The China Assessment of Antifungal Therapy in Hematological Disease study, the first large-scale observational study of invasive fungal disease (IFD) in China, enrolled 1401 patients undergoing hematopoietic stem cell transplantation (HSCT) (75.2% allogeneic and 24.8% autologous) at 31 hospitals across China. The overall incidence of proven or probable IFD was 7.7% (108 of 1401); another 266 cases (19.0%) were possible IFD. After allogeneic or autologous HSCT, the incidence of proven/probable IFD was 8.9% (94 of 1053) and 4.0% (14 of 348), respectively. Some cases (14 of 108) developed during conditioning before transplantation. The cumulative incidence of proven/probable IFD increased steeply in the first month after transplantation and after 6 months, the incidence was significantly higher in allogeneic than it was in autologous transplant recipients (9.2% versus 3.5%; P = .001) and when stem cells were derived from cord blood or bone marrow and peripheral blood (P = .02 versus other sources). Independent risk factors for proven/probable IFD in allogeneic HSCT were diabetes, HLA-matched unrelated donor, prolonged severe neutropenia (absolute neutrophil count > 500/mm(3) for >14 days), and immunosuppressants (odds ratio, 2.0 to 3.4 for all). Antifungal prophylaxis was independently protective (P = .01). Previous IFD and prolonged severe neutropenia were significant independent risk factors among autologous transplantation patients (P < .01, P = .04, respectively). In total, 1175 (83.9%) patients received antifungal prophylaxis (91.6% triazoles) and 514 (36.7%) were treated in the hospital with therapeutic antifungals (89.1% triazoles; median 27 days). Empirical, pre-emptive, and targeted antifungals were used in 82.3%, 13.6%, and 4.1% of cases, respectively. Overall mortality (13.4%; 188 deaths) was markedly higher in patients with proven (5 of 16; 31.3%), probable (20 of 92; 21.7%), or possible (61 of 266; 22.9%) IFD; allogeneic (171 of 1053; 16.2%) rather than autologous (17 of 348; 4.9%) HSCT and was significantly higher in patients receiving pre-emptive (18.6%) rather than empirical (6.1%) or targeted (9.5%) antifungal therapy (P = .002). Improvements in the selection and timing of prophylactic antifungals would be welcome. Health care providers should remain alert to the increased risk of IFD and associated mortality in allogeneic HSCT recipients and the ongoing risk of IFD even after discharge from the hospital.

Delayed platelet engraftment (DPE) is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This phenomenon is also a predictor of increased treatment-related mortality and poor survival. Therefore, therapies that promote platelet engraftment to prevent DPE are needed. This prospective randomized controlled trial was designed to investigate whether recombinant human thrombopoietin (rhTPO), administered subcutaneously at a daily dose of 15,000 U from the first day after transplantation, promotes platelet engraftment after haploidentical HSCT. The cumulative incidence of platelet engraftment (platelet recovery to ≥20×10 9 /L without transfusion support for seven consecutive days) on day 60 posttransplantation was significantly higher in the rhTPO group (n=60) than in the control group (n=60) (91.7±3.8 % vs. 74.5 ±5.8 %, P=0.041). Additionally, the number of platelet transfusions from day 14 to day 60 was significantly lower in the rhTPO group than in the control group (4±5 vs. 7±9 Units, P=0.018). No severe adverse effects were observed, with a median follow-up duration of 256 days (range, 48-586 days). The incidences of acute graft-versus-host disease (GVHD), chronic GVHD, and cytomegalovirus viremia and the probabilities of overall survival and disease-free survival did not differ between the two groups. A multivariate analysis of all patients revealed that regardless of assignment to the rhTPO group or the control group (hazard ratio (HR)=1.514; 95 % CI (1.024-2.238); P=0.038), the number of total infused CD34 + cells (HR=1.304; 95 % CI (1.148-1.482); P<0.001) and slower neutrophil engraftment (HR=2.777; 95 % CI (1.841-4.189); P<0.001) were associated with platelet engraftment. In conclusion, rhTPO promotes platelet engraftment and safely reduces the requirement for platelet transfusion in patients after unmanipulated haploidentical HSCT. This trial was registered with the Chinese Clinical Trial Registry (www.chictr. org) as ChiCTR-TRC-11001774. http://www.chictr.org/cn/ proj/show.aspx?proj=2132.

