Gabriele Ihorst

Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology

While for most cancers incidence and mortality are decreasing, those of non-Hodgkin’s lymphoma (NHL) are steadily increasing. Research to define reasons for this increase is extensive, but has not yet resolved them. We have conducted a literature analysis on trends regarding changes in the incidence, geographic distribution, and etiologic factors of NHL. From our own and previous analyses, an increasing NHL incidence at a rate of 3–4% per year was observed for the 1970s and 1980s. This stabilized in the 1990s, nevertheless still with an annual rise of 1–2%, resulting in almost a doubling of the NHL incidence. This rise has been noted worldwide, particularly in elderly persons >55 years. Concerning gender subgroups, a male predominance throughout all age groups is apparent. Although the NHL incidence has historically been higher in whites than blacks, disproportional increases have recently been observed in the latter group. Increases in high-grade NHL and extranodal disease are predominant. Differences in geographic distribution are striking for follicular lymphoma, which is more common in Western countries than elsewhere. Asians have higher rates of aggressive NHL, T-cell lymphomas, and extranodal disease. In the Middle East, high rates of intestinal extranodal disease are observed, whereas in Africa, endemic Burkitt’s lymphoma accounts for a substantial proportion. Risks for developing NHL include immunosuppression and a causal link between infectious agents, and lymphomagenesis has also been determined, particularly for human T-cell leukemia/lymphoma virus type 1 (HTLV-1), Epstein-Barr virus (EBV), and Helicobacter pylori infections. Exposure to environmental agents and occupational risks have been studied; however, their significance is as yet uncertain.

High-Dose Chemotherapy With Autologous Stem-Cell Transplantation and Hyperfractionated Radiotherapy As First-Line Treatment of Primary CNS Lymphoma

PURPOSE To improve survival and reduce toxicity in primary CNS lymphoma (PCNSL) treatment, we conducted a multicenter phase II study with early high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) followed by hyperfractionated whole-brain radiotherapy (WBRT) for newly diagnosed PCNSL patients younger than 65 years of age. PATIENTS AND METHODS Chemotherapy included three steps: three cycles of methotrexate (8 g/m2); cytarabine (AraC; two doses of 3 g/m2) and thiotepa (40 mg/m2) followed by stem-cell harvest; HDT with carmustine (400 mg/m2) and thiotepa (two doses of 5 mg/kg body weight) followed by ASCT. WBRT (45 Gy, two doses of 1 Gy/d) was administered for consolidation. RESULTS Thirty patients with PCNSL younger than 65 years of age (median, 54 years; range, 27 years to 64 years) were enrolled (nine pilot-phase; 21 phase II). Twenty-eight patients responded to methotrexate: six patients with complete remission (CR), 15 patients with partial remission (PR), and seven patients with stable disease (SD) with clinical improvement. Of 26 patients proceeding to AraC and thiotepa, 10 patients achieved CR, 14 patients achieved PR, one patient experienced SD with clinical improvement, and one patient suffered disease progression. Twenty-three patients received HDT plus ASCT, resulting in 15 patients with CRs and eight patients with PRs. After WBRT, 21 of 21 patients had CRs. One patient died from liver failure after methotrexate. HDT was well tolerated apart from WHO grade 3/4 cytopenia. With a median follow-up of 63 months (range, 4 months to 84 months), 5-year overall survival probability is 69% for all patients and 87% for the 23 patients receiving HDT plus ASCT. The 5-year probability of relapse-related death is 21% for all patients (n = 30) and 8.7% for patients treated with HDT plus ASCT (n = 23). CONCLUSION Sequential systemic methotrexate and AraC and thiotepa followed by HDT plus ASCT and hyperfractionated WBRT is very effective with little toxicity as initial therapy for PCNSL.

