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  • 1
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4030-4030
    Abstract: Background and Objectives: Chimeric antigen receptor modified T (CAR-T) cell therapy has emerged as a promising strategy for the treatment of relapsed and refractory hematological malignancies recently. CD19 chimeric antigen receptor T (CD19CAR-T) cell therapy is a representative case showing promising results in treating relapsed and refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, challenges remain due to the concurrent severe side-effects such as cytokine release syndrome (CRS) or neurological toxicities which may cause death if they are not properly managed. So, how to safely use the CAR-T cell therapy in patients has drawn a lot of concern and attention worldwide. The objective of this study was to investigate the cytokine patterns to early identify and monitor the severe side-effects of cytokine release syndrome (CRS) and neurotoxicity caused by the therapy so that the therapy can be safely administered. Patients and Method: From December 2015 to March 2017, five patients with r/r B-ALL treated with CD19CAR-T cells were enrolled in this study. The Th1/Th2 cytokines including Interleukin (IL)-2, IL-4, IL6, IL-10, Tumor necrosis factor (TNF) and Interferon-gamma (IFN-γ ) in the serum and cerebral spinal fluid (CSF) were quickly measured by cytometric bead array (CBA) technology which allowed the result being available within 5 hours after the samples taken. The test were repeated more than once a day during the therapy. Results: 5 pediatric patients (2 boys and 3 girls) with r/r B-ALL aged 4 months -12 years old were treated by CD19CAR-T cell therapy. Four patients achieved complete remission (80% of CR rate) with minimal residual diseases (MRD) negative detected by flow cytometry within 2 weeks. One patient did not respond to the therapy due to the poor quality of his T cells. Five to 10 times of cytokine measurements were carried out for the five patients. Two types of cytokine patterns were identified: (1) very high levels of IL-6, IFN-γ with moderately elevated IL-10 indicated the CAR-T therapy effective pattern; (2) IL-6 slightly - severely elevated IL-6 level without concurrent elevation of IFN-γ represented a CAR-T cell therapy ineffective pattern but rather indicating a current infection. All the four responding patients presented the CAR-T therapy effective cytokine pattern, while the non-responding patient presented the CAR-T therapy ineffective cytokine pattern. We also analyzed the relationship between the cytokine levels and the severity of the side-effects and found that they were highly correlated. The cytokine levels in the CSF of two patients with seizure were also measured and we found that the elevation of the cytokine pattern in the CSF was paralleled to those in their serum but CNS-leukemia and CAR-T cells in their CSFs were not detected, indicating that the neurotoxicity concurrently presented in these two patients might be caused by the cytokines in the serum leaked into the CSF through the blood brain barrier. Extremely high level of cytokines occurred at 12 hours after CAR-T cell infusion in a patient was identified immediately and treated timely in onn-ICU setting to avoid the fatal consequence. Acute toxicities including fever, hypotension and other neurological toxicities occurred in responding patients within 2 weeks post infusion and managed properly with tocilizumab and/or steroids according to the "real-time" monitoring of this simple 6-Th1/Th2 cytokine patterns at the non-ICU setting. In conclusion, our study demonstrates that CD19CAR-T cell therapy can be administered safely for patients with relapsed and refractory leukemia under the "real-time" monitoring of a simple 6-cytokine pattern. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
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  • 2
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2014
    In:  The Indian Journal of Pediatrics Vol. 81, No. 9 ( 2014-9), p. 871-875
