequate prophylaxis. The development of new therapies, including targeted treatments and monoclonal antibodies in various haematological diseases, justifies constant vigilance in order to identify new at-risk populations and give prophylaxis accordingly. The fifth and sixth European Conferences on Infections in Leukaemia (ECIL-5 and ECIL-6) aimed to review risk factors for PCP in haematology patients and to establish evidence-based recommendations for PCP diagnosis, prophylaxis and treatment. This article focuses on the magnitude of the problem, the main differences in clinical presentation between haematology patients and other immunocompromised populations, especially HIV-infected patients, and the main risk factors.

Revisiting nutritional support for allogeneic hematologic stem cell transplantation—a systematic review

In 2009, the American Society of Parenteral and Enteral Nutrition and its European counterpart (Euopean Society for Parenteral and Enteral Nutrition) published guidelines regarding nutritional support of patients with hematologic stem cell transplantation. Our aim was to do an up-to-date literature review regarding benefit of nutritional interventions and treatment recommendations. We searched MEDLINE, EMBASE and Cochrane Library for interventional and observational clinical studies. We extracted data based on a predefined case report form and assessed bias. Out of 459 potential abstracts, 13 studies of mostly moderate quality with a total of 18 167 patients were included. Two very large trials reported negative associations of malnutrition and survival, transplant-related mortality and relapse risk. Some trials found enteral nutrition (EN) to be as effective as parenteral nutrition (PN) with lower complication rates. In addition, EN was associated with better survival, less acute GvHD and faster neutrophil recovery. A neutropenic diet was not superior regarding overall survival, but in contrast resulted in higher infection risk. Current moderate quality studies show negative associations of malnutrition and clinical outcomes, with EN being superior to PN. There was no benefit of neutropenic diets. Large, randomized controlled studies are needed to better understand optimal nutritional support in this patient population.

Prevalence, predictors, and outcomes of steroid-induced hyperglycemia in hospitalized patients with hematologic malignancies.

To determine prevalence, predictors, and outcomes of steroid-induced hyperglycemia in hospitalized patients with hematologic malignancies METHODS: We performed retrospective analysis of patients who were hospitalized on any of the four hematology services or bone marrow transplant service and who received systemic steroids during a 2-month period. Mean glucoses for days 1-4 and maximum glucose were calculated and the total daily steroid dose was converted to equivalent dose of dexamethasone. Hyperglycemia was defined as any glucose >9.917 mmol/l during days 1-4. We examined associations between variables using Spearman's correlations and multivariable linear regression RESULTS: 168 patients were included in the analysis. Mean age was 57.1 ± 14.4 years with 59% males and 90% Caucasians. The prevalence of hyperglycemia was 39%. Eight patients received intravenous insulin. In patients without diabetes, steroid dose equivalent to >12 mg dexamethasone and longer acting steroids caused greater degree of hyperglycemia compared to a dose <12 mg. Maximum glucose was a predictor of hospital length of stay among patients without diabetes (but not those with diabetes), and with acute leukemia or stem cell transplant (but not other hematologic malignancies). There were no significant differences in in mortality or other outcomes between the groups with and without hyperglycemia CONCLUSIONS: Hyperglycemia is common in patients with hematologic malignancies, which require frequent corticosteroids. Higher steroid dose and long-acting steroids caused a greater degree of hyperglycemia. Maximum glucose was a predictor of length of stay but this was only significant for patients without diabetes, those with acute hematologic malignancy or stem cell transplant.

To Compare the Safety and Efficacy of Voriconazole Versus Posaconazole in the Prevention of Invasive Fungal Infections in High-Risk Patients with Hematologic Malignancies or Hematopoietic Stem Cell Transplant

To Compare the Safety and Efficacy of Voriconazole Versus Posaconazole in the Prevention of Invasive Fungal Infections in High-Risk Patients with Hematologic Malignancies or Hematopoietic Stem Cell Transplant

The expanding role of the clinical haematologist in the new world of advanced therapy medicinal products.

