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This study aimed to explore the health-related quality of life (HRQoL) and associated variables in children with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitors (TKIs). A cross-sectional questionnaire was given to children with CML and their parents, who were

To explore the differences in the clinical features, treatment responses, and outcomes among children, adolescents, and adults with chronic myeloid leukemia in the chronic phase (CML-CP) receiving imatinib as first-line therapy. Data from children (0–8 years for girls and 0–10 years for boys), adolescents (9–19 years for girls and 11–19 years for boys), and adults (age ≥ 20 years) with newly diagnosed CML-CP receiving imatinib as first-line therapy between 2006 and 2019 were retrospectively reviewed. In total, 135 children (cohort 1), 189 adolescents (cohort 2), and 658 adults (cohort 3: age 20–39 years, n = 305; cohort 4: age 40–59 years, n = 270; and cohort 5: age 60–83 years, n = 83) were included in this study. When compared with children, adolescents showed a significantly higher white blood cell count (P = 0.033) and basophil percentage in peripheral blood (P = 0.002) and a significantly higher prevalence of splenomegaly (P = 0.004). Both children and adolescents presented with more aggressive clinical features than adults. During median follow-ups of 28 months (range, 3–161 months) in children, 33 months (range, 3–152 months) in adolescents, and 48 months (range, 3–157 months) in adults, multivariate analysis showed that children and adolescents had higher probabilities of achieving complete cytogenetic response, major molecular response, and molecular response4.5. Notably, compared with not only adults (cohort 3 vs. cohort 1: HR = 2.03 [1.03, 3.98], P = 0.040; cohort 4 vs. cohort 1: HR = 2.15 [1.07, 4.33], P = 0.033; cohort 5 vs. cohort 1: HR = 4.22 [1.94, 9.15], P

Background Acute megakaryoblastic leukemia (AMKL) is a biologically heterogeneous subtype of acute myeloid leukemia that originates from megakaryocytes. Patients with AMKL with non-Down syndrome (DS) had a poorer prognosis. However, clear prognostic indicators and treatment recommendations for this subgroup remain controversial. Patients and Methods Herein, we performed a retrospective study on 40 patients (age ≤ 18 years) with non-Down syndrome AMKL at our institution. We assessed the effect of different prognostic factors, such as their cytogenetic abnormalities, early treatment response, and the role of hematopoietic stem cell transplantation (HSCT) as post-remission treatment on the outcomes. Results The complete remission (CR) rate of the patients was 57.9% and 81.1%, respectively, at the end of induction therapy 1 and 2. The overall survival (OS) and event-free survival rates at 2 years were 41% ± 13% and 41% ± 10%, respectively. An analysis of the cytogenetic features showed that patients with +21 or hyperdiploid (> 50 chromosomes) had significantly better OS than those in other cytogenetic subgroups (Plog-rank = .048 and Plog-rank = .040, respectively). Besides cytogenetics, an excellent early treatment response (CR and minimal residual disease Conclusion AMKL in patients with non-Down syndrome has a poor outcome. With poor OS but CR rates comparable with other acute myeloid leukemia subtypes, allogenic HSCT may be a better option for post-remission therapy than conventional chemotherapy, especially for those having a poor response to induction therapy.

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease whose prognostic factors include minimal residual disease (MRD) and cytogenetic abnormalities. To explore the significance of MRD in ALL subtypes, we analyzed the outcomes of 1126 children treated with risk-stratified therapy based on sequential MRD monitoring. MRD distributions and treatment outcomes differed between distinct leukemia subtypes. Patients with ETV6-RUNX1 or hyperdiploidy had the best prognosis (5-year OS: 97 ± 1.5% and 89.2 ± 2.7%). However, hyperdiploidy patients with MRD ≥ 10% on day 15 had a higher risk of relapse (36.4%) than those with ETV6-RUNX1. TCF3-PBX1 patients had the fastest disease clearance (negative MRD rate on day 33: 92.1%), but the overall prognosis was intermediate (5-year OS: 82.5%). Patients with high-risk characteristics and ALL-T had inferior outcomes: even with undetectable MRD on day 33, cumulative incidence of relapse was 19.9% and 23.4%, respectively. Moreover, those with poor early-treatment response and detectable week-12 MRD had a worse prognosis. After adjusting for other risk factors, re-emergent MRD was the most significant adverse prognostic indicator overall. Sequential MRD measurement is important for MRD-guided therapy, and integration of MRD values at different timepoints based on leukemia subtype could allow for more refined risk stratification.

The presence of minimal residual disease (MRD) is a risk factor for relapse among children with acute myeloid leukemia (AML), and eliminating MRD can usually improve survival rates. To investigate the effect of expanded activated autologous lymphocytes (EAALs) combined with chemotherapy on eliminating MRD and improving survival rates of children with AML, we retrospectively analyzed the results of 115 children with low- or intermediate-risk AML with MRD treated at the Pediatric Hematological Center, Peking University People's Hospital, between January 2010 and January 2016. The patients were assigned to the chemotherapy plus EAAL (combined therapy) group (n = 61) and chemotherapy group (n = 54). The MRD-negativity rates were 95.1% (58/61) in the combined therapy group and 63.0% (34/54) in the chemotherapy group (P 0.0001) during consolidation treatment. The 5-year event-free survival rate was higher in the combined therapy group than in the chemotherapy group (86.3 ± 4.6% vs. 72.1 ± 6.1%, P = 0.025). No severe adverse event was observed after EAAL infusion. The present study showed that EAAL combined with chemotherapy could improve the MRD-negativity rate and event-free survival rate among children with AML with low level MRD-positive status.

Background The impact of extramedullary infiltration (EMI) on the clinical outcomes of pediatric patients with acute myeloid leukemia (AML) are controversial. Patients and Methods A total of 214 pediatric patients with low-risk AML were classified as having EMI (central nervous leukemia [CNSL] and/or myeloid sarcoma [MS]) and not having EMI. Patients with isolated MS before AML diagnosis by bone marrow examination were confirmed with histopathologic examination. For patients diagnosed with AML by bone marrow examination, a thorough physical examination and radiologic imaging were used to confirm MS. Results Male gender, a high white blood cell count, the FAB-M5 subtype, t(8;21) and t(1;11) abnormalities, and c-KIT mutations were associated with EMI. The presence of MS was associated with a low complete remission rate (63.6% vs. 79.4%; P = .000) and poor 3-year relapse-free survival (RFS) (62.6% ± 7.5% vs. 87.0% ± 2.8%; P = .000) and 3-year overall survival (73.5% ± 7% vs. 88.8% ± 2.6%; P = .011). Multivariate analysis revealed that MS was a poor prognostic factor for RFS and overall survival. Bone infiltration was an independent risk factor for inferior RFS with MS. Patients with CNSL had a low complete remission rate (58.3% vs. 77.2%; P = .045); however, CNSL did not significantly affect the survival of low-risk patients with AML. Conclusion MS should be considered an independent risk factor to guide stratified treatment.

Abnormally high ecotropic viral integration site 1 (EVI1) expression has been recognized as a poor prognostic factor in acute myeloid leukemia patients. However, its prognostic impact in B cell precursor acute lymphoblastic leukemia (BCP-ALL) remains unknown. A total of 176 pediatric Ph-negative BCP-ALL patients who received at least 1 course of chemotherapy and received chemotherapy only during follow-up were retrospectively tested for EVI1 transcript levels by real-time quantitative PCR at diagnosis, and survival analysis was performed. Clinical and EVI1 expression data of 129 pediatric BCP-ALL patients were downloaded from therapeutically applicable research to generate effective treatments (TARGET) database for validation. In our cohort, the median EVI1 transcript level was 0.33% (range, 0.0068���136.2%), and 0.10% was determined to be the optimal cutoff value for patient grouping by receiver operating characteristic curve analysis. Low EVI1 expression (P = 0.017 and 0.018, respectively). Multivariate analysis showed that EVI1 expression P = 0.066). In conclusion, low EVI1 expression at diagnosis could predict poor outcomes in pediatric Ph-negative BCP-ALL patients receiving chemotherapy. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1939818 .

