Hematologic health services and practical characteristics: report of a nationwide survey among Chinese hematologists.

BACKGROUND: In the past 40 years, China has experienced tremendous economic development, but the current situation of hematologists has rarely been reported. A landscape survey of human resources is essential for healthcare development and policy formulation in the future. METHODS: The Chinese Society of Hematology initiated a survey of Chinese hematologists in mainland China for evaluating demographic and practice characteristics. Respondents were anonymous, and there were no limitations regarding their age, sex, etc. RESULTS: Totally 2032 hematologists responded, with a median age bracket of 36-45 years. Respondents were well engaged into subspecialties, and 28.1% acquired doctorates of philosophy. Hematopoietic cell transplantation (HCT) centers have been established all over China. Higher-GDP regions reported more advantages, including bigger scale of transplant centers (P < 0.001), younger age structure (P = 0.039), better education qualifications (P = 0.001) and less turnover intentions (P = 0.004), despite of increased risk of medical disputes (P = 0.028). Although females accounted for 65.5% of hematologists, males were older (P < 0.001), and had more senior professional titles (P < 0.001), academic positions (P < 0.001), opportunities for continuing education (P < 0.001), and paper publishing in the recent two years (P = 0.001). For turnover intention, the higher GDP regions led to an independently reduced risk (HR = 0.673, 95%CI [0.482-0.940], P = 0.020), whereas medical disputes resulted in an increased the risk (HR = 2.037, 95%CI [1.513-2.743], P < 0.001). Considering the impact of the COVID-19 pandemic, majority of respondents believed that the decline in patient visits and delay in treatment was within 30%. 67.9% of respondents reported a decrease of the use of bone marrow as grafts but 18.8% reported an increase of cord blood units. 35.0% of the respondents switched their daily work to support the anti-epidemic medical activities. CONCLUSIONS: We concluded the discipline of hematology in China has flourished in recent years with a young workforce, while regional economic and gender disparities warrant further continuous optimization. Joint efforts against the impact of COVID-19 are needed in the post-pandemic era.

Optimized therapeutic strategy for patients with refractory or relapsed acute myeloid leukemia: long-term clinical outcomes and health-related quality of life assessment.

BACKGROUND: Patients with refractory or relapsed acute myeloid leukemia (AML) have poor survival, necessitating the exploration of optimized therapeutic strategy. Here, we aimed to investigate clinical outcomes and health-related quality of life (HR-QoL) after total therapy, which included allogeneic hematopoietic stem cell transplantation (allo-HSCT), and prophylactic donor lymphocyte infusion (DLI) in the early phase after transplantation, followed by multiple measurable residual disease (MRD) and graft-versus-host disease (GvHD)-guided DLIs. METHODS: Consecutive patients who had refractory or relapsed AML and had received non-T-cell-depleted allo-HSCT at Peking University Institute of Hematology were included in the study. If the patients achieved complete remission at 30 days after transplantation and had no evidence of relapse, severe infection, organ failure, and active GvHD at the time of planned DLI, prophylactic DLI was administered at 30 days after transplantation for human leukocyte antigen (HLA)-matched related HSCT or at 45-60 days after transplantation for haploidentical or unrelated HSCT. Subsequently, multiple DLIs were administered based on MRD results and whether they developed GvHD after transplantation. RESULTS: A total of 105 patients were eligible. Eighty-seven patients received prophylactic DLI (group B), while 18 did not receive prophylactic DLI (group A). Among 105 patients, the cumulative incidence of grade 2-4 acute GvHD and chronic GvHD was 40.6% (95% confidence interval [CI] = 30.6%-50.6%) and 73.3% (95% CI = 67.4%-79.2%), respectively. The cumulative incidence of relapse (CIR), transplant-related mortality (TRM), and leukemia-free survival (LFS) at 5 years after transplantation were 31.5% (95% CI = 21.9%-41.1%), 22.1% (95% CI = 11.3%-32.9%), and 46.4% (95% CI = 36.8%-56.0%), respectively. In group B, the CIR, TRM, and LFS at 5 years after transplantation were 27.6% (95% CI = 17.6%-37.6%), 21.6% (95% CI = 11.2%-32.0%), and 50.8% (95% CI = 40.0%-61.6%), respectively. At the end of follow-up, 48 patients survived, and more than 90% of survivors had satisfactory recoveries of HR-QoL. CONCLUSIONS: Our study indicated that total therapy is not only associated with decreased CIR, comparable TRM, and better long-term LFS, but also with satisfactory HR-QoL for refractory or relapsed AML, compared with those of standard of care therapy reported previously. Therefore, total therapy may be an optimized therapeutic strategy for refractory or relapsed AML.