Advanced therapy medicinal products (ATMPs) represent the current pinnacle of 'patient-specific medicines' and will change the nature of medicine in the near future. They fall into three categories; somatic cell-therapy products, gene therapy products and cells or tissues for regenerative medicine, which are termed 'tissue engineered' products. The term also incorporates 'combination products' where a human cell or tissue is combined with a medical device. Plainly, many of these new medicines share similarities with conventional haematological stem cell transplant products and donor lymphocyte infusions as well as solid organ grafts and yet ATMPs are regulated as medicines and their development has remained predominantly in academic settings and within specialist centres. However, with the advent of commercialisation of dendritic cell vaccines, chimeric antigen receptor (CAR)-T cells and genetically modified autologous haematopoietic stem cells to cure single gene-defects in β-thalassaemia and haemophilia, the widespread availability of these therapies needs to be accommodated. Uniquely to ATMPs, the patient or an allogeneic donor is regularly part of the manufacturing process. All of the examples given above require procurement of blood, bone marrow or an apheresate from a patient as a starting material for manufacture. This can only occur in a clinical facility licensed for the procurement of human cells for therapeutic use and this is likely to fall to haematology departments, either as stem cell transplant programmes or as blood transfusion departments, to provide under a contract with the company that will manufacture and supply the final medicine. The resource implications associated with this can impact on all haematology departments, not just stem cell transplant units, and should not be under-estimated.

Successful use of oseltamivir prophylaxis in managing a nosocomial outbreak of influenza A in a hematology and allogeneic stem cell transplant unit.

To describe a nosocomial outbreak of H1N1 influenza A in an inpatient hematology and allogeneic stem cell transplant unit and outcomes of universal oseltamivir prophylaxis. Medical records of all patients admitted to the unit were reviewed to define the nosocomial outbreak, commencing 1 week prior to the index case until 4 weeks following institution of oseltamivir prophylaxis. Timelines for clinical symptoms, viral spread, management, patient outcomes and follow up testing were constructed. All cases of influenza were confirmed on nasopharyngeal swabs and/or bronchoalveolar lavages collected for polymerase chain reaction testing. In addition to the index case, further 11 patients were diagnosed with influenza A during the outbreak. Six patients (50%) had influenza-like-illness, five (42%) had respiratory symptoms only and one (8%) was asymptomatic. In total, five patients died, including four (33%) patients who were admitted to intensive care. A clustering of seven cases led to recognition of the outbreak and subsequent commencement of universal prophylaxis with oseltamivir 75 mg/day in all inpatients within the unit. Strict infection control processes were reinforced concurrently. There were no further cases of influenza A linked to the outbreak after the implementation of universal oseltamivir prophylaxis. Three later cases were linked to H1N1 exposure during the original outbreak. H1N1 influenza infection is associated with significant mortality in hematology patients. Universal prophylaxis with oseltamivir during a nosocomial outbreak appeared to be effective in controlling spread of the virus. We recommend early institution of infection control and universal prophylaxis in any nosocomial outbreak of influenza.

Emergence of linezolid- and vancomycin-resistant Enterococcus faecium in a department for hematologic stem cell transplantation