We explored the prognostic factors for children with very high-risk (VHR) Philadelphia chromosome (Ph) negative B-cell acute lymphoblastic leukaemia (B-ALL) and compared the therapeutic effects of intensive chemotherapy and unmanipulated haploidentical haematopoietic stem cell transplantation (haplo-HSCT) as post-remission treatment in these patients undergoing first complete remission (CR1). A total of 104 paediatric patients with VHR B-ALL in CR1 were retrospectively enrolled in this study, including 42 receiving unmanipulated haplo-HSCT (Group A) and 62 receiving ongoing chemotherapy (Group B). Estimated 3-year overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) at 36·2 months median follow-up were 69·5 ± 4·7%, 63·5 ± 4·8% and 32·4 ± 4·7%, respectively. Maintenance of persistent positive or conversion from negative to positive of measurable residual disease (MRD) and chemotherapy were independent risk factors associated with inferior long-term survival and higher CIR. OS, DFS, and CIR differed significantly between the groups in patients with persistent positive or negative-to-positive MRD. Haplo-HSCT may be an option for children with VHR Ph-negative B-ALL in CR1, especially for patients with persistent positive or negative-to-positive MRD, and could achieve better survival than intensive chemotherapy as post-remission treatment.

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly haploidentical (haplo)-HSCT, in pediatric patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in the tyrosine kinase inhibitor (TKI) era is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of Ph+ ALL in the TKI era. We analyzed clinical data of Ph+ ALL patients aged 1 to 18 years who received imatinib added to intensive chemotherapy at the start of induction therapy. Among the 68 patients who completed at least 2 consolidation cycles, 44 underwent transplantation (transplant arm) and 24 received continuous TKI with chemotherapy (nontransplant arm). At the 3-year follow-up the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 23.5%, 73.4%, and 80.3%, respectively. Multivariate analysis showed that hematologic response (whether complete remission [CR] was achieved) at the induction end, BCR-ABL levels (whether major molecular response [MMR] was achieved) at 3 months, and transplantation were independent affecting factors for CIR, EFS, and OS. In the risk stratification analysis based on the first 2 prognostic factors mentioned above, no significant difference existed between the transplant and nontransplant arms for the probabilities of 3-year OS, EFS, and CIR in the standard-risk group (no poor prognostic factors). Meanwhile, OS, EFS, and CIR rates were significantly better in the transplant arm in the high-risk group (≥1 poor prognostic factor). Among the 44 patients in the transplant arm, 37 underwent haplo-HSCT. Achieving CR at the induction end, MMR at 3 months, and haplo-transplant were also independent favorable factors of CIR, EFS, and OS in the nontransplant and haplo-HSCT arms. Haplo-HSCT showed a significant survival advantage in the high-risk group only. Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph+ ALL patients at a high risk of relapse in the TKI era. Children with Ph+ ALL in first CR may benefit from allo-HSCT, particularly those at high risk. Haplo-HSCT could achieve good long-term survival for pediatric Ph+ ALL. Thus, haplo-HSCT can be an alternative approach for high-risk Ph+ ALL patients.

Introduction Residual disease (RD) detected using multiparametric flow cytometry (MFC) is an independent predictive variable of relapse in acute myeloid leukaemia (AML). However, RD thresholds and optimal assessment time points remain to be validated. Material and methods We investigated the significance of RD after induction therapy in paediatric AML with normal karyotype between June 2008 and June 2018. Bone marrow samples from 73 patients were collected at the end of the first (BMA-1) and second (BMA-2) induction courses to monitor RD using MFC. Results Presence of RD after BMA-1 and/or BMA-2 correlated with poor relapse-free (RFS) and overall survival at 0.1% RD cutoff level. Receiver operating characteristic curve showed that RD cutoff levels of 1.3% and 0.5% after BMA-1 and BMA-2, respectively, predicted events with the highest sensitivity and specificity. In multivariable analysis, RD after BMA-2 was the strongest independent risk predictor for poor RFS (hazard ratio 2.934; 95% confidence interval: 1.106-7.782; P = .031). Conclusions Our study therefore suggests that an RD level ≥0.5% after BMA-2 has a significant predictive impact on the prognosis of AML patients having normal karyotype and thus guide the stratification of treatment strategies.

PurposeWhile the role of minimal residual disease (MRD) assessment and the significance of achieving an MRD-negative status during treatment have been evaluated in previous studies, there is limited evidence on the significance of MRD re-emergence without morphological relapse in acute lymphoblastic leukemia (ALL). We sought to determine the clinical significance of MRD re-emergence in pediatric ALL patients.MethodsBetween 2005 and 2017, this study recruited 1126 consecutive patients newly diagnosed with ALL. Flow cytometry was performed to monitor MRD occurrence during treatment.ResultsOf 1030 patients with MRD-negative results, 150 (14.6%) showed MRD re-emergence while still on morphological complete remission (CR). Patients with white blood cell counts of ≥50 × 109/L (p = 0.033) and MRD levels of ≥0.1% on day 33 (p = 0.012) tended to experience MRD re-emergence. The median re-emergent MRD level was 0.12% (range, 0.01–10.00%), and the median time to MRD re-emergence was 11 months (range, p = 0.005). Of the 150 patients, 113 continued to receive chemotherapy and 37 underwent transplantation. The transplantation group demonstrated a significantly higher 2-year overall survival (88.7 ± 5.3% vs. 46.3 ± 4.8%, p < 0.001) and cumulative incidence of relapse (23.3 ± 7.4% vs. 64.0 ± 4.6%, p < 0.001) than the chemotherapy group.ConclusionsMRD re-emergence during treatment was associated with an adverse outcome in pediatric ALL patients. Transplantation could result in a significant survival advantage for these patients.

Background chimeric antigen receptor–modified T cell (CAR-T) therapy is an effective and promising treatment for refractory and multiply relapsed B-cell acute lymphoblastic leukemia (B-ALL). Because of its side effects and poor responses such as neurotoxicity and cytokine release syndrome, patients with central nervous system leukemia were excluded in most previous clinical trials of CAR-T treatment. Patients and Methods We enrolled 3 B-ALL patients with central nervous system leukemia relapse. They were infused with CD19-specific CAR-Ts, and their clinical responses were evaluated by bone marrow smear, flow cytometry, and cytogenetic alterations detected by quantitative PCR, interleukin-6, and the expansion and persistence of circulating CAR-Ts in peripheral blood and cerebrospinal fluid. Results After CAR-T infusion, 2 of the 3 patients experienced bone marrow minimal residual disease–negative complete remission, and all patients tested negative for residual leukemia cells in cerebrospinal fluid tested by flow cytometry. These 3 patients experienced grade 2 or 3 cytokine release syndrome, which resolved completely after symptomatic treatment. None experienced neurotoxicity or needed further intensive care. Conclusion CAR-T infusion is a potentially effective treatment for relapsed/refractory B-ALL patients with central nervous system involvement.

Objective: Malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) in children is a relatively rare but life-threatening secondary hemophagocytic lymphohistiocytosis (sHLH). Until now, onl...