Intended and unintended impacts of the comprehensive reform of urban public hospitals: A mixed-method study in Hangzhou, China.

Objectives: Public hospital reform is a key area in the Chinese healthcare system reform with the aim of controlling excessive growth of medical expenditures. This study aims to evaluate the impacts of two rounds of urban public hospital reforms respectively starting in 2018 and 2019. Method: A mixed-method method was conducted in Hangzhou. In the quantitative phase, monthly data covering 7 provincial, 12 municipal, and 35 district hospitals from March 2017 to June 2020 was analyzed using a panel-interrupted time-series. Thematic content analysis was conducted using qualitative data collected from 32 in-depth interviews. Results: Quantitative data showed a considerable reduction in the proportion of drug revenue (provincial hospitals: -4.937%; municipal hospitals: -2.765%; district hospitals: -2.189%) and an increase in the proportion of consumable (provincial hospitals: ß 2 = 2.025; municipal hospitals: ß 3 = 0.206) and examinations (provincial hospitals: ß 2 = 1.354, ß 3=0.159; municipal hospitals: ß 2 = 1.179) revenue after the first reform. In post-reform 2, The respective instant decrease and increase in the proportion of consumable (provincial hospitals: -2.395%; municipal hospitals: -0.898%) and medical services (provincial hospitals: 2.115%; municipal hospitals: -2.604%) revenue were observed. Additionally, quantitative and qualitative data indicated inpatient expenditures dropped considerably after the reform. However, insufficient compensation for medical services and increased financial pressure on hospitals were repeatedly mentioned as unintended consequences in qualitative interviews. Conclusions: Overall, the urban public hospital reforms in China created positive effects in adjusting hospital revenue structure and constraining soaring medical expenditures. Unintended consequences remind policymakers to establish rational and dynamic compensation mechanisms for public hospitals.

Impacts of a New Episode-Based Payment Scheme on Volume, Expenditures, and Efficiency in Public Hospitals: A Quasi-Experimental Interrupted Time-Series Study in Jinhua, China.

Purpose: Based on the diagnosis-related groups payment, China developed an innovative episode-based payment scheme, called "payment method by disease types with point counting", to control health expenditures inflation. This study aimed to investigate the impacts of this new payment method on volume, expenditures, and efficiency in Chinese public hospitals. Methods: The study sample consisted of 7 tertiary hospitals and 14 secondary hospitals in Jinhua (intervention group) and 4 tertiary hospitals and 14 secondary hospitals in Taizhou (control group). Monthly data points were collected for each sampled hospital from June 2016 to June 2019 using a self-administered questionnaire with impact evaluation indicators. Controlled interrupted time-series analysis was employed to estimate the effect of the new payment method. Results: The significant slowing trends in inpatient expenditures per visit (tertiary hospitals: ß7=-123.16, p=0.042; secondary hospitals: ß7=-89.24, p=0.021) and out-of-pocket payments (tertiary hospitals: ß7=-4.18, p=0.027; secondary hospitals: ß7=-4.87, p=0.019) were observed after policy intervention. However, outpatient expenditures per visit in tertiary (ß7=1.67, p=0.018) and secondary hospitals (ß7=1.24, p=0.003) rose faster with the new payment method. Additionally, payment reform also caused an increase in the number of inpatient visits (ß7=100.01, p=0.038) and reduced the length of stay (ß7=-0.10, p=0.036) in tertiary hospitals. Conclusion: The introduction of payment method by disease types with point counting causes the cost containment for inpatient care, whereas the increase in outpatient expenditures. The findings suggest this new payment scheme has the potential for rollout in other areas, but the cost-shifting from the inpatient to outpatient setting should be prevented.

