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Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia. We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16–80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10×109 per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664. 197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33·5% (95% CI 22·2–43·1; p<0·0001) in all patients (2·44 [2·22–2·67] in prophylactic group vs 1·63 [1·42–1·83] in therapeutic group), 31·6% (18·6–42·6; p<0·0001) in those with acute myeloid leukaemia (2·68 [2·35–3·01] vs 1·83 [1·58–2·10]), and 34·2% (6·6–53·7; p=0·0193) in those who had had autologous transplantation (1·80 [1·45–2·15] vs 1·18 [0·82–1·55]. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding. The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding. Deutsche Krebshilfe eV (German Cancer Aid).

Reduced-intensity conditioning regimens have been developed to minimise early toxic effects and deaths after allogeneic haemopoietic cell transplantation. However, the efficacy of these regimens before this procedure has not been investigated in a randomised trial. In this prospective, open-label randomised phase 3 trial we compared a reduced-intensity fludarabine-based conditioning regimen with a standard regimen in patients with acute myeloid leukaemia in first complete remission. Patients were aged 18–60 years and had intermediate-risk or high-risk acute myeloid leukaemia (defined by cytogenetics) in first complete remission; an available HLA-matched sibling donor or an unrelated donor with at least nine of ten HLA alleles; and adequate renal, cardiac, pulmonary, and neurological function. Between Nov 15, 2004, and Dec 31, 2009, patients were randomly assigned (1:1, by a computer-based minimisation procedure that balanced patients for age, cytogenetic risk, induction therapy, and donor type) to receive either reduced-intensity conditioning of four doses of 2 Gy of total-body irradiation and 150 mg/m2 fludarabine or standard conditioning of six doses of 2 Gy of total-body irradiation and 120 mg/kg cyclophosphamide. All patients were given ciclosporin and methotrexate as prophylaxis against graft-versus-host disease. Neither investigators nor patients were blinded to study treatment. Our primary endpoint was the incidence of non-relapse mortality, analysed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00150878. The trial was stopped early on Dec 31, 2009, because of slow accrual of patients. 99 patients were randomly assigned to receive reduced-intensity conditioning and 96 to receive standard conditioning. The incidence of non-relapse mortality did not differ between the reduced-intensity and standard conditioning groups (cumulative incidence at 3 years 13% [95% CI 6–21] vs 18% [10–26]; HR 0·62 [95% CI 0·30–1·31]). Relapse incidence (cumulative incidence 3 years 28% [95% CI 19–38] vs 26% [17–36]; HR 1·10 [95% CI 0·63–1·90]), disease-free survival (3 year disease-free survival 58% [95% CI 49–70] vs 56% [46–67]; HR 0·85 [95% CI 0·55–1·32]), and overall survival (3 year overall survival 61% [95% CI 50–74] vs 58% [47–70]; HR 0·77 [95% CI 0·48–1·25]) did not differ significantly between groups. Grade 3–4 of oral mucositis was less common in the reduced-intensity group than in the standard conditioning group (50 patients in the reduced-intensity conditioning group vs 73 patients in the standard conditioning group); the frequency of other side-effects such as graft-versus-host disease and increased concentrations of bilirubin and creatinine did not differ significantly between groups. Reduced-intensity conditioning results in a similar incidence of non-relapse mortality and reduced toxic effects compared with standard conditioning without affecting survival outcomes, and thus could be preferentially used in patients younger than 60 years with acute myeloid leukaemia transplanted in first complete remission. Medical Faculty of Dresden University.

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23); KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria ( n  = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p  < 0.001), OS (HR = 0.14, p  < 0.001), RI (HR = 0.23, p  = 0.001), and NRM (HR = 0.16, p  = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p  = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.