Although chimeric antigen receptor T-cell (CAR-T) therapy produces a high complete remission rate among patients with relapsed/refractory B-cell acute lymphoblastic leukemia, relapse remains an urgent issue. It is uncertain whether consolidative haploidentical-allogeneic hematopoietic stem cell transplantation (haplo-HSCT) is suitable for achieving sustainable remission. Therefore, we aimed to assess the efficacy and safety of bridging CAR-T therapy to haplo-HSCT. Fifty-two patients with relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia who underwent haplo-HSCT after CAR-T therapy were analyzed. The median time from CAR-T therapy to haplo-HSCT was 61 days. After a median follow-up of 24.6 months, the 1-year probabilities of event-free survival, overall survival, and cumulative incidence of relapse were 80.1% (95% confidence interval (CI), 69.0-90.9), 92.3% (95% CI, 85.0-99.5), and 14.1% (95% CI, 10.7-17.4), respectively, while the corresponding 2-year probabilities were 76.0% (95% CI, 64.2-87.7), 84.3% (95% CI, 74.3-94.3), and 19.7% (95% CI, 15.3-24.0), respectively. No increased risk of 2-year cumulative incidence of graft-versus-host disease, treatment-related mortality, or infection was observed. A pre-HSCT measurable residual disease-positive status was an independent factor associated with poor overall survival (hazard radio: 4.201, 95% CI: 1.034-17.063; P = 0.045). Haplo-HSCT may be a safe and effective treatment strategy to improve event-free survival and overall survival after CAR-T therapy.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders and is rare in children. Allogeneic hematopoietic stem cell transplantation (HSCT) is commonly used in children with MDS with excess blasts and in patients with refractory cytopenia of childhood (RCC) associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. We recruited 27 children with MDS who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT). At transplantation, 10 patients had RCC, 12 patients had advanced MDS (RAEB and RAEB-T), and 5 patients had myelodysplasia-related acute myeloid leukemia (MDR-AML). All patients received granulocyte colony-stimulating factor (G-CSF)-mobilized bone marrow cells and peripheral blood stem cells. At a median follow-up of 24.1 months (range: 2.0-74.5 months) after HSCT, the estimated probabilities of 3-year disease-free survival (DFS) and overall survival (OS) were both 81.9% (95% CI, 66.8-100.0%). The estimated 3-year incidences of relapse (CIR) and non-relapse mortality (NRM) were both 7.4% (95% CI, 1.2%-21.4%). The 100-day cumulative incidence of grade II-IV aGVHD was 52.6% (95% CI, 42.9-62.3%), while that of grade III-IV aGVHD was 11.1% (95% CI, 5.1-17.1%). The 3-year cumulative incidences of overall and extensive cGVHD were 42.3% (95% CI, 19.8%-57.5%) and 21.1% (95% CI, 2.5%-63.2%), respectively. Univariate analysis showed that chronic GVHD significantly affected OS and DFS. Haploidentical HSCT may be an effective treatment option with easier donor availability for pediatric patients with MDS.

The prognosis of myeloid sarcoma (MS) is controversial. Many reports indicated that orbital-MS has a good prognosis and is closely related to t(8;21), but the prognostic role of MS in pediatric t(8;21) AML is unclear. We retrospectively analyzed data from 127 patients with pediatric t(8;21) AML diagnosed between January 2010 and June 2018. We compared patients with (

Background The role of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for children with intermediate-risk acute myeloid leukemia (IR-AML) in first complete remission has been controversial. The present study compared the effect of chemotherapy with unmanipulated haplo-HSCT as treatment of patients with IR-AML in first complete remission (CR1). Patients and Methods We retrospectively analyzed the outcomes of 80 children with IR-AML and compared the effects of chemotherapy (n = 47) with those of haplo-HSCT (n = 33) as treatment in CR1. Results The 3-year overall survival, event-free survival (EFS), and cumulative incidence of relapse (CIR) was 85.4% ± 4.1%, 73.2% ± 5.0%, and 25.4% ± 4.5%, respectively. Compared with the chemotherapy group, the patients in the haplo-HSCT group had a lower CIR (P = .059) and better EFS (P = .108), but roughly equivalent overall survival (P = .841). Multivariate analysis revealed chemotherapy and minimal residual disease (MRD) of ≥ 10−3 after induction therapy as independent risk factors affecting CIR and EFS. EFS (P = .045) and CIR (P = .045) differed significantly between the 2 treatment groups in patients with MRD of ≥ 10−3 after induction therapy. Conclusion Haplo-HSCT might be a feasible option for children with IR-AML in CR1, especially for patients with MRD of ≥ 10−3 after induction therapy.

Background Pediatric acute myeloid leukemia (AML) with t(8;21) (q22;q22) is classified as a low-risk group. However, relapse is still the main factor affecting survival. We aimed to investigate the effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on reducing recurrence and improving the survival of high-risk pediatric t(8;21) AML based on minimal residual disease (MRD)-guided treatment, and to further explore the prognostic factors to guide risk stratification treatment and identify who will benefit from allo-HSCT. Methods Overall, 129 newly diagnosed pediatric t(8;21) AML patients were included in this study. Patients were divided into high-risk and low-risk group according to RUNX1-RUNX1T1 transcript levels after 2 cycles of consolidation chemotherapy. High-risk patients were divided into HSCT group and chemotherapy group according to their treatment choices. The characteristics and outcomes of 125 patients were analyzed. Results For high-risk patients, allo-HSCT could improve 5-year relapse-free survival (RFS) rate compared to chemotherapy (87.4% vs. 61.9%; P = 0.026). Five-year overall survival (OS) rate in high-risk HSCT group had a trend for better than that in high-risk chemotherapy group (82.8% vs. 71.4%; P = 0.260). The 5-year RFS rate of patients with a c-KIT mutation in high-risk HSCT group had a trend for better than that of patients with a c-KIT mutation in high-risk chemotherapy group (82.9% vs. 75%; P = 0.400). Extramedullary infiltration (EI) at diagnosis was associated with a high cumulative incidence of relapse for high-risk patients (50% vs. 18.4%; P = 0.004); allo-HSCT can improve the RFS (P = 0.009). Conclusions allo-HSCT can improve the prognosis of high-risk pediatric t(8;21) AML based on MRD-guided treatment. Patients with a c-KIT mutation may benefit from allo-HSCT. EI is an independent prognostic factor for high-risk patients and allo-HSCT can improve the prognosis.

After reconstruction of a segmental mandibular defect with a fibular free flap, a vascular crisis can be detected clinically and a "no-flow" phenomenon found during re-exploration. Traditional methods used to solve this include removal of the failed flap and delayed mandibular reconstruction, or restoration of the defect with a functional reconstruction plate or contralateral fibular free flap. Our aim therefore was to investigate under what circumstances it is feasible to use a non-vascularised fibular bone graft (NVFB) as a free bone graft after the failure of a vascularised fibular free flap. From 1 January 2010-31 December 2014, 10 patients who had NVFB after failure of a fibular free flap were included in the study. All patients were treated at the Peking University School and Hospital of Stomatology. NVFB were preserved successfully without infection in all 10 cases, and follow-up imaging showed that it had incorporated well with the residual mandible, the basic function and facial aesthetics of which were maintained. In conclusion we have identified that by precise selection of patients, detailed preoperative planning, and meticulous postoperative care, NVFB can be used as a "rescue" technique after failure of a fibular free flap, and can successfully restore the segmental mandibular defect and facial contour.

A seven-color panel was used to detect minimal residual disease (MRD) in T cell acute lymphoblastic leukemia (T-ALL) via flow cytometry (FCM). Its availability and clinical significance were studied in T-ALL patients with newly diagnosed (n = 64), relapsed (n = 48) and morphologically complete remission (n = 103). The following four features were used to identify immature cCD3+ T cells: CD34+, TdT+, but mCD3-/dim+, and CD45dim+. Among these features, either TdT or CD34 expression was the most useful and were found in 93.8% of patients at diagnosis and 86.7% of patients who relapsed. Although some of the immature markers had disappeared in 23 of 59 cases after therapy, only one case presented with a false negative MRD. Of the 74 consecutive patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), MRD-positive patients showed a higher relapse rate, a higher cumulative incidence of relapse at 4 years and a shorter median relapse-free survival than MRD-negative patients at post-HSCT(72.7% vs 17.3%, P = 0.000; 100% vs 19.9%, P 0.0001; and 16 months vs undefined, P 0.0001). We demonstrated that this panel could be applied to97% of T-ALL patients to detect MRD and predict relapse after allo-HSCT even in the absence of the initial immunophenotype.