Significance of WT1 and multiparameter flow cytometry assessment in patients with chronic myelomonocytic leukemia receiving allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: The objective of this study was to investigate the clinical significance of minimal residual disease (MRD) monitoring through Wilms tumor 1 (WT1) gene expression and multicolor flow cytometry (FCM) in patients with chronic myelomonocytic leukemia (CMML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: For this purpose, WT1 gene expression and the CMML-related abnormal immunophenotype were examined using real-time quantitative polymerase chain reaction and FCM, respectively. RESULTS: In total, 59 patients with CMML who underwent allo-HSCT were enrolled in this study. Thirteen cases (22.0%) developed hematological relapse, and 15 patients (25.4%) expired during the follow-up period. Thirty-four patients (37.6%) were positive for WT1 (WT1+), and 44 patients (74.6%) were positive for FCM prior to allo-HSCT. After allo-HSCT, there were 21 WT1+ patients (35.6%) and 10 patients (16.9%) who were positive in FCM (FCM+). Post-transplant WT1+ (post-WT1 0.6+; 50.7% vs. 7.6%, p < .001) and post-transplant FCM+ (post-FCM+; 90.0% vs. 8.8%, p < .001) indicated a higher 3-year cumulative incidence of relapse (CIR) compared with the WT1- or FCM-patients. Multivariate analysis of event-free survival (EFS), overall survival (OS), and CIR showed that the FCM status after transplantation was an independent prognostic factor for relapse (p < .05). CONCLUSION: Both FCM and WT1 after HSCT were identified as important predictors of recurrence of CMML following transplantation and may be useful in guiding interventions against disease relapse.

Real-world assessment of the effectiveness of posaconazole for the prophylaxis and treatment of invasive fungal infections in hematological patients: A retrospective observational study.

ABSTRACT: The aim of the study was to analyze the efficacy of posaconazole for the prophylaxis and treatment of invasive fungal diseases (IFDs) in patients with hematological malignancies.In this retrospective observational multi-center study, 762 patients from 25 Chinese hematological centers were enrolled. Inclusion criteria were patients with hematological malignancy or they had undergone hematopoietic stem cell transplantation and received at least 1 dose of posaconazole. The primary endpoints were the observation of breakthrough rates and the clinical efficacy of posaconazole prophylaxis. The secondary endpoint was the efficacy of posaconazole for the treatment of IFDs.Of the 762 enrolled patients, 456 (59.8%) were prescribed posaconazole prophylactically while 243 (31.9%) received posaconazole as an IFD treatment (12 proven, 61 probable, 109 possible, and 61 unclassified IFD cases) for ≥7 days. The overall IFD breakthrough rate (probable cases) for the ≥4 days prophylactic treatment (n = 445) group was 1.6% (95% Cl: 0.6%-3.2%), with breakthrough rates of 2.6% for acute myeloid leukemia/myelodysplastic syndrome patients undergoing chemotherapy and 2.2% for hematopoietic stem cell transplantation patients. For primary antifungal prophylaxis, the breakthrough rate was 1.9% and for secondary antifungal prophylaxis 0%. The overall effective IFD remission rate of patients treated for ≥7 days with posaconazole was 56.0% and the effective remission rate of proven/probable/possible IFD cases was 59.3%. The effective remission rate of posaconazole as salvage therapy was 50% (95% CI: 32.4%-67.6%) including 75% (CI: 19.4%-99.4%) for Aspergillus infections.The present retrospective study confirmed posaconazole as IFD prophylaxis and medication for hematological malignancy patients undergoing various treatments in China.

Clinical risk score for predicting invasive fungal disease after allogeneic hematopoietic stem cell transplantation: Analysis of the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study.