BackgroundPrevalence of vancomycin-resistant enterococci has increased in Germany. Here, we report the cluster of linezolid- and vancomycin-resistant Enterococcus faecium (LVRE) in a German department for hematologic stem cell transplantation (HSCT).MethodsIn this retrospective analysis we included all patients with LVRE in a university-based department for HSCT in 2014 and 2015. Patients chart reviews were used to investigate the epidemiology and clinical outcome. Available LVRE isolates underwent detailed microbiological characterization and genotyping by pulsed-field gel electrophoresis (PFGE).ResultsIn total, 20 patients with LVRE were identified within the observed time period. All except two patients underwent allogeneic HSCT. Surveillance culture results from incoming patients and chart review revealed that 10 of 20 patients were colonized at hospital admission. Eight of 10 patients with in-hospital acquired LVRE had previous linezolid treatment. Analysis of spatio-temporal patterns showed no evidence for LVRE patient-to-patient or environment-to-patient transmission within the HSCT department. In five cases (25 %) LVRE bloodstream infection occurred. Nine LVRE isolates could be saved for characterization. Eight isolates carried vanA, one isolate vanB. PFGE analysis showed that four different LVRE clones were responsible for the cluster. One single genotype was present in six LVRE isolates whereupon the corresponding patients were all referred from the same hospital to the HSCT department.ConclusionsThis is the first report demonstrating the emergence of LVRE in a German HSCT department. (L)VRE screening at patients’ admission and appropriate infection control strategies were sufficient to prevent any transmission. Further studies in this predisposed patient collective are warranted.

Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV-negative recipients with an anti-HBc-positive donor

The overall rate of hepatitis B virus (HBV) reactivation was evaluated in a population of 373 haematological stem cell transplant (HSCT) patients treated with lamivudine (LMV) if they were anti-HBc-positive/HBV-DNA-negative recipients or if they were HBV-negative recipients with an anti-HBc-positive donor. The incidence of HBV reactivation was calculated in two groups of autologous (auto) or allogeneic (allo) HSCT patients who were stratified according to their HBV serostatus. The former group included 57 cases: 10 auto-HSCT and 27 allo-HSCT anti-HBc-positive recipients, two auto-HSCT and three allo-HSCT inactive carriers, and 15 allo-HSCT recipients with an anti-HBc-positive donor. Forty-seven (82.4%) patients in this group received LMV prophylaxis (the median (interquartile range, IQR) of LMV treatment was 30 (20–38) months). The second group consisted of 320 anti-HBc-negative auto-HSCT and allo-HSCT recipients with anti-HBc-negative donors. None of these patients received any prophylaxis. Two patients in the first group and two in the second group experienced reactivation of HBV infection, with an incidence of 3.5% (95% CI 0.4-12.1%) and 0.6% (95% CI 0.1-2.2%), respectively. Only one out of four reactivated patients was LMV-treated. The cumulative probability of HBV reactivation at 6 years from HSCT was 15.8% (95% CI 15.2-16.4%). Three of four viral isolates obtained from the HBV-reactivated patients harboured mutations in the immune-active HBsAg-region. In a HSCT population carefully evaluated for HBV prophylaxis, a risk of HBV reactivation persisted in the group of patients who were not LMV-treated. Only one LMV-treated patient experienced reactivation of HBV with a resistant HBV isolate.

Vaccinations for immunocompromised hosts – focussing on patients after a hematological stem cell or organ transplantation, with HIV or with functional or anatomical asplenia

Patients with an acquired immune deficiency, for example due to HIV-infection, after a solid organ or haematological stem cell transplantation or due to functional or anatomical asplenia, have a greater risk to experience severe complications or a chronic course of infection compared to healthy individuals. Vaccinations would pose an ideal primary preventive method. However, their efficacy is reduced if applied during the immunosuppressed period. Therefore, whenever possible, vaccinations should be administered before the period of immunosuppression starts – or caught up later during the period of minimal possible immunosuppression. Nevertheless, the benefit conveyed through vaccines is undisputed, particularly if indications regarding dosing of vaccines (amount and frequency of doses) are optimized according to the given state of immunosuppression. Live attenuated vaccines are contraindicated during severe immunosuppression. Serologies should still be analysed and documented however, since these vulnerable patients require passive immunization through specific or standard intravenous immunoglobulins in case of relevant exposure to the respective antigens. For all patients therefore, careful documentation and communication of previous vaccinations and serologies (protective or not) among the various medical specialties is required to optimize patient management. For all immunosuppressed patients the efficacy of polysaccharide vaccines (such as the pneumococcal and meningococcal vaccines PSV-23 and MPV-ACWY) is strongly reduced compared to the conjugated ones (PCV13 and MCV-ACWY). Therefore, contrary to most other national guidelines, the Swiss guidelines recommend to use only the conjugated versions in primary vaccination series as well as in boosters – this applies strongly for immunosuppressed patients, but is recommended also for the general population in Switzerland. Another common management recommendation specific for transplant patients is the indication to control vaccine efficacy by measuring titers. This is also indicated for hepatitis B in HIV-positive patients, but not required for any vaccine in asplenic patients. In summary, vaccines pose an important opportunity for primary and secondary prevention for vulnerable patients at highest risk of experiencing the worst forms of the diseases to be prevented.