Background Intellectual disabilities (IDs) have become a public health concern worldwide, but few studies on rehabilitation service utilisation in this population were conducted in developing countries. We aimed to examine trends and socioeconomic disparities in the utilisation of rehabilitation services among adults with IDs in China. Methods We obtained data from a population-based survey by using a multistage, randomised, cluster sampling process to ascertain adults with IDs in 2006 and a selected subsample for follow-up surveys during 2007-2013. Psychiatrists ascertained individuals with IDs ascertained by intelligence quotient score under 70, deficits in two or more adaptive behaviours and age of onset under 18 years. Results Overall, the utilisation rate of rehabilitation services significantly increased from 10.1% in 2007 to 33.7% in 2013, with an annual average percentage growth of 34.3% when adjusting for multiple confounders. The mounting trends remained significant in all socioeconomic groups. The growth rates among lower socioeconomic participants were much higher than those among higher socioeconomic participants, and the strength in the association between socioeconomic position (education and region) and rehabilitation service utilisation declined in 2007-2013. Conclusions This study found an upward trend in rehabilitation service utilisation in Chinese adults with IDs during 2007-2013, and socioeconomic disparities in rehabilitation service use in this population showed a downward trend over time.

Objectives To examine treatment outcomes and factors associated with poor outcome of multidrug-resistant (MDR) tuberculosis (TB) in China. Methods We conducted a prospective observational cohort study including consecutive patients with MDR-TB between 2009 and 2013 in six regions of Zhejiang province. Patients were prescribed treatments by infectious disease specialists, and treatment outcomes were recorded. Sociodemographic characteristics were obtained through a structured questionnaire. The primary endpoint was poor treatment outcomes, defined as treatment failure based on microbiologic persistence, default (lost to follow-up) or death at 24 months. We assessed risk factors for poor treatment outcomes using a Cox proportional hazards model. Results A total of 820 MDR-TB patients were observed, and 537 with known treatment outcomes were included in our study. Overall, the treatment success rate was 40.2 per 100 years (374/537 participants, 69.6%), while treatment failure, death and default rates were 10.0 per 100 years (101 participants, 18.8%), 3.4 per 100 years (36 participants, 6.7%) and 2.7 per 100 years (26 participants, 4.8%) respectively. Independent predictors of poor treatment outcomes included age >60 years (hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2–4.2), patients registered as experiencing relapse (HR 2.2, 95% CI 1.1–4.4), patients registered as receiving treatment after failure (HR 2.4, 95% CI 1.2–4.9), use of standardized MDR-TB regimens (HR 0.6, 95% CI 0.4–1.0), cavitary disease (HR 4.9, 95% CI 2.8–8.6) and adverse events (HR 2.5, 95% CI 1.2–5.5). Conclusions Under well-designed treatment and management scheme, high treatment success rates were achieved in a high-MDR-TB-burden country. Antimicrobial susceptibility testing for all second-line drugs should be conducted to further assist in the treatment of MDR-TB.

To investigate the prognostic value of PRAME expression in pediatric acute lymphoblastic leukemia(ALL), we measured PRAME transcript levels at diagnosis in 191 patients(146 B-ALL; 45T-ALL)receiving chemotherapy only. PRAME overexpression was defined as transcript levels higher than 0.30%, which is the upper limit of normal bone marrow and the optimal cutoff value derived from ROC curve analysis. PRAME overexpression was identified in 45.5% of patients. In B-ALL, PRAME overexpression was significantly associated with lower CIR(cumulative incidence of relapse), higher DFS (disease-freesurvival), and OS(overall survival) rates at 3 years, respectively (5.8% vs. 14.9%, P = 0.014; 94.2% vs. 85.1%, P = 0.014; 96.0% vs. 87.4%, P = 0.039). PRAME overexpression had no impact on outcome in T-ALL patients. Among B-ALL patients with non-poor cytogenetic risk, those with PRAME overexpression showed significantly lower CIR, higher DFS and OS rates at 3 years, respectively (8.47% vs. 14.5%, P = 0.009; 96.5% vs. 85.5%, P = 0.009; 98.4% vs. 88.0%, P = 0.023). Furthermore, PRAME overexpression was an independent good prognostic factor for relapse in all B-ALL patients and B-ALL patients with non-poor cytogenetic risk. Therefore, the prognostic significance of PRAME overexpression differed by ALL subtype; It predicted good outcome in pediatric B-ALL receiving chemotherapy.

To explore new risk predictors for a high risk of relapse in Philadelphia chromosome negative (Ph-) B cell acute lymphoblastic leukaemia (B-ALL) patients, 196 paediatric Ph- B-ALL patients (≤ 18 years) were retrospectively analysed. We mainly focus on investigating the prognostic value of CD38 and CD58 expression in leukemic blasts in these patients by four colour flow cytometry. The CD38+ CD58- group (n=16) had a higher relapse rate, a shorter 3-year event-free survival (EFS) and overall survival (OS) than the CD38+ CD58+ group (n=157; 31.3% vs 10.2%, P=0.04; 52.4% vs 92.3%, P

The mandible has an important role in appearance and function. The aim of this study was to describe and evaluate surgical navigation-assisted mandibular reconstruction with the fibula flap. Patients recruited into the study had a custom dental splint fabricated to maintain the mandible in a fixed position. Later, the computed tomography (CT) scan, preoperative design, and operation on the mandible were done in the same position. At 1 week after surgery, a CT scan was done to evaluate the repeatability between the preoperative design and the postoperative result. Twenty patients were enrolled in this study. Good repeatability between the postoperative CT and the preoperative design was found. The repeatability between the preoperative plan and postoperative outcome was 79.1 ± 8.6% at within 1mm, 87.1 ± 6.7% at within 2mm, and 91.9 ± 5.4% at within 3mm. From this study, it can be concluded that surgical navigation techniques can precisely transfer the preoperative design to the operation in mandible reconstruction with a fibula flap. This will assist the surgeon in achieving good cosmetic and functional outcomes.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-HCT) is a standard treatment for relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However ~30-40% of patients (pts) still relapse after HCT. We report a cohort of 20 r/rB-ALL pts, who relapsed after HCT, and enrolled in the CAR2.0 study receiving one or two types of CAR-T cells targeting various B-ALL antigens. METHOD: Pts with r/r B-ALL who relapsed after allo-HCT and did not have significant active comorbiditeis, were enrolled in the study. The target antigens were determined based on immunostaining of each pt's leukemia cells, and CAR-T infusions included a single, or a combination of CAR-Ts targeting the following antigens: CD19, CD22, CD123 and CD38. T cells were collected from pts (N=4) or their allogeneic donors (N=16) and transduced with an apoptosis-inducible, safety-engineered lentiviral CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). Pts received cyclophosphamide/fludarabine lymphodepleting therapy before infusion of 0.2-5.8x106 CAR-T/kg per infusion. In addition to disease response, we carefully monitored the quality of apheresis cells, efficiency of gene transfer, T cell proliferation rate, CAR-T infusion dose, and the CAR-T copy number in peripheral blood. RESULTS: Among the 20 enrolled pts, 11 were 10% blasts in bone marrow, 8 pts had 1 year. None of these 20 pts received a second HCT after CAR-T infusion. GVHD developed in 5/16 (31%) pts after donor source CAR-T cell infusion within one month, but all responded well to treatment. CONCLUSION: This study focuses on CAR-T cell therapy following relapse after HCT. While the expanded study is ongoing, we present results of the first 20 pts. Use of donor-derived or recipient-derived CAR-T products in pts who relapsed after allo-HCT is well tolerated and it may prolong life expectancy of these pts while maintaining good quality of life. Table Disclosures No relevant conflicts of interest to declare.