Background. With the advent of new antifungal agents, the identification of a causative pathogen is crucial to guide the antifungal treatment of invasive mold infection. However, tissue cultures often fail to grow a fungal pathogen in cases of suspected mold infection. Methods. In a prospective multicenter study, we compared the results of histopathological analysis, culture, and 2 seminested polymerase chain reaction assays identifying Aspergillus species and Zygomycetes as causative agents of invasive mold infections using respiratory tract biopsy samples obtained from 56 immunocompromised patients who had suspected mold infection. Results. Mold hyphae were detected histopathologically in 27 (48%) of the tissue specimens. Hyphae corresponded to either aspergillosis (n = 18) or zygomycosis (n = 6) or could not be further specified (n = 3). A mold was cultured from 14 of 18 samples with aspergillus hyphae, 2 of 6 samples with Zygomycetes hyphae, and 1 of 3 samples with unspecified hyphae. Polymerase chain reaction was superior to culture in detecting the infecting mold (26 of 27 samples vs. 17 of 27 samples, respectively; P = .006) from histopathologically positive samples. Genus or species identification by sequencing of the polymerase chain reaction products were in accordance with culture results in 16 of 18 culture-positive samples. Both polymerase chain reaction assays failed to detect fungal DNA in 1 sample that had unspecified hyphae and negative culture results. Conclusion. The PCR assays offer a reliable etiologic diagnosis that is superior to culture in patients with proven invasive mold infection. This may improve patient management through tailored antifungal therapy when cultures fail to grow a pathogen.

Central nervous system (CNS) invasive aspergillosis (IA) is a fatal complication in immunocompromised patients. Confirming the diagnosis is rarely accomplished as invasive procedures are impaired by neutropenia and low platelet count. Cerebrospinal fluid (CSF) cultures or galactomannan (GM) regularly yield negative results thus suggesting the need for improving diagnostic procedures. Therefore the performance of an established Aspergillus-specific nested polymerase chain reaction assay (PCR) in CSF samples of immunocompromised patients with suspicion of CNS IA was evaluated. We identified 113 CSF samples from 55 immunocompromised patients for whom CNS aspergillosis was suspected. Of these patients 8/55 were identified as having proven/probable CNS IA while the remaining 47 patients were classified as having either possible (n = 22) or no CNS IA (n = 25). PCR positivity in CSF was observed for 8/8 proven/probable, in 4/22 possible CNS IA patients and in 2/25 NoIA patients yielding sensitivity and specificity values of 1.0 (95% CI 0.68-1) and 0.93 (95% CI 0.77-0.98) and a positive likelihood ratio of 14 and negative likelihood ratio of 0.0, respectively, thus resulting in a diagnostic odds ratio of ∞. The retrospective analysis of CSF samples from patients with suspected CNS IA yielded a high sensitivity of the nested PCR assay. PCR testing of CSF samples is recommended for patients for whom CNS IA is suspected, especially for those whose clinical condition does not allow invasive procedures as a positive PCR result makes the presence of CNS IA in that patient population highly likely.

Background Primary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML. Methods The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors ( n  = 660) versus unrelated donors ( n  = 381), for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant ≥90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality. Conclusions HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients’ outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated.

Background Allogeneic stem cell transplantation is the only curative option for patients with acute myeloid leukemia (AML) experiencing relapse. Either matched sibling donor (MSD) or unrelated donor (UD) is indicated. Methods We analyzed 1554 adults with AML transplanted from MSD ( n  = 961) or UD ( n  = 593, HLA-matched 10/10, n  = 481; 9/10, n  = 112). Compared to MSD, UD recipients were older (49 vs 52 years, p  = 0.001), transplanted more recently (2009 vs 2006, p  = 0.001), and with a longer interval to transplant (10 vs 9 months, p  = 0.001). Conditioning regimen was more frequently myeloablative for patients transplanted with a MSD (61 vs 46 %, p  = 0.001). Median follow-up was 28 (range 3–157) months. Results Cumulative incidence (CI) of neutrophil engraftment ( p  = 0.07), grades II–IV acute GVHD ( p  = 0.11), chronic GVHD ( p  = 0.9), and non-relapse mortality (NRM, p  = 0.24) was not different according to the type of donor. At 2 years, CI of relapse (relapse incidence (RI)) was 57 vs 49 % ( p  = 0.001). Leukemia-free survival (LFS) at 2 years was 21 vs 26 % ( p  = 0.001), and overall survival (OS) was 26 vs 33 % ( p  = 0.004) for MSD vs UD, respectively. Chronic GVHD as time-dependent variable was associated with lower RI (HR 0.78, p  = 0.05), higher NRM (HR 1.71, p  = 0.001), and higher OS (HR 0.69, p  = 0.001). According to HLA match, RI was 57 vs 50 vs 45 %, ( p  = 0.001) NRM was 23 vs 23 vs 29 % ( p  = 0.26), and LFS at 2 years was 21 vs 27 vs 25 % ( p  = 0.003) for MSD, 10/10, and 9/10 UD, respectively. In multivariate analysis adjusted for differences between the two groups, UD was associated with lower RI (HR 0.76, p  = 0.001) and higher LFS (HR 0.83, p  = 0.001) compared to MSD. Interval between diagnosis and transplant was the other factor associated with better outcomes (RI (HR 0.62, p  < 0.001) and LFS (HR 0.67, p  < 0.001)). Conclusions Transplantation using UD was associated with better LFS and lower RI compared to MSD for high-risk patients with AML transplanted in first relapse.