37 - Cord Blood-Derived Mesenchymal Stromal Cells for the Treatment of Graft-Versus Host Disease Following Hematological Stem Cell Transplantation

37 - Cord Blood-Derived Mesenchymal Stromal Cells for the Treatment of Graft-Versus Host Disease Following Hematological Stem Cell Transplantation

ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients.

The Fifth European Conference on Infections in Leukaemia (ECIL-5) convened a meeting to establish evidence-based recommendations for using tests to diagnose Pneumocystis jirovecii pneumonia (PCP) in adult patients with haematological malignancies. Immunofluorescence assays are recommended as the most sensitive microscopic method (recommendation A-II: ). Real-time PCR is recommended for the routine diagnosis of PCP ( A-II: ). Bronchoalveolar lavage (BAL) fluid is recommended as the best specimen as it yields good negative predictive value ( A-II: ). Non-invasive specimens can be suitable alternatives ( B-II: ), acknowledging that PCP cannot be ruled out in case of a negative PCR result ( A-II: ). Detecting β-d-glucan in serum can contribute to the diagnosis but not the follow-up of PCP ( A-II: ). A negative serum β-d-glucan result can exclude PCP in a patient at risk ( A-II: ), whereas a positive test result may indicate other fungal infections. Genotyping using multilocus sequence markers can be used to investigate suspected outbreaks ( A-II: ). The routine detection of dihydropteroate synthase mutations in cases of treatment failure is not recommended ( B-II: ) since these mutations do not affect response to high-dose co-trimoxazole. The clinical utility of these diagnostic tests for the early management of PCP should be further assessed in prospective, randomized interventional studies.

ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients.

The 5th European Conference on Infections in Leukaemia (ECIL-5) meeting aimed to establish evidence-based recommendations for the prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in non-HIV-infected patients with an underlying haematological condition, including allogeneic HSCT recipients. Recommendations were based on the grading system of the IDSA. Trimethoprim/sulfamethoxazole given 2-3 times weekly is the drug of choice for the primary prophylaxis of PCP in adults ( A-II: ) and children ( A-I: ) and should be given during the entire period at risk. Recent data indicate that children may benefit equally from a once-weekly regimen ( B-II: ). All other drugs, including pentamidine, atovaquone and dapsone, are considered second-line alternatives when trimethoprim/sulfamethoxazole is poorly tolerated or contraindicated. The main indications of PCP prophylaxis are ALL, allogeneic HSCT, treatment with alemtuzumab, fludarabine/cyclophosphamide/rituximab combinations, >4 weeks of treatment with corticosteroids and well-defined primary immune deficiencies in children. Additional indications are proposed depending on the treatment regimen.

Pneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients.

Pneumocystis jirovecii can cause life-threatening pneumonia following treatment for haematological malignancies or after HSCT. The mortality rate of P. jirovecii pneumonia (PCP) in these patients is 30%-60%, especially after HSCT. The clinical presentation of PCP in haematology differs from that associated with HIV infection, with the disease being acute and more often severe, having a lower fungal burden and being more frequently linked to treatment with corticosteroids. Most cases occur in patients not receiving adequate prophylaxis. The development of new therapies, including targeted treatments and monoclonal antibodies in various haematological diseases, justifies constant vigilance in order to identify new at-risk populations and give prophylaxis accordingly. The fifth and sixth European Conferences on Infections in Leukaemia (ECIL-5 and ECIL-6) aimed to review risk factors for PCP in haematology patients and to establish evidence-based recommendations for PCP diagnosis, prophylaxis and treatment. This article focuses on the magnitude of the problem, the main differences in clinical presentation between haematology patients and other immunocompromised populations, especially HIV-infected patients, and the main risk factors.