BACKGROUND: Chimeric antigen receptor-modified T cell (CART) therapy holds great promise as a novel cancer therapy approach. Although CART cell therapy has revolutionized the treatment of B-cell non-Hodgkin lymphomas (NHLs), relapsed/refractory NHLs including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and follicular lymphoma (FL) have not responded well to the currently approved CART cell products. The existing limitations include antigen escape, toxicities of currently approved CART cells, and the high cost of manufacture of a product which is only used for a single patient (pt). The development of an innovative multi-CART therapy using a safety improved CAR design may overcome the above limitations. METHODS: Lymphoma pts who have exhausted all available treatments with progressive or stable disease and life expectancy >2 months were enrolled in the study. Lymphoma biopsies were immunostained for various target antigens including CD19, CD20, CD22, CD30, CD38, CD70 and PSMA. An advanced CART therapy regimen, CAR 2.0, has been developed, which involves a primary and a booster CAR-T cell infusions targeting multiple antigens identified on each pt's tumor. Autologous T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentiviral CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). Pts received cyclophosphamide/fludarabine chemotherapy conditioning 1-2 days before infusion of 1.21- 4.87x106 CART cells/kg per infusion. The quality of apheresis cells, efficiencies of gene transfer and T cell proliferation, CAR T infusion dose and blood CAR copies were quantitatively documented. RESULTS: Total 60 pts were evaluated at three months follow-up time, including 42 pts with DLBCL, 10 with PMBCL, 7 with FL and 1 with gastric mucosal associated lymphoid tissue lymphoma (MALT). The median age was 47 years (range, 2-77), including 31 males and 29 females. Pt characteristics include 16 pts with stage IV disease (27%), 2 after allo-transplantation (3.3%), 4 with bone marrow involvement (6.7%), 8 with CNS involvement (13%), and 7 received prior PD-1 antibody treatment (12%). The performance status of 52 of the 60 patients (87%) was Eastern Co-operative Oncology Group score 0 at time of infusion. The study included two treatment cohorts: 30 pts received single 4SCAR19 cells, and 30 pts received CAR2.0 targeting CD19 plus an additional target, depending on the individual pt's tumor antigen staining results. In the DLBCL cohort, 25 pts received single target 4SCAR19 cell infusion, at an average dose of 1.42x106 CART cells/kg, and resulted in 7 complete response (CR), 9 partial response (PR), 3 stable disease (SD) and 6 progressive disease (PD). The other 17 DLBCL pts received dual target CART infusions (CD19 plus CD20, CD22, CD38 or CD70) at an average dose of 2.32x106 CART cells/kg, and resulted in 7 CR, 8 PR ,1 SD and 1 PD. The 5 FL pts received dual target CD19+CD22 CART infusions, at an average dose of 4.64x106 CAR-T cells/kg, and resulted in 4 CR, and 1 PR. The 10 PMBCL pts, 3 received single target 4SCAR19 cell infusions, at an average dose of 2.85x106 CART cells/kg, and resulted in 1 PR and 2 PD; the other 7 PMBCL pts received dual target CART infusions (CD19+CD22, CD30, or CD20), at an average dose of 4.87x106 CART cells/kg, and resulted in 4 CR, 2 PR and 1 PD. The MALT pt received double CART cell infusions, 2.8x106 4SCAR19 cells/kg and 2x106 4SCAR-PSMA cells/kg, and achieved PR. None of these pts developed greater than grade 2 CRS response, except for 1 DLBCL pt, who achieved CR following a grade 3 CRS. The toxicity profile of the 4SCART is consistent with our previous experience with B cell acute lymphoblastic leukemia. In summary, the comparison between single versus double CART cell infusions clearly illustrates an increased response rate for the double CART cohorts, either in DLBCL pts or in all lymphoma pts, as illustrated in the summary pie graphs below. CONCLUSIONS: The results of the multi-target 4SCAR2.0 therapy for the treatment of highly resistant lymphomas have demonstrated increased safety and improved response rate with this novel approach. There is clear overall clinical benefit with the multi-target CART regimen as compared with the single CD19 CART treatment. Continued follow-up will verify whether the 4SCAR2.0 therapy regimen can achieve long term overall survival. Figure Disclosures No relevant conflicts of interest to declare.

To investigate the effect of tyrosine kinase inhibitors (TKIs) on the statural growth in children with acute lymphoblastic leukemia (ALL).We retrospectively collected data from 344 children with ALL younger than 17 years old at diagnosis identified in pediatric department of Peking University People's Hospital. The children were divided into three groups: conventional chemotherapy group, imatinib group and dasatinib group. Height was expressed as standard deviation score(HtSDS). In the three groups, we compared the HtSDS and △HtSDS at the start of treatment and during follow-up period and also compared the adult height and median parental height(MPH). We further compared the HtSDS classified by age and gender in imatinib group. At last, univariate analysis was used to analyze the influencing factors on the deceleration of height growth by imatinib.There were 298 children in conventional chemotherapy group, 39 in imatinib group and 7 in dasatinib group. In imatinib group, the mean HtSDS of children at follow-up time was significantly lower than that at the start of treatment (P0.05), regardless of age and gender. In imatinib group, the decrease of HtSDS in girls was more obvious than in boys(P = 0.031). The HtSDS gradually decreased in the first and the second year in imatinib group. After discontinuation of imatinib, the HtSDS had no obvious change. Multivariate analysis showed that the HtSDS at the start of imatinib was negatively correlated with severe growth impairment on imatinib therapy. The HtSDS in dasatinib group and conventional chemotherapy group maintained a high degree of consistency.Imatinib can affect growth velocity in children with ALL, regardless of age and gender. With the discontinuation of imatinib, the inhibitory effect will not continue. The lower HtSDS at the start of imatinib therapy, the more obvious effect of imatinib on growth impairment will be, and the effect will be more obvious in girls than boys.

B-cell acute lymphoblastic leukemia (B-ALL) with MLL-rearrangements (MLL-r) is rare in pediatric patients (aged1 year), and optimal treatment strategies remain unclear. This study aimed to retrospectively evaluate the clinical characteristics, outcomes, and effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) of 37 non-infant children with t(v;11q23)/MLL-r B-ALL. Their 4-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 69.8 %, 58.2 %, and 39.1 %, respectively, and differed significantly between patients receiving allo-HSCT (18/19 cases received haploidentical [haplo]-HSCT) at the first complete remission (HSCT at CR1, n = 19; 87.4 %, 89.5 % and 5.3 %) and those continuing consolidation therapy (Non-HSCT at CR1, n = 18; 52.2 %, 25.9 %, and 74.1 %, respectively), and the p values were 0.022,0.001 and0.001, respectively. Of the 13 patients experiencing relapse during consolidation chemotherapy, the five continuing with chemotherapy only died within 44 months, and the eight patients opting for allo-HSCT after CR2 had a 4-year OS of 57.1 %. Multivariate analysis revealed HSCT at CR1 as the only independent protective factor for OS, EFS, and CIR. The present results indicate that allo-HSCT (especially haplo-HSCT) at CR1 may decrease the relapse rate and improve the prognosis of non-infant children with t(v;11q23)/MLL-r B-ALL.