BACKGROUND AND OBJECTIVE: Invasive fungal disease (IFD) is associated with a high mortality for patients with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed not only to develop a proven/probable IFD risk-scoring model but to identify high-risk populations that would benefit from anti-fungal prophylaxis. METHODS: Data from the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study were retrieved, and all patients (n = 1053) undergoing allo-HSCT were randomly divided into the training set (n = 685) for model development and the validation set (n = 368) for model verification. A weighted risk score for proven or probable IFD was established through multivariate logistic regression analysis. RESULTS: The study population had a mean age of 28.95 years and the majority underwent myeloablative transplantation in complete remission 1 (53.4%). Five risk factors of IFD were identified, namely neutropenia lasting longer than 14 days, corticosteroid use, diabetes, haploidentical donor, and unrelated donor. Based on the risk score for IFD, the patients were categorized into three groups: low risk (score 0-4, 1.5%-4.0%), intermediate risk (score 5-8, 9.8%), and high risk (score>8, 24.7%-14.0%). Anti-fungal prophylaxis may provide benefits for patients with intermediate (8.5% vs. 18.5%, P = .0085) or high risk (19.4% vs. 30.8%, P = .4651) but not low risk (2.1% vs. 3.8%, P = .6136) of IFD. CONCLUSION: A practical weighted risk score for IFD in patients receiving allo-HSCT was established, which can aid decision-making regarding the administration of anti-fungal prophylaxis.

Fluconazole is as effective as other anti-mold agents in preventing early invasive fungal disease after allogeneic stem cell transplantation: assessment of antifungal therapy in haematological disease in China.

BACKGROUND: The introduction of mold-active antifungal drugs has led clinicians to reconsider the use of fluconazole for preventing invasive fungal disease (IFD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study of recipients of allo-HSCT, we evaluated the effects of different antifungal prophylaxes on the incidence of IFD at different times after transplantation. METHODS: Among the 1,401 patients registered in the prospective China Assessment of Antifungal Therapy in Haematological Disease (CAESAR) study database, there were 661 eligible patients who received primary antifungal prophylaxis. The incidence of IFD at different times after transplantation (early, late, and very late) and overall survival were compared for patients who received different drugs. RESULTS: The overall incidence of probable IFD was 7.0% in the fluconazole group, 12.6% in the itraconazole group, 1.4% in the voriconazole group, and 5.2% in the micafungin group (P=0.0379). However, the four groups had no significant differences in early, late, or very late IFD. The risk factors associated with IFD were neutropenia for more than 14 days, age greater than 18 years, and receipt of transplantation from an alternative (unrelated and haploidentical) donor (P<0.05). Sub-group analysis of alternative donors indicated that the efficacy of fluconazole was similar to the other three drugs in preventing early IFD. CONCLUSIONS: Our results suggest that the efficacy of fluconazole is similar to that of mold-active drugs in preventing early IFD in HSCT patients, even in high-risk patients receiving transplantation from alternative donors. Further prospective randomized studies are needed to confirm this conclusion.

Assessment of chronic renal injury in patients with chronic myeloid leukemia in the chronic phase receiving tyrosine kinase inhibitors.

We aimed to evaluate the incidence of chronic renal injury in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitors (TKIs) and to identify the associated factors. Data for CML-CP patients with normal estimated glomerular filtration rate (eGFR) at baseline and receiving TKI therapy ≥ 3 months were retrospectively reviewed. The CRAE (chronic renal adverse event, defined as a 30% eGFR reduction from baseline or eGFR < 60 ml/min/1.73 m2 ≥ 90 days whichever occurred first)-free survival rates at 3 years in the imatinib cohort (n = 360) were significantly lower than those in the nilotinib cohort (n = 100) (55% versus 77%, P = 0.001) as a first-line TKI therapy. In multivariate analyses, imatinib, male sex, increasing age, and previous non-TKI treatment were associated with poor CRAE-free survival. In newly diagnosed patients who received imatinib treatment (n = 40), 24-h urine protein levels significantly increased after 6 months, and urinary ß2-microglobulin values significantly increased compared to those in the nilotinib cohort (n =15) at 36 months (P = 0.042) and 42 months (P = 0.039). There was no significant difference in CRAE-free survival rates at 3 years between the nilotinib (n = 65) and dasatinib (n = 74) cohorts (67% versus 83%, P = 0.832) as second- or third-line TKI therapies. In multivariate analyses, previous non-TKI treatment was associated with poor CRAE-free survival. We concluded that imatinib was significantly correlated to chronic renal injury, possibly associated with glomerulus and renal tubular injury, compared with nilotinib as a first-line TKI therapy in CML-CP patients. However, nilotinib and dasatinib had similar mild adverse impacts on renal function as second- or third-line therapies.