Croup Is Associated with the Novel Coronavirus NL63

Background The clinical relevance of infections with the novel human coronavirus NL63 (HCoV-NL63) has not been investigated systematically. We therefore determined its association with disease in young children with lower respiratory tract infection (LRTI). Methods and Findings Nine hundred forty-nine samples of nasopharyngeal secretions from children under 3 y of age with LRTIs were analysed by a quantitative HCoV-NL63-specific real-time PCR. The samples had been collected from hospitalised patients and outpatients from December 1999 to October 2001 in four different regions in Germany as part of the prospective population-based PRI.DE study and analysed for RNA from respiratory viruses. Forty-nine samples (5.2%), mainly derived from the winter season, were positive for HCoV-NL63 RNA. The viral RNA was more prevalent in samples from outpatients (7.9%) than from hospitalised patients (3.2%, p = 0.003), and co-infection with either respiratory syncytial virus or parainfluenza virus 3 was observed frequently. Samples in which only HCoV-NL63 RNA could be detected had a significantly higher viral load than samples containing additional respiratory viruses (median 2.1 × 106 versus 2.7 × 102 copies/ml, p = 0.0006). A strong association with croup was apparent: 43% of the HCoV-NL63-positive patients with high HCoV-NL63 load and absence of co-infection suffered from croup, compared to 6% in the HCoV-NL63-negative group, p < 0.0001. A significantly higher fraction (17.4%) of samples from croup patients than from non-croup patients (4.2%) contained HCoV-NL63 RNA. Conclusion HCoV-NL63 infections occur frequently in young children with LRTI and show a strong association with croup, suggesting a causal relationship.

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: A multicenter survey

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1–7) and SR-cGVHD (1–10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3–90.7%, 95% confidence interval (CI)) and 97.4% (92.3–100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Prospective Study of Human Metapneumovirus Infection in Children Less Than 3 Years of Age

ABSTRACT Most lower respiratory tract infections (LRTIs) in children under the age of 3 years are due to respiratory syncytial virus (RSV). Epidemiological, host, and viral factors eventually account for the severity of LRTIs, but they do not completely explain it. Human metapneumovirus (hMPV) was recently identified in children with LRTIs. In a population-based prospective multicenter study (the PRI.DE study, conducted in Germany over 2 years), we tested 3,369 nasopharyngeal secretions from children younger than 3 years of age with LRTIs for RSV A and B, influenza viruses (IVs) A and B, and parainfluenza viruses (PIVs) 1 to 3. Of the children requiring intensive care (n = 85), 18% had hMPV infections, and 60% of these children were infected with hMPV in combination with RSV. We did not detect hMPV in a randomly selected subset of RSV-positive nasopharyngeal secretions (n = 120) from children not requiring intensive care support. hMPV was detected in <1% of virus-negative samples from patients without intensive care support (n = 620). Our data support the hypothesis that coinfections with RSV and hMPV are more severe than infections with either RSV or hMPV alone, at least in children younger than 3 years of age.

Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome

Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/’fatigue’ of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/’fatigue’ of 50 or over, are likely to have poor outcomes.

Effect of mite‐impermeable mattress encasings and an educational package on the development of allergies in a multinational randomized, controlled birth‐cohort study – 24 months results of the Study of Prevention of Allergy in Children in Europe

Background Sensitization to house dust mite (HDM) is an important risk factor for the development of asthma and allergic disease in childhood. Higher levels of HDM allergen are linked to increased sensitization to HDM.

Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies

Toxicity-reduced conditioning is being used for allogeneic stem cell transplantation in older and/or comorbid patients. We report on the treatment of 133 patients (median age: 55.6 years [23-73 years]) with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS; n = 81), myeloproliferative syndromes (MPS; n = 20), and lymphoid malignancies (n = 32) using conditioning with FBM: fludarabine (5 x 30 mg/m(2)), 1,3-bis(2-chloroethyl)-1-nitrosourea (or carmustine, BCNU; 2 x 200 mg/m(2)), and melphalan (140 mg/m(2)). Patients 55 years or older received fludarabine with reduced BCNU (2 x150 mg/m(2)) and melphalan (110 mg/m(2)). After engraftment, chimerism analyses revealed complete donor hematopoiesis in 95.7% of patients. With a median follow-up of 58.5 months, 3- and 5-year overall survival (OS) was 53.0% and 46.1%, event-free survival (EFS) was 46.4% and 41.9%. No significant differences in OS and EFS were evident considering disease status (early vs advanced), patient age (<55 vs> or =55 years), or donor type (related vs unrelated) in univariate and multivariate analyses. The cumulative 5-year incidence of death due to relapse was 20.1%. Nonrelapse mortality (NRM) after 100 days and 1 year was 15.8% and 26.3%. Among patients with AML/MDS, advanced cases (n = 64, including 61 with active disease) showed an OS of 44.6% and 42.4% after 3 and 5 years, respectively. Therefore, FBM conditioning combines effective disease control with low NRM.

Economic impact of community-acquired and nosocomial lower respiratory tract infections in young children in Germany

Data on the economic burden of lower respiratory tract infections (LRTI) in young children are lacking in Germany. The objective of the cost-of-illness study was to estimate the economic impact of community-acquired LRTI and nosocomial LRTI as well as of infections due to respiratory syncytial virus (RSV), parainfluenza viruses (PIV) and influenza viruses (IV). The economic analysis is part of the PRI.DE study, a prospective, multi-centre, population-based epidemiological study on the impact of LRTI in children aged 0 to 36 months in Germany. The analysis includes children with community-acquired infections (1329 cases treated as outpatients, 2039 cases treated as inpatients) and nosocomial infections (90 cases). Medical services consumed were generated by chart abstraction and parental expenses data by telephone interviews within four weeks after physician visit or hospitalisation. Costs were evaluated from following perspectives: third party payer, parent and society. Total costs for outpatient treatment are €123 per LRTI case. Stratified by virus type, total costs per case are €163 (RSV), €100 (PIV) and €223 (IV). Total costs per hospitalised LRTI case amount to €2579. Stratified by virus type, total costs per case are €2772 (RSV), €2374 (PIV) and €2597 (IV). Total costs per nosocomial case are €2814. Economic burden due to LRTI is €213 million annually. It is concluded that treatment of LRTI in children up to age three causes a considerable economic burden in Germany. Presented results are the first data describing the economic burden of LRTI in young children assessed by means of the incidence data for Germany. This cost-of-illness study provides basic data for further decision-making, focusing on the economic assessment of preventive strategies for RSV, PIV and IV infections.

Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation

Both conventional chimerism analysis (CCA) and lineage-specific chimerism analysis (LCA) have potential pitfalls as diagnostic means for the detection of minimal residual disease after allogeneic hematopoietic cell transplantation (aHCT). Therefore, the present study examines the results of both methods in order to determine how predictive consecutive evaluations were, with respect to the risk that the patient would relapse during post-transplant follow-up and with respect to responsiveness to immunomodulatory treatment. A total of 168 individuals with acute myeloid leukemia (AML) (n=137) and myelo dysplastic syndrome (n=31) were investigated with CCA and LCA at mean intervals of 24 days (range: 11–116). The median follow-up after myeloablative aHCT was 22 months (range: 4–49). Of 168 patients, 65 experienced a clinical relapse after aHCT. CCA and LCA were comparatively sensitive and specific for relapse at the intervals of chimerism testing employed in this study. Of 32 patients, 10 who were offered donor lymphocyte infusions (DLI) treatment for increasing (n=29) or stable (n=3) mixed chimerism (MC) achieved at least transitory CC. The observation that all patients with increasing MC relapsed despite DLI treatment (54%) or withdrawal of immune suppression (24%) indicates that novel strategies to deal with rapidly evolving relapse in AML patients, such as shortening of chimerism monitoring intervals, need to be evaluated.