Background In childhood B-precursor acute lymphoblastic leukemia (B-ALL), the ETV6/RUNX1 fusion transcript is considered to have an excellent outcome. However, few studies of children with ETV6/RUNX1-positive ALL from China have been conducted. It is largely unknown whether clinical outcomes for patients with this genotype and important factors that influence such outcomes are similar to those reported in other countries. Therefore, it is important to analyze the outcomes of children with ETV6/RUNX1-positive ALL treated at our institution with the aim of identifying significant prognostic variables in a Chinese population. Methods We studied the clinical characteristics and treatment outcomes for 77 pediatric patients diagnosed with ETV6/RUNX1-positive ALL between 2005 and 2015 at our institution. Results The 5-year event-free survival (EFS) and the disease-free survival (DFS) were reported to be 90% ± 3% and 96% ± 3% respectively. Two patients had a relapse at a median of 42 months from diagnosis and the 5-year cumulative incidence of relapse was 2.1%. Despite intensive chemotherapy or allogeneic hematopoietic cell transplantation, the 2 relapsed patients succumbed to the disease progression and the 5-year overall survival (OS) was 97% ± 2%. Multivariate analysis for EFS revealed that the minimal residual disease (MRD) ≥10− 3 on Day + 33 negatively affected the outcome. Conclusions In conclusion, patients with ETV6/RUNX1 fusion transcript can achieve a high rate of complete remission and the long-term curative effect was excellent under risk-stratified treatment. In case of relapse, the MRD level at the end of induction therapy should be taken into consideration while deciding the appropriate chemotherapy dosage.

We assessed long-term outcomes of autologous microvascular submandibular gland (SMG) transplantation for severe dry eye disease and investigated factors influencing long-term results. From August 1999 to January 2015, 185 patients (200 eyes) with severe dry eye received SMG transplantation. Subjective assessments and ophthalmologic evaluations were performed before and after transplantation. Follow-up results showed successful transplantation in 180 of 200 eyes (success rate: 90%), resulting in marked symptomatic relief of xerophthalmia. Surgery failed due to vascular thrombosis (15 glands) and duct obstruction (5 glands). Follow-up data were available for 163 eyes. Epiphora occurred in 98 (60.1%) eyes and was effectively managed by surgical reduction of graft, topical atropine gel and botulinum toxin injection. Wharton's duct obstruction occurred in 16 (10.6%) eyes and was treated by duct reconstruction. Subjective satisfaction was achieved in 143 (87.7%) eyes. Mean score of fluorescent staining reduced from 11.25±1.42 to 7.25±3.37. Postoperative best-corrected visual acuity improved in 85 (56.3%) eyes. Our clinical experience proved that SMG transplantation is effective and grants long-term improvement in severe dry eye. Secretory function of transplanted SMGs remains active and stable. Blood vessel thrombosis, Wharton's duct obstruction, and epiphora are primary factors influencing results.

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. The trial Chinese Children Leukemia Group (CCLG)-ALL 2008 was a prospective clinical trial designed to improve treatment outcome of childhood ALL through the first nation-wide collaborative study in China. Totally 2231 patients were recruited from ten tertiary hospitals in eight cities. The patients were stratified according to clinical-biological characteristics and early treatment response. Standard risk (SR) and intermediate risk (IR) groups were treated with a modified BFM based protocol, and there was 25%-50% dose reduction during intensification phases in the SR group. Patients in high risk (HR) group received a more intensive maintenance treatment. Minimal residual disease (MRD) monitoring with treatment adjustment was performed in two hospitals (the MRD group). Complete remission (CR) was achieved in 2100 patients (94.1%). At five years, the estimate for overall survival (OS) and event-free survival (EFS) of the whole group was 85.3% and 79.9%, respectively. The cumulative incidence of relapse (CIR) was 15.3% at five years. The OS, EFS and CIR for the SR group were 91.5%, 87.9%, and 9.7%, respectively. The outcome of the MRD group is better than the non-MRD group (5y-EFS: 82.4% vs 78.3%, P = .038; 5y-CIR: 10.7% vs 18.0%, P < .001). Our results demonstrated that the large-scale multicenter trial for pediatric ALL was feasible in China. Dose reduction in the SR group could achieve high EFS. MRD-based risk stratification might improve the treatment outcome for childhood ALL.

Purpose: Classical introduction therapy of etoposide combined with cytarabine and daunorubicin (DAE) is commonly applied in childhood acute myeloid leukemia (AML), but etoposide has an increasing risk of secondary cancer. In this study the non-inferiority effect of homoharringtonine (H) versus Etoposide was compared in induction phase for Chinese childhood AML treated by CCLG-AML 2015 protocol. Patients and Methods: The total of 818 childhood AML patients (median age of 80 months; range from 1 to 193 months) from CCLG-AML 2015 study group (40 centers) were randomly allocated to two induction arms of DAE and DAH. During the course of induction I, 467 patients in DAE group received daunorubicin and cytarabine (DA) plus etoposide (D: 40 mg/m2 per day on days 1, 3 and 5; A: 100 mg/m2 every 12 hours from day 1 to 7; E: 100 mg/m2 per day from days 1 to 5), and 351 patients in DAH group received the same DA does plus homoharringtonine ( H: 3 mg/m2 per day from days 1 to 5). During the course of induction II, Idarubicin (10 mg/m2 per day on days 1, 3 and 5) was used to instead of daunorubicin, and patients accepted corresponding IAE or IAH treatment. All patients were divided into standard, intermediate or high risk group (SR, IR or HR group) according to CCLG-AML 2015 regimen (table 1). They were assessed by bone marrow (BM) aspiration and morphologically defined complete remission (CR: blasts ≤5%), partial remission (PR: blasts between 6~19%), or non-remission (NR: blasts ≥20%) on days 28 of induction. Results: DAH/IAH group showed non-inferiority for remission rates both in induction Ⅰ (DAE 70.2% vs DAH 76.6%, P = 0.041) and induction Ⅱ (IAE 79.4% vs IAH 87.7%, P = 0.016). Total CR rate at end of induction Ⅰ reached 73.0% and it didn't differ between DAE and DAH group for IR or HR group (IR group: DAE, 73.9% vs. DAH, 77.3%, P = 0.529; HR group: DAE, 53.9% vs. DAH, 62.6%, P = 0.128). But for SR group, CR rate of DAH group is significantly higher than DAE group (DAE, 85.1% vs. DAH, 95.1%, P = 0.013). It has similar results after induction Ⅱ. Total CR rate reached 83.1% and all patients has almost gained CR/PR for SR or IR group, only 2 patients still couldn't obtain remission. There was no significant difference in SR or IR group between two arms, but for HR group, CR rate significantly increased in those who accepted IAH chemotherapy (SR group: IAE, 91.2% vs. IAH, 95.0%, P = 0.398; IR group: IAE, 87.1% vs. IAH, 92.5%, P = 0.275; HR group: IAE, 66.1% vs. IAH, 78.8%, P = 0.050). Conclusion: Homoharringtonine is an effective cytotoxic drug and DAH regimen showed non-inferiority induction effect compared with classical DAE regimen in childhood AML, especially for patients of standard risk group. Disclosures No relevant conflicts of interest to declare.

Background: B-acute lymphoblastic leukemia (B-ALL) with t(v;11q23)/MLL-rearrangement (MLL-r) in children (1 year or older) is rare, and its outcome and optimal treatment options remain controversial. This study aimed to analyze the clinical characteristics and outcomes of these patients, and to explore the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially haploidentical HSCT (haplo-HSCT) in the treatment of these patients. Methods: At the time of the last follow-up (July 1, 2019), we retrospectively analyzed clinical data of 42 non-infant children with t(v;11q23)/MLL-r B-ALL. Comparison of outcomes was made between patients received allo-HSCT in the first complete remission (CR1) and chemotherapy only. Results: The median follow-up was 41 (1-106) months. The median age at diagnosis was 4.5(1-14) years and the median leukocyte count was 56.0 (2.2-735.2)×109/L. One was excluded for death during induction. For the remaining 41 patients, the complete remission rate after induction therapy was 40/41 (97.6%), the estimated 4-year probabilities of overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 59.7%, 51.6% and 43.4%, respectively. 19 patients received allo-HSCT in CR1 (HSCT in CR1 cohort), notably, 18/19 cases in this cohort received haplo-HSCT, and the remaining 22 patients continued the consolidation therapy (Non-HSCT in CR1 cohort). The estimated 4-year probabilities of OS, EFS and CIR in the HSCT in CR1 cohort were 86.6%, 89.2% and 5.3%, respectively. Meanwhile, the estimated 4-year probabilities of OS, EFS and CIR in the Non-HSCT in CR1 cohort were 37.5%, 19.9% and 75.6%, respectively. They were considered to be statistically significant. Of the 17 patients who relapsed during consolidation chemotherapy, 9 patients who underwent chemotherapy only (Non-HSCT after relapse cohort) all died within 44 months. For the remaining 8 patients who chose allo-HSCT (HSCT in CR2 cohort) when they achieved the second complete remission (CR2), the estimated 4-year probability of OS was 47.6% (P=0.002). Multivariate analysis showed that HSCT in CR1 was the only independent protective factor for OS, EFS and CIR, and age at diagnosis (≥10 years) was an independent risk factor of OS. Conclusions: Allo-HSCT (especially haplo-HSCT) in CR1 may reduce the risk of relapse and improve prognosis in non-infant children with MLL-r B-ALL. In addition, allo-HSCT also seemed to be an effective approach to improve the prognosis of relapsed patients. Thus, haplo-HSCT could be an alternative approach for non-infant children with MLL-r B-ALL. Disclosures No relevant conflicts of interest to declare.