Both high and low levels of cellular Epstein-Barr virus DNA in blood identify failure after hematologic stem cell transplantation in conjunction with acute GVHD and type of conditioning.

The level of Epstein-Barr virus DNA in blood has proven to be a biomarker with some predictive value in allogeneic hematopoietic stem cell transplantation patients (HSCT). We evaluated the impact of EBV load on survival of 51 patients (32M/19F, median age: 32 years, from < 1 to 68 years old), who had received HSCT for different types of malignancies (49 cases) or non-malignancies (2 cases). The overall survival [1]was compared between patients with extreme and moderate cell bound EBV DNA levels. Different sources of stem-cells (peripheral blood stem, n = 39; bone marrow, n = 9; or umbilical cord blood, n = 3) were used. Twenty patients received reduced-intensity conditioning regimen while the other 31 received myeloablative conditioning. Patients with high or very low level of cell bound EBV-DNA levels had a shorter OS than those with moderate EBV load: OS at 5 years was 67% vs 90% (p < 0.03). There was a conspicuous relationship between EBV load and the reconstitution dynamics of total and EBV-specific T cells, CD4+ and CD4- CD8- (double negative) T cells in the few patients where it was analyzed. This was not statistically significant. Two other factors were associated to early mortality in addition to high or low EBV load: acute GVHD II-IV (p < 0.02) and pre-transplant conditioning with total body irradiation (TBI) ≥6 Gy, (p < 0.03). All the patients meeting all three criteria died within two years after transplantation. This points to a subgroup of HSCT patients which deserve special attention with improvement of future, personalized treatment.

Immune Reconstitution Inflammatory Syndrome in Invasive Fungal Infections: What We Know and What We Need to Know?

Invasive fungal infections (IFIs) cause significant mortality and morbidity in HIV-infected patients, patients with malignancy on chemotherapy, recipients of solid organ and haematological stem cell transplantation, patients with primary immunodeficiencies and those on immunomodulators such as steroids and tumour necrosis factor-alpha inhibitors. Immune reconstitution inflammatory syndrome (IRIS), an exaggerated, unexpected inflammatory phenomena occurring in temporal association with enhanced immune function in these conditions, is difficult to recognise and manage. Here, we detail what we have learnt from studies in cryptococcosis-associated IRIS and discuss other common fungal IRIS including histoplasmosis-IRIS, talaromycosis/penicilliosis-IRIS, pneumocystis-IRIS and a less well-recognised IRIS seen with invasive aspergillosis in the setting of neutrophil recovery. We also reflect on the enormity of what we are yet to understand about IRIS immunopathogenesis, diagnosis and management.

Isolated acquired factor VII deficiency: review of the literature

Objectives:: Isolated acquired factor VII (FVII) deficiency is a rare haemorrhagic disorder. We report what is currently known about the pathogenesis, clinical features, diagnosis, treatment and prognosis of acquired FVII deficiency.Methods:: We performed a literature search and included all articles published between 1980 and August 2015.Results and Conclusions: Acquired FVII deficiency has been reported in 42 patients. There are well-established clinical diseases associated with acquired FVII deficiency, most notably infections, malignancy and haematological stem cell transplantation. The exact pathogenesis of the diseases is still unknown, but different pathophysiological hypotheses have been suggested. The clinical manifestation of acquired FVII deficiency varies greatly in severity; asymptomatic course as well as severe life-threatening bleeding diathesis and fatal bleedings have been described.