    In: The Indian Journal of Pediatrics, Springer Science and Business Media LLC, Vol. 81, No. 9 ( 2014-9), p. 871-875
    Type of Medium: Online Resource
    ISSN: 0019-5456 , 0973-7693
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2065273-2
    detail.hit.zdb_id: 218231-2
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  • 3
    In: Heliyon, Elsevier BV, Vol. 10, No. 12 ( 2024-06), p. e32816-
    Type of Medium: Online Resource
    ISSN: 2405-8440
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2024
    detail.hit.zdb_id: 2835763-2
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  • 4
    In: BMC Pediatrics, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2023-02-04)
    Abstract: The 5-year survival rate of children with acute lymphoblastic leukemia (ALL) is 85–90%, with a 10–15% rate of treatment failure. Next-generation sequencing (NGS) identified recurrent mutated genes in ALL that might alter the diagnosis, classification, prognostic stratification, treatment, and response to ALL. Few studies on gene mutations in Chinese pediatric ALL have been identified. Thus, an in-depth understanding of the biological characteristics of these patients is essential. The present study aimed to characterize the spectrum and clinical features of recurrent driver gene mutations in a single-center cohort of Chinese pediatric ALL. Methods We enrolled 219 patients with pediatric ALL in our single center. Targeted sequencing based on NGS was used to detect gene mutations in patients. The correlation was analyzed between gene mutation and clinical features, including patient characteristics, cytogenetics, genetic subtypes, risk stratification and treatment outcomes using χ 2 -square test or Fisher’s exact test for categorical variables. Results A total of 381 gene mutations were identified in 66 different genes in 152/219 patients. PIK3R1 mutation was more common in infants ( P  = 0.021). KRAS and FLT3 mutations were both more enriched in patients with hyperdiploidy (both P   〈  0.001). NRAS , PTPN11 , FLT3 , and KMT2D mutations were more common in patients who did not carry the fusion genes (all P   〈  0.050). PTEN mutation was significantly associated with high-risk ALL patients ( P  = 0.011), while NOTCH1 mutation was common in middle-risk ALL patients ( P  = 0.039). Patients with ETV6 or PHF6 mutations were less sensitive to steroid treatment ( P  = 0.033, P  = 0.048, respectively). Conclusion This study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.
    Type of Medium: Online Resource
    ISSN: 1471-2431
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 5
    In: Journal of Pediatric Hematology/Oncology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 6 ( 2019-08), p. e346-e354
    Abstract: The minimal residual disease (MRD) has been shown to be very important to evaluate the prognostic significance in childhood acute lymphoblastic leukemia (ALL), but the impact under the current treatment protocol in China has not been fully elucidated. The aim of this study was to investigate the efficacy of MRD-guided risk restratification of ALL. A total of 676 children with ALL were enrolled. In the predictive study group, 476 patients were enrolled with 5-year cumulative incidence of relapse rates of the low-risk (LR), intermediate-risk (IR), and high-risk groups being 11.0%±2.3%, 12.6%±3.3%, and 32.7%±4.9%, respectively. In the intervention study group, 19/200 patients enrolled were reclassified into risk groups according to the MRD levels. The 3-year event-free survival and overall survival were 85.2%±2.9% and 90.6%±2.1%, respectively, which were higher than those of the predictive study group (79.1%±1.9% and 84.7%±1.7%, respectively; P 〈 0.05). The 3-year cumulative incidence of relapse in the LR and IR groups of the intervention study group were 4.2%±3.1% and 6.4%±3.1%, respectively, which were significantly lower than those in the predictive study group (7.2%±1.8% and 11.8%±3.2%, respectively; P 〈 0.05). We conclude that the risk of relapse in the LR and IR groups can be significantly reduced after MRD-guided risk restratification.