The conventional treatment for benign tumours arising in the submandibular gland (SMG) has always involved whole gland excision with the tumour. In light of developments in parotid gland functional surgery, this prospective study was performed to evaluate the effectiveness and safety of partial sialoadenectomy (PS) for benign tumours in comparison with conventional total sialoadenectomy (TS). Thirty-one consecutive patients with a preoperative diagnosis of benign tumour in the SMG were included in the study from December 2008 to December 2010. Eleven patients were treated with PS and 20 patients underwent conventional TS. Salivary gland function and surgery-related complications were assessed. No difference in resting saliva flow was found between the two groups before the operation, while this was significantly higher in the PS group than in the TS group at 1 year after surgery (P=0.009). With regard to complications, there was less deformity in facial appearance in the PS group. There was no recurrence in any of the 31 patients during the follow-up period (range 41-82 months). It is believed that this modification to SMG surgery is consistent with the idea of functional and minimal invasive salivary gland surgery. This technique represents a good choice for the management of benign tumours of the SMG for appropriately selected cases.

BACKGROUND Acute renal failure in chronic kidney disease (A/C) constitutes an important part of acute renal failure (ARF), but until now there has been no research focusing on this entity. PATIENTS AND METHODS Clinical data were collected from all patients diagnosed as A/C by clinical materials and renal biopsy over a 12-year period (January 1990 - December 2001) in the renal department of a teaching hospital, and the incidence, etiology, pathological and clinical features of A/C, and factors predicting prognosis were studied. RESULTS Altogether, 104 patients of A/C were identified, which accounted for 35.5% of biopsied acute renal failure cases during the same period. Drug-induced acute renal interstitial/tubular-interstitial disease, prerenal ARF and flare-up of lupus nephritis were the most common causes of ARF in A/C patients. More than one third of A/C were associated with drugs, which occurred more commonly in older patients. After an average hospitalization of 28.5 days, about 39 patients required dialysis, 23 patients became dialysis-independent. The mortality was 1.9%. Furthermore, serum creatinine (Scr) returned to normal level (< 133 micromol/l) in 46.2% of all patients; Scr decreased by 15%, yet not normal in 26.0%. Multivariate logistic regression analysis indicated that hypertension, requirement of dialysis therapy and high Scr level were independent predictors of poor renal outcome. CONCLUSION A/C constitutes an important part of ARF, and drug-induced ARF is prominent in China. Because early diagnosis and correct treatment may obviously affect prognosis, enough attention should be paid to this entity.

Background: CD19 chimeric antigen receptor (CAR)-modified T cell therapy has demonstrated clinical efficacy but often associated with severe adverse effects manifested by cytokine release syndrome (CRS). To increase safety and efficacy of CAR T therapy, a 4thgeneration CAR design has been developed and investigated in a multi-center trial in China. Patients and Methods: From July 2013 to July 2016, the 4SCAR19 phase I/II multi-center trial has enrolled 125 patients (pts) with chemo-resistant, CD19-positive, acute B cell lymphoblastic leukemia (B-ALL) eligible for CAR T cell preparation and infusion. Laboratory data and clinical records were carefully evaluated and 102 pts were qualified for statistical evaluation, including 55 children and 47 adults; 27 had received allo-HSCT prior to CAR T therapy. The median age is 9 (2 to 17) and 37 (19 to 70) for pediatric and adult pts, respectively. The median leukemia blast count in the bone marrow (BM) is 14.5%, with BM blast >50% accounting for nearly one third (33 pts). Autologous/donor T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentivector CAR containing four intracellular signaling domains: CD19-scFv//CD28/CD137/CD27/CD3ζ-iCasp9 (4SCAR19). Pts received conditioning regimens of cyclophosphamide (17), cyclophosphamide/fludarabine (54), other chemotherapy (29) or none (2), followed by CAR-T cell infusion (average 1.05x106cells/kg). The quality of apheresis cells, gene transfer and T cell proliferation efficiencies, and effective CAR T infusion dose were quantitatively monitored. Statistical analysis used COX proportional hazard model involving categorical or continuous covariates, univariates, or multivariates analyses, and survival analysis was based on right-censored data and Kaplan-Meier estimation (KM curve). Results: The compiled data indicate that the quality of CAR T cells positively correlated with overall survival (OS). The median follow-up time was 7 months (range from 1~35 months). Patient (Pt) cohort 1 ( 5%) BM blasts, the CRS grade showed no significant correlation with disease burden (P = 0.45 for low burden group, and P = 0.06 for high burden group). Of note that total 73 of the 102 pts experienced 0-1 grade CRS and 8 of them had very high BM leukemia load (>80%), suggesting a very low toxicity of the 4SCAR19 T cells. In addition, of the 17 high (> 80%) BM blast pts, only 3 experienced grade 3-4 CRS. For 38 pts with BM blast ≥ 50%, most had grade 1 (30) or grade 2 (13) CRS, and only 5 pts had grade 3, and 3 pts had grade 4 CRS. For low burden pts (0-5% BM blasts), 86% (42 pts) developed low grade CRS (0 or 1), and even pts with BM blasts above 5%, 53% experienced low grade CRS (0 or 1). Further analysis of inflammatory genetic profile reveals that high CRS might correlate with high inflammatory profile, as several pts with high inflammatory gene patterns, while only had residual disease or no detectable leukemia cells (BM blasts 0-0.005%), developed grade 3-4 CRS. Conclusion: The three-year follow-up of the 4SCAR19 T cell therapy further supports that CAR T immunotherapy could benefit not only low leukemia burden pts, but also late-stage, chemo-resistant, very high-burden leukemia pts. Importantly, our study demonstrates a good safety profile of the 4SCAR19 T cells even under high disease burden. While the multicenter trial involves 22 clinical centers, the variable clinical settings do not seem to impact patient outcomes due to the highly standardized CAR T cell preparation protocol and manageable CRS in most. Disclosures No relevant conflicts of interest to declare.