After allogeneic hematopoietic cell transplantation (alloHCT) liver biopsy is performed for enigmatic liver disorders when noninvasive diagnostic steps have failed in establishing a definitive diagnosis. This document provides an updated consensus on the prerequisites for proper evaluation of liver biopsies in alloHCT patients and the histological diagnostic criteria for liver graft-versus-host disease (GvHD). The Working Group’s recommendations for the histological diagnosis of liver GvHD were derived from the peer-reviewed literature and from the consensus diagnosis of a total of 30 coded liver biopsies. Acceptance of the recommendations was tested by a survey distributed to all HCT centers in Austria, Germany and Switzerland. Consensus was achieved for biopsy indications, methods of sample acquisition and processing, reporting and interpretation of biopsy findings. As GvHD is variably treated and the treatment modalities have changed over time, the panel endorses the use of more frequent biopsies in clinical studies in order to improve the present challenging clinical and diagnostic situation.

Background Data comparing fully matched and mismatched-unrelated-donor (M- and mM-URD) allogeneic hematopoietic stem cell transplant (allo-SCT) following reduced intensity conditioning regimens for acute myeloid leukemia are limited. Methods We retrospectively compared the outcome of 3398 patients above the age of 50 years who underwent 10/10 M-URD ( n  = 2567), 9/10 ( n  = 723), or 8/10 ( n  = 108) mM-URD allo-SCT for acute myeloid leukemia after reduced intensity conditioning regimen between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HLA matching had no impact on engraftment ( p  = 0.31). In univariate analysis, in comparison to 10/10 M-URD, mM-URD was associated with higher incidence of grade II–IV acute graft-versus-host disease (GVHD) ( p  = 0.0002), similar rates of chronic GVHD ( p  = 0.138) but increased incidence of its extensive form ( p  = 0.047). Compared to 10/10 M-URD, patients transplanted in the first complete remission (CR1) with a 9 or an 8/10 mM-URD had decreased 2-year leukemia free (LFS) ( p  = 0.005) and overall survivals (OS) (56.7, 46.1, and 50.2 %, respectively, p  = 0.005), while outcomes were comparable between all groups for patients transplanted beyond CR1. In multivariate analysis, 9/10 versus 10/10 URD was associated with higher non-relapse mortality (HR 1.34, p  = 0.001), similar risk of relapse and chronic GVHD and inferior LFS (HR 1.25, p  = 0.0001), and OS (HR 1.27, p  = 0.0001). There was no difference in adjusted transplant outcomes between 9/10 and 8/10 mM-URD. Conclusions Reduced intensity conditioned allo-SCT with a 10/10 M-URD remains the preferable option for AML patients above the age of 50 years. The use of a 9/10 or an 8/10 mM-URD in patients not having a fully matched donor represents an alternative therapeutic option that should be compared to other alternative donor transplant strategies.

This report compares major outcomes after treatment of acute leukemia in adults with either bone marrow or umbilical-cord blood from an unrelated donor. Except for delayed recovery of neutrophils and a reduced risk of graft-versus-host disease in recipients of cord blood, the results with cord blood and bone marrow were similar. It has become apparent that transplanting cord blood into adults is feasible. This report shows that cord blood is an alternative source of hematopoietic stem cells for transplantation. Umbilical-cord blood is considered an alternative to bone marrow as a source of hematopoietic stem cells for transplantation, 1 and its use in adults with hematologic cancers is increasing. 2 There is considerable evidence that cord blood is a promising option for patients who lack an HLA-matched bone marrow donor. 3 – 9 The advantages of cord blood are the immediate availability of cells, the absence of risk to the donor, and a lower need for HLA compatibility between the donor and the recipient. 8 – 11 A limiting factor is the low number of hematopoietic stem cells in a unit of cord blood. For this . . .