    Type of Medium: Online Resource
    ISSN: 1077-4114
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 6
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4079-4079
    Abstract: Introduction and objectives Hemophogocytic syndrome (HPS) is an infrequent disease in children with a high mortality rate. Currently, the diagnosis of HPS largely depends on non-specific clinical manifestations, but the clinical features allowing to meet the criteria of diagnosis of HPS usually do not appear simultaneously which make the early diagnosis very difficult. According to the literature, hypercytokinemia has been noticed for this disease. However, the pattern of hypercytokinemia in HPS has not been proposed. In this study, the quick determination of Th1/Th2 cytokines in the sera from patients with HPS was performed and the patterns of the cytokines were analyzed to seek for the possibility of using the cytokine pattern for the early diagnosis of HPS and its prognostic significance. Patients and Methods A total of 16 children with HPS based on the 2004 HPS criteria from June 2005 ∼ December 2006 were enrolled into this study. Peripheral blood samples were collected at the time of diagnosis, during the induction therapy and at the time of relapse. Sera from 21 healthy children, 17 ALL at remission and 17 with sepsis were used as controls. A cytometric bead assay (CBA) was used to quantitatively determine the Th1/Th2 cytokines including IL-2, IL-4, IL-6, IL-10, TNFα and IFNγ. Results Levels of IL-6 (22.20 (10.60–139.25) pg/ml), IL-10 (195.60(63.85–918.70)pg/ml) and IFNγ (4740.20(1054.72– 〉 5000.00)pg/ml) from patients with HPS were significantly higher than those of normal control (3.35 (2.50–5.40) pg/ml, P 〈 0.05; 2.90(2.20–4.80)pg/ml, P 〈 0.01; 52.80(37.50–66.60)pg/ml, P 〈 0.01). Although the IFNγ levels in septic patients were also elevated, the levels (4740.20(1054.72- 〉 5000.00)pg/ml) of IFNγ in HPS patients were much higher than those (52.80(37.50∼66.60)pg/ml, P 〈 0.01) in septic patients. Another important finding was that the levels of IL-6 in HPS (22.20(10.60∼139.25)pg/ml) were significantly less elevated than those in septic patients (526.55(194.80∼979.00)pg/ml, P 〈 0.01). After effective therapy with HLH2004 protocol, the IL-6 (3.30(2.30∼6.80)pg/ml, IL-10(6.60(3.10∼23.20)pg/ml and IFNγ (65.45(27.30∼144.10)pg/ml) levels from patients with HPS sensitive to chemotherapy were significantly decreased as compared to those (22.20(10.60∼139.25)pg/ml, P=0.005; 195.60(63.85∼918.70)pg/ml, P=0.004; 4740.20(1054.72∼ 〉 5000.00)pg/ml, P=0.002) of prior to treatment. While those in patients insensitive to chemotherapy were not significantly reduced (P 〉 0.05). No significant differences in the IL-2, IL-4 and TNFα levels among patients at acute phase, remission stage and the healthy controls were observed. Univariate analysis showed that the initial IL-10 level 〉 100pg/ml and IFNγ concentration 〉 4000pg/ml were both unfavorable prognostic factors for HPS (IFNγ, P =0.034; IL-10, P=0.034). Positive correlations between the levels of IFNγ and IL-10(r=0.893, P 〈 0.001), IFNγ and IL-6(r=0.791, P 〈 0.001), IL-10 and IL-6(r=0.676, P 〈 0.001) were found. All of the three parameters stayed at a high level in acute phase and returned to normal when achieving remission. Conclusion s The quick determination of Th1/Th2 cytokines is a useful approach for the early and quick diagnosis in HPS patients based on the pattern of significant elevations of IFNγ and IL-10 with slight elevation of IL-6 and it can be used for the monitoring of the progress and the prognosis of the disease.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 7
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-11-17)
    Abstract: While the prognostic role of immunoglobulin heavy chain locus (IGH) rearrangement in minimal residual disease (MRD) in pediatric B-acute lymphoblastic leukemia (B-ALL) has been reported, the contribution of light chain loci (IGK/IGL) remains elusive. This study is to evaluate the prognosis of IGH and IGK/IGL rearrangement-based MRD detected by next-generation sequencing in B-ALL at the end of induction (EOI) and end of consolidation (EOC). IGK/IGL rearrangements identify 5.5% of patients without trackable IGH clones. Concordance rates for IGH and IGK/IGL are 79.9% (cutoff 0.01%) at EOI and 81.0% (cutoff 0.0001%) at EOC, respectively. Patients with NGS-MRD  〈  0.01% at EOI or 〈 0.0001% at EOC present excellent outcome, with 3-year event-free survival rates higher than 95%. IGH-MRD is prognostic at EOI/EOC, while IGK-MRD at EOI/EOC and IGL-MRD at EOI are not. At EOI, NGS identifies 26.2% of higher risk patients whose MRD  〈  0.01% by flow cytometry. However, analyzing IGK/IGL along with IGH fails to identify additional higher risk patients both at EOI and at EOC. In conclusion, IGH is crucial for MRD monitoring while IGK and IGL have relatively limited value.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 8