Clinical risk score for invasive fungal diseases in patients with hematological malignancies undergoing chemotherapy: China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study.

Invasive fungal disease (IFD) is a major infectious complication in patients with hematological malignancies. In this study, we examined 4889 courses of chemotherapy in patients with hematological diseases to establish a training dataset (n = 3500) by simple random sampling to develop a weighted risk score for proven or probable IFD through multivariate regression, which included the following variables: male patients, induction chemotherapy for newly diagnosed or relapsed disease, neutropenia, neutropenia longer than 10 days, hypoalbuminemia, central-venous catheter, and history of IFD. The patients were classified into three groups, which had low (0-10, ~1.2%), intermediate (11-15, 6.4%), and high risk ( > 15, 17.5%) of IFD. In the validation set (n = 1389), the IFD incidences of the groups were ~1.4%, 5.0%, and 21.4%. In addition, we demonstrated that antifungal prophylaxis offered no benefits in low-risk patients, whereas benefits were documented in intermediate (2.1% vs. 6.6%, P = 0.007) and high-risk patients (8.4% vs. 23.3%, P = 0.007). To make the risk score applicable for clinical settings, a pre-chemo risk score that deleted all unpredictable factors before chemotherapy was established, and it confirmed that anti-fungal prophylaxis was beneficial in patients with intermediate and high risk of IFD. In conclusion, an objective, weighted risk score for IFD was developed, and it may be useful in guiding antifungal prophylaxis.

Total MRI burden of cerebral vessel disease correlates with the progression in patients with acute single small subcortical strokes.

BACKGROUND: The patients of single small subcortical strokes (SS) commonly have neurological worsening with risk factors, and mechanisms remain unclear. Asymptomatic lacunes, white matter lesions, cerebral microbleeds, and enlarged perivascular spaces are MRI markers of cerebral small vessel disease (cSVD). Previous studies mostly explored the association between the neurological deterioration and presence of above markers separately. The relationship between progressive single small SS and the simultaneous presence of multiple markers of cSVD has not been fully identified. We aimed to investigate whether total burden of cSVD detected with MRI was associated with progressive small SS in this study. METHODS: Patients with single small SS (2.0 cm in diameter) were prospectively recruited during January 2016 and May 2018. Progression was defined as worsening by ≥1 point in National Institutes Health Stroke Scale (NIHSS) motor score within 72 hr from onset. The presence and burden of cSVD were determined by brain MRI, producing a score between 0 and 4. Besides, the patients' characteristics, clinical data, medical treatments during hospitalization stay were collected and statistically analyzed. Associations with progression were tested with forward stepwise regression analyses. RESULTS: Fifty-seven (35.6%) patients underwent progression. No significant difference was observed in the distribution of any single vascular risk factor and its related laboratory data among these patients. After adjustment for age, sex, NIHSS score at admission, and time from stroke to MRI in separate models, severe WMHs (OR = 4.892; 95% CI = 2.011-11.904, p = 0.016), moderate- and high-grade basal ganglia EPVS (OR = 2.970; 95% CI = 1.861-6.121, p = 0.009), and total cSVD score (OR = 3.359; 95% CI = 2.016-5.599, p = 0.010) were associated with progression. CONCLUSION: This study demonstrated that total MRI cSVD burden was independently associated with progression after single small subcortical strokes.

An Inter-Ethnic Comparison Study of Ziprasidone Plasma Levels, Dosage and Clinical Response in Patients with Schizophrenia.