Astrovirus outbreak at a pediatric hematology and hematopoietic stem cell transplant unit despite strict hygiene rules

Astrovirus outbreak at a pediatric hematology and hematopoietic stem cell transplant unit despite strict hygiene rules

Ocular Graft versus Host Disease: A Review of Clinical Manifestations, Diagnostic Approaches and Treatment

Allogenic haematological stem cell transplantation (allo-SCT) from a human leukocyte antigen (HLA) matched related or unrelated donor is used as a curative therapy for a large number of malignant and non-malignant haematological diseases. The curative effect of allo-SCT is achieved by graft versus leukaemia effect while the downside of the graft versus patient activity is the graft-versus-host-disease (GVHD), a major reason for mortality and morbidity. The search of articles for this review had been accomplished using Ovid, Medline, Embase, Pubmed and was supplemented by retrieving cross references also. Electronic literature search for English language articles with full text access was performed using graft versus host disease, ocular, management, dry eyes as key words. This review has been intended to explicate the classification, pathogenesis, risk factors and management of ocular graft versus host disease.

Changes in serum uric acid levels after allogeneic hematologic stem cell transplantation: A retrospective cohort study.

BackgroundSince cell turnover in the hematopoietic system constitutes a major source of uric acid (UA) production, we investigated whether hematopoietic stem cell transplantation (HSCT) is associated with significant changes in serum UA levels in patients with hematological disorders.MethodsPatients who underwent HSCT at our institution between 2001 and 2012 were retrospectively enrolled. Serum UA levels at 3 months before, 1 week before, and 3 months and 1 year after HSCT were examined.ResultsComplete clinical and laboratory information including data regarding UA levels was available for 93 patients. At baseline, the mean UA level was 4.9±2.1 mg/dL, with an overall prevalence of hyperuricemia of 15% (defined as serum UA>6.8 mg/dL). Mean UA levels tended to be higher in patients with acute myeloid leukemia (4.8±2.0 mg/dL) and non-Hodgkin lymphoma (5.1±2.3 mg/dL) and lower in patients with aplastic anemia (mean, 4.2±1.8 mg/dL). UA levels dropped during myeloablative conditioning, reaching a nadir on the day of HSCT (3.27±1.4 mg/dL). Over the 3 months following HSCT, UA levels rose sharply (5.0±2.1 mg/dL) and remained stable up to 1 year after HSCT (5.5±1.6 mg/dL). UA levels in HSCT recipients at 12 months correlated with those of their respective graft donors (Pearson r=0.406, P=0.001).ConclusionHSCT is associated with significant changes in uric acid levels in patients with hematologic disorders.

Comparison of respiratory virus shedding by conventional and molecular testing methods in patients with haematological malignancy

Respiratory viruses (RV) are a leading cause of infection-related morbidity and mortality for patients undergoing treatment for cancer. This analysis compared duration of RV shedding as detected by culture and PCR among patients in a high-risk oncology setting (adult patients with haematological malignancy and/or stem cell transplant and all paediatric oncology patients) and determined risk factors for extended shedding. RV infections due to influenza virus, parainfluenza virus (PIV), human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) from two study periods—January 2009–September 2011 (culture-based testing) and September 2011–April 2013 (PCR-based testing)—were reviewed retrospectively. Data were collected from patients in whom re-testing for viral clearance was carried out within 5–30 days after the most recent test. During the study period 456 patients were diagnosed with RV infection, 265 by PCR and 191 by culture. The median range for duration of shedding (days) by culture and PCR, respectively, were as follows—influenza virus: 13 days (5–38 days) versus 14 days (5–58 days), p 0.5; RSV: 11 days (5–35 days) versus 16 days (5–50 days), p 0.001; PIV: 9 days (5–41 days) versus 17 days (5–45 days), p ≤0.0001; HMPV 10.5 days (5–29 days) versus 14 days (5–42 days), p 0.2. In multivariable analysis, age and underlying disease or transplant were not independently associated with extended shedding regardless of testing method. In high-risk oncology settings for respiratory illness due to RSV and PIV, the virus is detectable by PCR for a longer period of time than by culture and extended shedding is observed.