Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working ...Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria.
Summary Background Allogeneic stem-cell transplantation has had limited success for patients with refractory and relapsed aggressive B-cell or T-cell lymphoma. We investigated the effect of adding ...rituximab to standard prophylaxis for graft-versus-host disease after transplantation and estimated overall survival when using a lymphoma-directed myeloablative conditioning regimen. Methods We did this randomised, open-label, phase 2 study at seven German transplantation centres. We enrolled patients with aggressive B-cell or T-cell lymphoma and primary refractory disease, early relapse (<12 months after first-line treatment), or relapse after autologous transplantation. Conditioning with fludarabine (125 mg/m2 ), busulfan (12 mg/kg oral or 9·6 mg/kg intravenous), and cyclophosphamide (120 mg/kg) was followed by allogeneic stem-cell transplantation. Patients were randomly assigned (1:1) to receive rituximab (375 mg/m2 on days 21, 28, 35, 42, 175, 182, 189, and 196) or not. Allocation was done with a centralised computer-generated procedure; patients were stratified by histological subtype (B-cell vs T-cell lymphoma) and donor match (HLA-identical vs non-identical). Neither investigators nor patients were masked to allocation. The primary endpoints were the incidence of acute graft-versus-host disease grade 2–4 in each treatment group and overall survival at 1 year in both groups combined. All analyses were done for the intention-to-treat population. The study is registered with ClinicalTrials.gov , number NCT00785330. Findings Between June 16, 2004, and March 24, 2009, we screened 86 patients and enrolled 84; 42 were randomly assigned to each group. The cumulative incidence of grade 2–4 acute graft-versus-host disease was 46% (95% CI 32–62) in the rituximab group and 42% (95% CI 29–59) in the no rituximab group (hazard ratio HR 0·91, 95% CI 0·52–1·60; p=0·74). Overall survival at 1 year for the whole study population was 52% (95% CI 41–62). Grade 4 haematological toxic effects and grade 3 alopecia occurred in all patients. The most common non-haematological grade 5 toxic effects were pneumonia (nine in the no rituximab group vs ten in the rituximab group) and other infections (seven vs four). Interpretation The lymphoma-directed myeloablative conditioning regimen developed here is promising for patients with refractory and relapsed aggressive B-cell and T-cell lymphomas. However, the addition of rituximab did not affect the incidence of graft-versus-host disease or overall survival. Funding Hoffmann-La Roche, Amgen, Astellas Pharma.
Therapy-resistant viral reactivations contribute significantly to mortality after hematopoietic stem cell transplantation. Adoptive cellular therapy with virus-specific T cells (VST) has shown ...efficacy in various single-center trials. However, the scalability of this therapy is hampered by laborious production methods. In this study we describe the in-house production of VST in a closed system (CliniMACS Prodigy® system, Miltenyi Biotec). In addition, we report the efficacy in 26 patients with viral disease following hematopoietic stem cell transplantation in a retrospective analysis (adenovirus, n=7; cytomegalovirus, n=8; Epstein-Barr virus, n=4; multi-viral, n=7). The production of VST was successful in 100% of cases. The safety profile of VST therapy was favorable (n=2 grade 3 and n=1 grade 4 adverse events; all three were reversible). A response was seen in 20 of 26 patients (77%). Responding patients had a significantly better overall survival than patients who did not respond (P<0.001). Virus-specific symptoms were reduced or resolved in 47% of patients. The overall survival of the whole cohort was 28% after 6 months. This study shows the feasibility of automated VST production and safety of application. The scalability of the CliniMACS Prodigy® device increases the accessibility of VST treatment.
The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. ...Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient’s risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
Limited data are available on characteristics of viral encephalitis in patients after allogeneic stem cell transplantation.
We analyzed 2,628 patients after allogeneic stem cell transplantation to ...identify risk factors and characteristics of viral encephalitis.
Viral encephalitis occurred in 32 patients (1.2%, 95% confidence interval 0.8%-1.6%) and was associated with the use of OKT-3 or alemtuzumab for T-cell depletion (P < 0.001) and an increased mortality (P = 0.011) in comparison to patients without viral encephalitis. Detected viruses included human herpesvirus-6 (28%), Epstein-Barr virus (19%), herpes simplex virus (13%), JC virus (9%), varicella zoster virus (6%), cytomegalovirus (6%) and adenovirus (3%). More than one virus was identified in 16% of the patients. The median onset time was 106 days after allogeneic stem cell transplantation for the total group of 32 patients, but onset times were shortest in those with human herpesvirus-6 encephalitis and longest in those with JC virus-associated progressive multifocal leukoencephalopathy. The probability of a sustained response to treatment was 63% (95% confidence interval 44%-82%) with a median survival of 94 (95% confidence interval 36-152) days after onset, but significant variation was found when considering different causative viruses. Patients with herpes simplex virus encephalitis had the most favorable outcome with no encephalitis-related deaths.
The use of OKT-3 or alemtuzumab for in vivo T-cell depletion is associated with an increased risk of viral encephalitis after allogeneic stem cell transplantation. Different viruses are frequently associated with distinct characteristics such as onset time, response to treatment and outcome.
Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. ...Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive Candida infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection.
Gastrointestinal graft-versus-host disease (GVHD) is a common and potentially life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Noninvasive tests for ...assessment of GVHD activity are desirable but lacking. In the present study, we were able to visualize intestinal GVHD-associated inflammation in an allogeneic murine transplantation model by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in vivo. A predominant localization of intestinal GVHD to the colon was verified by histology and fluorescence reflectance imaging of enhanced green fluorescent protein (EGFP)–expressing donor cells. Colonic infiltration by EGFP+ donor lymphocytes matched increased FDG uptake in PET examinations. These preclinical data were prospectively translated into 30 patients with suspected intestinal GVHD beyond 20 days after transplantation. A total of 14 of 17 patients with a diagnostic histology showed significant FDG uptake of the gut, again predominantly in the colon. No increased FDG uptake was detected in 13 patients without histologic evidence of intestinal GVHD. Our findings indicate that FDG-PET is a sensitive and specific noninvasive imaging technique to assess intestinal GVHD, map its localization, and predict and monitor treatment responsiveness. Novel targeted tracers for PET may provide new insights into the pathophysiology of GVHD and bear the potential to further improve GVHD diagnosis.
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