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4560-4560
    Abstract: Owing to the intensification of chemotherapy, the complete remission (CR), overall survival (OS), disease free survival (DFS) and event free survival (EFS) rates in childhood AML have been significantly improved during the past two decades in western countries. However, reports on the long-term outcome of this disease in Chinese children remain to be very limited. Objectives The aims of this study were to investigate the outcome and prognostic factors in Chinese childhood AML treated in our hospital during the past 7 years and to provide the basis for further improvement of outcome in children with AML. Methods From April 1998 to August 2005, 96 children (51 boys and 45 girls, aged 1.5 ~ 16.1 yrs with a median age of 9) with de novo AML diagnosed in our hospital based on MICM criteria were enrolled into this study. In total, 57 patients with non-APL AML were treated with the induction therapy of daunorubicin (maximum total cumulative dose 360 mg/M2) + Ara-C (DA) or homoharringtonine + Ara-C (HA), post-remission therapy with high-dose (1~2 g/M2 q12h for 6 doses) Ara-C containing regimens for three-month courses, and low-dose therapy with daunorubicin, homoharringtonine, etoposide (maximum total cumulative dose 1800 mg/M2) and Ara-C for three-month courses, followed by maintenance therapy for a total of 2~2.5 yrs. The 39 patients with APL were treated with all-trans retinoic acid (ATRA) and drugs above. Results Out of 96 patients, 86 children (89.6%) achieved CR. The estimated OS rates at three, five and seven years were (67.2±5.5)%, (58.1±6.4)% and (49.6±8.0)%, respectively, while the EFS rates were (52.3±5.8)%, (47.6±6.2)% and (47.6±6.2)%, and the DFS rates were (55.9±6.0)%, (50.7±6.4)% and (50.7±6.4)%, respectively. Univariant analysis showed that the variables predicted higher CR rates included the WBC counts (93.2% for patients & lt; 100 × 109/L vs 50.0% for those ≥ 100 × 109/L, P = 0.004) at diagnosis, and the blasts (100% for patients without blasts vs 85.2% for those with blasts, P = 0.023) in the peripheral blood. The variables predicted longer survival duration included WBC counts ((49.1±6.5)% of 5yr EFS for patients & lt; 100 × 109/L vs (33.3±18.0)% for those ≥ 100 × 109/L, P = 0.022) at diagnosis, FAB subtypes ((55.9±9.7)% for M3 vs (40.4±7.7)% for non-M3, P =0.048), course numbers [(76.0±12.2)% of 5-yr ESF for 1 course vs (31.1±9.0)% for more than 2 courses, P = 0.026) for achieving CR, CD38+ ((57.9± 7.3)% for CD38+ vs (16.7%± 10.8)% for CD38−, P = 0.005), CD14− ((49.9± 7.3)% for CD14− vs (21.5%± 14.2)% for CD14+, P = 0.001), CD34− ((54.7± 9.7)% for CD34− vs (32.6%± 8.8)% for CD34+, P = 0.038) and HLA-DR- ((57.7± 17.7)% for HLA-DR- vs (39.9%± 7.4)% for HLA-DR+, P = 0.024). 17 patients lost follow-up. The total cumulative relapse rate was 31.6% (25/79) with all BM relapse. The total treatment related modality rate was 5.3%. No secondary malignancy case was identified. Conclusions DA-based induction and high dose Ara-C-based post-remission treatment are effective to improve the CR rate and long-term survival in Chinese children with AML. The results are comparable to those reported in western countries. Initial WBC counts, early response to chemotherapy, FAB subtypes and some immunological markers are proved to be the significant prognostic factors for childhood AML under our current protocol.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4567-4567