Clin Microbiol Infect 2012; 18: 997–1003 Abstract In recent years, we have successfully established a novel method of haploidentical haematopoietic stem cell transplantation (HSCT) without in vitro T‐cell depletion. This study was aimed at analysing the incidence and risk factors of invasive fungal infection (IFI) with this transplantation method. The study comprised 291 patients who had undergone haploidentical HSCT from 1 January 2007 to 31 December 2008. IFI was diagnosed according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group 2002 criteria, and only proven or probable cases of IFI were regarded as true cases. A total of 39 patients were documented as having IFI, including four proven cases and 35 probable cases. The median time of diagnosis was 26 days (range: 6–405 days) after transplantation. The cumulative incidence rates of IFI at 40 days, 1 year, 2 years and 3 years after transplantation were 8.25%, 13.1%, 13.4% and 13.4%, respectively. Multivariate analysis identified platelet engraftment time (>17 days) (p 0.027; hazard ratio (HR) 2.432; 95% CI 1.105–5.355), a high risk of underlying disease (p 0.001; HR 2.916; 95% CI 1.515–5.611) and grade III–IV acute graft‐versus‐host disease (p 0.019; HR 2.407; 95% CI 1.154–5.022) as risk factors for IFI. The incidence rates of IFI in patients with no, one, two or three risk factors at 3 years after transplantation were 4.48%, 7.86%, 29.6% and 23.1%, respectively. In conclusion, IFI is an important complication following haploidentical HSCT without in vitro T‐cell depletion.

The modified busulfan-cyclophosphamide (mBuCy) regimen, combined with hydroxyurea, cytarabine and semustine, is the most frequently used myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation in our unit. It is unknown, however, whether fludarabine can be substituted for cyclophosphamide in the mBuCy regimen. We carried out a prospective study to compare modified busulfan-fludarabine (mBuF) with mBuCy, aiming to reduce the treatment-related mortality, with non-inferiority of other outcomes. The mBuCy regimen consisted of hydroxyurea 80 mg/kg on day -10; cytarabine 2 g/m(2) on day -9; busulfan 9.6 mg/kg, intravenously on day -8 through -6; and cyclophosphamide 3.6 g/m(2) on day -5 and -4 and semustine 250 mg/m(2) on day -3. In the mBuF regimen, cyclophosphamide was substituted with fludarabine 30 mg/m(2) through day -5 to -1. Mobilized blood and marrow stem cells were collected from HLA-matched siblings. The trial was suspended due to a tendency of higher incidence of severe pneumonia in the mBuF arm, in which 105 patients were enrolled. After follow-up for another 22 months, a significantly increased incidence of severe pneumonia (31.1 %) was observed in the mBuF arm (11.6 % in mBuCy). This finding suggests that it is uncertain whether it is appropriate to substitute fludarabine for cyclophosphamide under any drug combination. This study was registered at www.chictr.org/cn under identifier ChiCTR-TRC-09000470.

The aim of this study was to determine the incidence, clinical features and outcome of invasive fungal disease (IFD) after either unmanipulated haploidentical haematopoietic stem cell transplantation (HSCT) or human leukocyte antigen (HLA)-matched sibling HSCT. This was a head-to-head comparative study performed at a single centre. Patients were admitted between 2007 and 2010, and IFD was evaluated according to the revised EORTC/MSG criteria, with only proven and probable cases included. Of the 1042 consecutive patients enrolled, 390 received the HLA-matched HSCT and 652 received unmanipulated haploidentical HSCT. A total of 61 (5.8%) patients had IFD, including 15 proven cases and 46 probable cases. The incidence of IFD after unmanipulated haploidentical HSCT was significantly higher than that after HLA-matched transplantation (7.1% vs. 3.3%, respectively; p 0.007). IFD occurred later in patients receiving HLA-matched transplantation compared with patients receiving unmanipulated haploidentical HSCT (141.5 vs. 23 days, respectively; p 0.04). In multivariate analysis, acute graft-versus-host disease (GVHD) grades III to IV (HR = 2.214, 95% CI, 1.139-4.304; p 0.019), extensive chronic GVHD (HR = 2.413, 95% CI, 1.377-4.228; p 0.002) and haploidentical transplantation (HR = 2.648, 95% CI, 1.111-6.310; p 0.028) were identified as significant risk factors associated with IFD. The response to antifungal therapy and the IFD-attributable mortality were similar between the two types of transplantation. In conclusion, patients who received unmanipulated haploidentical HSCT had a higher risk of IFD than those patients who received HLA-matched HSCT, but the prognosis of IFD was not associated with the HLA type.