Efficacy, safety and pharmacokinetics of clofarabine in Chinese pediatric patients with refractory or relapsed acute lymphoblastic leukemia: a phase II, multi-center study

Background: Relapsed/refractory leukaemia is associated with poor prognosis. T cells genetically modified to express CD19-specific chimeric antigen receptor (CD19CAR) in patients (pts) with chronic lymphoblastic leukemia (CLL) and acute lymphoblastic leukemia (ALL) have shown a remarkable ant-cancer activity. However, many questions remain related to the predictive indicators of long-term response and the management of cytokine release syndrome (CRS) after CAR-T cell infusion. In this phase II multi-center clinical trial, we evaluated the safety and efficacy of a fourth generation, safety-improved CD19-CAR (4SCAR19) in B-ALL pts. Patients and Methods: Fifty evaluable B-ALL patients (pts), with demonstrated persistent disease following salvage chemotherapy from 14 hospitals in China between July 2013 and June 2015 have been enrolled. The mean age is 14 (from 3 to 65) including 26 children and 24 adults. Leukemic genotypes include 16 Bcr-Abl (13 pT315I), 11 WT-1, 3 MLL-AF4, 3 E2A-PBX-1, 1 TEL/AML1, 1 IKZF1, 1 K-ras and the remaining 14 pts have undetectable genotype. Their disease characteristics include: 4 hypercritical acute leukemia, 10 extramedullary leukemia (7 CNSL, 3 multiple sites), with associated co-morbidity: 12 Aspergillus pneumonia, 4 cGVHD, 2 pleura/pericardial cavity effusion, 2 hepatitis B, 2 diabetes mellitus, 1 gastrointestinal hemorrhage, and 1 liver/spleen abscess. Twenty-one (42%) pts received allo-HSCT including 15 haplo-identical, 5 matched related donor (MRD) and 1 unrelated cord blood (URD-CB). These pts who relapsed after transplantation have received chemotherapy (chemo), combined with Tyrosine Kinase Inhibitors (TKIs, 10), donor leukocyte infusion (DLI, 19), or dendritic cells-cytokine induced killer cell (DC-CIK)/NK cell infusions (7). CAR-T cells were prepared from autologous (37), transplant donor (12) or non-transplant donor mother (1). T cells. Peripheral lymphocytes were collected from leukapheresis, and T cells were transduced with a 4th generation, safety-engineered, CD19scFv/CD28/CD137/CD27/CD3ζ-iCasp9 (4SCAR-19) lentivector. Pre-CAR-T lymphodepleting chemotherapy includes individualized chemo in 17 pts, and the others received Fludarabine (Flu) + Cyclophosphamide (Cy)(FC), or either Flu or Cy regimen: (1) FC: Cy 250mg/m2/d x3d and Flu 30mg/m2/d x3d ,or (2) either Flu x3 days, or (3) Cy x3 days, followed by CAR-T infusions at a dose of 2.13 (range from 0.42 - 5.9) x106 CAR-T cells per kg body weight per infusion. Results: For statistical analysis, 50 patients were divided into 2 cohorts: Cohort 1: B-ALL with morphological blast Toxicities: CRS occurred in most pts within the first 10 days of CAR-T cell infusion. 47/50 (94%) pts developed fever with elevated IL-2, IL-6, IL-10, and interferon gamma. Eight (16%) pts required either 12.5 mg Etanercept or 8 mg/kg tocilizumab, and three pts were treated with both drugs. Four pts developed hypotension and fully recovered after receiving dopamine. Four pts were treated once by methylprednisolone (1 mg/kg/day). The median follow-up was 4 months (range from 3~24 month), with 16 pts followed up for more than 6 months. Clinical outcomes: 1. LFS: The 120 days LFS for pts in cohort 1 and cohort 2 were 86% (CI,80%~93%) and 44.4% (CI, 31%~58%, P=0.0030), respectively. 2. OS (10 month) probabilities for patients in cohort 1 and cohort 2 were 82% (73%~91%) and 36% (19%~52%) (P= 0.0029), respectively. Conclusion: Our results indicate the potential of rapid leukemia eradication kinetics of 4SCAR19 therapy in treating chemo-resistant B-ALL. This therapy dramatically improves the prognosis of B-ALL pts by either providing a bridging approach to allo-HSCT or a better remission induction with longer period of CR than the routine treatment. Moreover, pts with morphological blasts Disclosures Dong: America Yuva Biotech: Consultancy, Other: clinical consultation.

Introduction CBF-acute myeloid leukemia (AML) is a heterogeneous disease that requires prognostic factors for patient differentiation. c-KIT mutations are predominantly detected in CBF-AML among AML cases, and reported frequencies vary significantly. To date, the clinical significance of c-KIT mutations in CBF-AML has been intensively studied; however, the results are controversial and a final conclusion has not been reached. Large-scale studies with subgroup analysis should be performed to elucidate the clinical effects of c-KIT mutations in CBF-AML. Methods A total of 351 patients with CBF-AML [t(8;21) (n = 253) or inv(16) (n = 98)] were included in this study. Overall, 250 patients [42 pediatric t(8;21);146 adult t(8;21); 11 pediatric inv (16) and 51 adult inv (16)] received standard treatment and underwent follow up. Induction therapy consisted of one or two cycles of combined anthracycline and cytarabine for adult patients, whereas cytarabine, idarubicin, and etoposide were used for pediatric patients. 131, 17, and 93 of the patients further received intermediate-dose cytarabine-based chemotherapy, chemotherapy with auto-hematopoietic stem cell transplantation (HSCT), and chemotherapy with allogeneic (allo)-HSCT for consolidation, respectively. c-KIT mutations in exon 8 and 17 were screened by direct sequencing. Patients who received allo-HSCT were censored at the time of transplantation for relapse and survival analysis to exclude the effects of allo-HSCT on outcome. The median follow up time was 10 months (3 to 93 months) for the 211 living patients. Results Overall, 36.5% (128/351) of the patients were found to have a c-KIT mutation. The frequencies of c-KIT mutations were similar between pediatric and adult patients with t(8;21) AML (41.7% vs. 38.5%, P > 0.05), whereas pediatric patients tended to have higher frequency of c-KIT mutations than the adult patients with inv(16) AML (53.8% vs 25.9%, P = 0.053). In adults, the frequency of c-KIT mutations was significantly higher in patients with t (8;21) than those with inv(16) (P = 0.043). In adults, the frequency of mutations in exon 17 was significantly higher in t(8;21) than inv(16) AML (P < 0.0001). In pediatric group, the frequencies of mutations in exon 17 and exon 8 were similar for t(8;21) and inv(16) AML (P > 0.05). The low PLT count (¡Ü 30∙109/L) in pediatric t(8;21) AML tended to be associated with the presence of c-KIT mutations ( P = 0.063). High white blood cell (WBC) count (>10∙109/L), WBC index, and AML1-ETO transcript levels in adult t(8;21) AML patients were significantly correlated with the presence of c-KIT mutations (P = 0.015, 0.0051, and 0.030, respectively). Moreover, low CBF¦Â-MYH11 transcript levels in adult inv(16) AML tended to be significantly related to c-KIT mutations (P = 0.059). No difference was observed in CR rates between patients with and without c-KIT mutations (P > 0.05). c-KIT mutations were significantly associated with less reduction in fusion transcript levels after the first induction therapy in adult inv(16) patients (P = 0.021). c-KIT mutations in adult t(8;21) AML patients (n = 137) significantly correlated with higher CIR rates at 2 years and low 2-year DFS and OS rates (73.2% vs. 46.2%, P = 0.0070; 26.8% vs. 49.1%, P = 0.013; 48.9% vs. 65.7%, P = 0.0055, respectively. Figure 1). In contrast, c-KIT mutations had no impact on CIR, DFS, and OS rates in pediatric t(8; 21)(n = 42), as well as in adult inv (16) (n = 51; all P > 0.05. Figure 1). Multivariate analysis demonstrated that c-KIT mutation was the only independent prognostic factor for relapse (hazard ratio (HR) = 2.47, 95% CI = 1.25 to 4.86, P = 0.009) and DFS (HR = 2.23, 95% CI = 1.17 to 4.41, P = 0.016). Moreover, c-KIT mutation and PLT count were independent prognostic factors for OS (HR = 3.68, 95% CI = 1.57 to 8.63, P = 0.003; HR = 0.37, 95% CI = 0.16 to 0.87, P = 0.023). Conclusion CBF-AML is a heterogeneous disease with regard to c-KIT mutations. c-KIT mutations have a strong adverse impact on relapse and survival in adult t(8;21) AML. Grant support Nature Science Foundation of China (81170483 and 81370639) and Beijing Municipal Science & Technology Commission£¨Z141100000214011). Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.