    Abstract: Acute promyelocytic leukemia (APL) is a specific type of hematopoietic malignancy, accounting for ~ 10% of the de novo acute myeloid leukemia (AML). During the old days, severe complications as disseminated intravascular coagulation (DIC) and intracranial hemorrhage were the most common causes of treatment failure after conventional chemotherapy without all-trans retinoic acid (RA). Owing to the application of RA for the induction treatment, the overall survival (OS), the disease free survival (DFS) and the event free survival (EFS) rates have been dramatically improved in adult patients with APL. However, data on long-term outcome of APL in children, especially in Chinese children, have been very limited. Objective The aim of this study was to investigate the clinical biological features, diagnosis, prognosis and long-term survival in childhood APL. Methods 46 children (26 boys and 20 girls, aged 1.5 ~13.8 yrs with a median of 9.3 yrs) with APL from April 1998 to October 2005 were enrolled into this study. Immunophenotyping analysis was carried out in 43 patients using multi-parameter flow cytometry. 32 patients went through PML/RARα fusion gene detection using RT-PCR. Induction treatment consisted of ATRA and daunorubicin(DNR) or pirarubicin (THP) followed by 6 courses of multi-drug chemotherapy consolidation and a long-term maintenance therapy including ATRA, high dose Ara-C (HD-Ara-C), DNR+Ara-C (DA), homoharringtonine+Ara-C (HA) and etoposide+Ara-C (EA). Results Pale, hemorrhage and fever were the most common symptoms in APL patients at the time of presentation. 19 patients (41.3%) were found to have WBC count more than 10.0×109/L at diagnosis. Immunophenotyping analysis showed that CD13, CD33, CD117 and MPO were the most commonly expressed antigens while HLA-DR, CD14 and CD34 were mostly the negative markers on APL cells. 71.9%(23/32) of the patients analyzed were PML/RARα fusion gene positive. Of the 39 patients receiving treatment, 36 children (92.3%) achieved complete remission. 7 children replased during therapy, and 3 relapsed after finishing the entire courses. The 5-year cumulative incidence of relapse (CIR) was 28.6%. The estimated overall survival (OS) rates at one, three and five years were 86.1%, 76.1%and 70.2%, respectively while the event free survival (EFS) rates were 78.4%, 63.6%and 53.1%, respectively. The probability of remaining alive after 5 years for patients with WBC≤10.0×109/L group was 81.4%, significantly higher than those with WBC & gt;10.0×109/L group (51.6%, P=0.026). 5 children with positive PML/RARα S (short) subtype died eventually although all of them achieved CR, which was significantly different from the group with the L (long) subtype (13/13, P=0.001). Conclusion Induction with ATRA + DNR or THP is an effective and safe therapy for newly diagnosed childhood APL with very high long-term survival rates after 2.5 years of alternative multi-drug chemotherapy and maintenance. High WBC count and S subtype of PML-RARα are the two poor prognostic factors for children with APL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Frontiers in Genetics, Frontiers Media SA, Vol. 13 ( 2022-3-28)
    Abstract: Acute lymphoblastic leukemia (ALL) is a malignancy associated with altered lymphoid precursor hyperplasia and accompanied with different genetic mutations. Few studies have been reported on the association between gene mutations and clinical features of IKZF1 mutation in children with B-cell ALL (B-ALL). We investigated clinical and genetic characteristics in 200 newly diagnosed pediatric B-ALL through multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) method. We found that IKZF1 mutations, including large segment deletions, small insertions or deletions (InDels) and single nucleotide variations (SNVs), were detected in 22 patients with a positive mutation rate of 11.0%. IKZF1 mutation was significantly associated with higher WBC count (19.38 × 10 9 /L vs. 5.80 × 10 9 /L, p = 0.002). Compared with IKZF1 wild-type cases, a higher frequency of IL7R gene mutation was discovered in IKZF1 mutant cases (9.1% vs. 0.0%, p = 0.012). Patients with IKZF1 mutation were less sensitive to glucocorticoid induction than patients without IKZF1 mutation (63.6% vs. 9.0%, p & lt; 0.001). On the 15th day of induction, minimal residual disease (MRD) & gt; 10 −3 level were higher in IKZF1 mutant patients than wild-type patients (45.5% vs. 22.3%, p = 0.018). In conclusion, our study reveals the association between genetic mutations and clinical features in Chinese children with B-ALL, which might contribute to molecular classification, risk stratification and prognosis evaluation, and provide new ideas for targeted therapy in ALL.
    Type of Medium: Online Resource
    ISSN: 1664-8021
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606823-0
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