OBJECTIVE: The aim of this study was to investigate ziprasidone plasma concentration, daily dose and clinical efficacy and safety in Han Chinese and Mongolian patients with first-episode schizophrenia. METHODS: A total of 123 inpatients affected by schizophrenia were recruited from the Mental Health Center of Inner Mongolia in China. Ziprasidone plasma concentration, clinical efficacy and side effects were systematically evaluated at baseline, and at 1, 2, 4, and 6 weeks. Metabolic measures such as changes in weight, body mass index (BMI), fasting blood glucose (FBG), triglycerides, and cholesterol, were also recorded. RESULTS: 90 patients completed the study. Compared with Han patients, on average, Mongolian patients received a significantly higher ziprasidone dosage for adequate symptom control during the 6-week period and had a lower plasma concentration-to-dose ratio. The Mongolian patients also experienced greater increases in weight and BMI. No significant differences between the two ethnic groups were found in the rate of reduction in the Positive and Negative Syndrome Scale (PANSS) score, Treatment Emergent Symptom Scale (TESS) total score, FBG, triglycerides, cholesterol or Q-Tc interval. CONCLUSION: Compared to Han Chinese patients, Mongolian patients appeared to have increased ziprasidone clearance and require higher doses to achieve effective treatment for schizophrenia.

Reduced medical costs and hospital days when using oral arsenic plus ATRA as the first-line treatment of acute promyelocytic leukemia.

We have demonstrated that oral arsenic (Realgar-Indigo naturalis formula, RIF) plus all-trans retinoic acid (ATRA) is not inferior to intravenous arsenic trioxide (ATO) plus ATRA as the first-line treatment of acute promyelocytic leukemia (APL). To compare the cost-effectiveness of oral and intravenous arsenic, we analyzed the results of 30 patients in each group involved in a randomized controlled trial at our center. The median total medical costs were $13,183.49 in the RIF group compared with $24136.98 in the ATO group (p<0.0001). This difference primarily resulted from the different costs of induction therapy (p=0.016) and maintenance treatment (p<0.0001). The length of hospitalization for the RIF group was significantly lower than that for the ATO group (24 vs. 31 days, p<0.0001) during induction therapy. During maintenance treatment, the estimated medical costs were $2047.14 for each patient in the RIF group treated at home compared with $11273.81 for each patient in the ATO group treated in an outpatient setting (p<0.0001). We conclude that oral RIF plus ATRA significantly reduced the medical costs and length of hospital stay during induction and remission therapy compared with ATO plus ATRA in APL patients.

Epidemiology, management, and outcome of invasive fungal disease in patients undergoing hematopoietic stem cell transplantation in China: a multicenter prospective observational study.

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.

The effect of HLA disparity on clinical outcome after HLA-haploidentical blood and marrow transplantation.

The relative importance of various human leukocyte antigen (HLA) loci has not been established for unmanipulated HLA-mismatched/haploidentical transplantation. To address this question, we analyzed the impact of HLA-A, HLA-B, HLA-DRB1, HLA-DRB3, HLA-DRB4, and HLA-DRB5 on the outcome of HLA-haploidentical transplantation. Four hundred and eighty-one donor-recipient pairs were fully typed before transplantation. In univariate analysis, HLA-B mismatch not only demonstrated significant adverse effects on acute graft-versus-host disease (GVHD) and transplant-related mortality but also was associated with reduced overall survival and leukemia-free survival (LFS). In multivariate analysis, HLA-B mismatch remained the independent risk factor for acute GVHD and transplant-related mortality. The high risk of disease and the female donor were found to be significant factors for reduced overall survival and LFS. Furthermore, multiple mismatch of the HLA locus was found to have no synergistic adverse effect on outcomes. Our results suggest that prospective matching of patients and donors for HLA-B antigen in the unshared HLA haplotype is warranted for HLA-mismatched/haploidentical transplantation.

Quantitative assessment of hematopoietic chimerism by quantitative real-time polymerase chain reaction of sequence polymorphism systems after hematopoietic stem cell transplantation.

BACKGROUND: Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation (HSCT) and sequential adoptive immunotherapy by donor lymphocyte infusions. We developed a sensitive, reliable and rapid real-time PCR method based on sequence polymorphism systems to quantitatively assess the hematopoietic chimerism after HSCT. METHODS: A panel of 29 selected sequence polymorphism (SP) markers was screened by real-time PCR in 101 HSCT patients with leukemia and other hematological diseases. The chimerism kinetics of bone marrow samples of 8 HSCT patients in remission and relapse situations were followed longitudinally. RESULTS: Recipient genotype discrimination was possible in 97.0% (98 of 101) with a mean number of 2.5 (1-7) informative markers per recipient/donor pair. Using serial dilutions of plasmids containing specific SP markers, the linear correlation (r) of 0.99, the slope between -3.2 and -3.7 and the sensitivity of 0.1% were proved reproducible. By this method, it was possible to very accurately detect autologous signals in the range from 0.1% to 30%. The accuracy of the method in the very important range of autologous signals below 5% was extraordinarily high (standard deviation <1.85%), which might significantly improve detection accuracy of changes in autologous signals early in the post-transplantation course of follow-up. The main advantage of the real-time PCR method over short tandem repeat PCR chimerism assays is the absence of PCR competition and plateau biases, with demonstrated greater sensitivity and linearity. Finally, we prospectively analyzed bone marrow samples of 8 patients who received allografts and presented the chimerism kinetics of remission and relapse situations that illustrated the sensitivity level and the promising clinical application of this method. CONCLUSION: This SP-based real-time PCR assay provides a rapid, sensitive, and accurate quantitative assessment of mixed chimerism that can be useful in predicting graft rejection and early relapse.

Related HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion: observations of a single Chinese center.

The Institute of Hematology, Peking University, is the largest hematopoietic stem cell transplantation (HSCT) center in China. A total of 400 HSCTs performed in 2010 accounted for a quarter of all allogeneic HSCTs performed in China. The GIAC protocol, which uses HLA-mismatched/haploidentical blood or bone marrow transplantation without in vitro T-cell depletion, entails administration of granulocyte-colony stimulating factor (G-CSF) to all donors, intensified immunological suppression, and treatment with anti-human thymocyte immunoglobulin. The stem cell grafts are a combination of G-CSF-primed bone marrow cells and G-CSF-mobilized peripheral blood stem cells, which may be critical to the success of this protocol through the immune modulation of G-CSF. Using this protocol, more than 99% engraftment and complete donor chimerism were achieved in pediatric and adult patients with hematological malignancies. The incidence of graft-versus-host disease (GVHD) grades 3 and 4 was 13.4% and that of extensive chronic GVHD 22.6%. Comparable relapse rates were observed between patients who received unmanipulated haploidentical transplantation, and those who received HLA-identical or unrelated HSCT. Patients with confirmed minimal residual disease, (expression levels of Wilms' tumor suppressor gene 1 and flow cytometry) after HSCT received pre-emptive modified donor lymphocyte infusion to prevent relapse. Infection was the main cause of non-relapse death. Prospective studies are ongoing to investigate the mechanisms of immune reconstitution in order to refine the protocol. In 1964, a patient with severe aplastic anemia received a bone marrow infusion from her syngeneic, pregnant sister, and remained disease-free over a 40-year follow-up period. Following this success, there was a 20-year interruption in the transplantation program at our center. The hiatus ended in 1981 with the first allogeneic HSCT, which was used to treat a girl with acute lymphoblastic leukemia (ALL). In the mid-1990s, the facility performed allo-HSCTs from unrelated donors (URD) and umbilical cord blood (UCB). Then, in 2000, a patient with refractory acute leukemia received related haploidentical HSCT and achieved long-term survival without relapse over an 11-year followup period. Coincident with the rapid economic development experienced in China since 2000, the transplantation program at our Institute has been expanded to include broadened indications, multiple sources of stem cells and improved outcomes. The Institute is the largest HSCT center in China, now with 130 beds in four wards, 33 of which are laminar-flow rooms. Between 2007 and 2009, over 350 HSCTs were performed per year, rising to a total of 400 in 2010. Further, in 2010, 94% of these HSCTs were allogeneic transplants, accounting for a quarter of all allo-HSCTs performed in China. Of these, transplants from URD accounted for 6%-7%, those using UCB for less than 5%, those from identical siblings for 25%-30%, and those from the related haploidentical for 55%-65%. The most common indications for treatment with allo-HSCT are intermediate-to-high risk of acute leukemia or myelodysplastic syndrome, advanced chronic myeloid leukemia (CML), refractory lymphoma, or severe aplastic anemia.