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  • 1
    Online Resource
    Online Resource
    Termedia Sp. z.o.o. ; 2023
    In:  Archives of Medical Science Vol. 19, No. 2 ( 2023-3-1), p. 556-556
    In: Archives of Medical Science, Termedia Sp. z.o.o., Vol. 19, No. 2 ( 2023-3-1), p. 556-556
    Type of Medium: Online Resource
    ISSN: 1734-1922 , 1896-9151
    Language: Unknown
    Publisher: Termedia Sp. z.o.o.
    Publication Date: 2023
    detail.hit.zdb_id: 2203781-0
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  • 2
    Online Resource
    Online Resource
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 13-13
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 13-13
    Abstract: Background Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in treating a variety of blood cancers, such as CD19 CAR-T for B-cell malignancies and BCMA CAR-T for myeloid myeloma (MM). However, similar progress has yet to be achieved with relapsed and refractory acute myeloid leukemia (R/R AML), primarily due to the heterogeneous nature of AML, making it difficult to find an ideal CAR-T target. Previous efforts have targeted single CD33, CD123, LeY, NKG2D, or CD70 receptors, but the overall response rate is much lower compared to CD19 CAR-T. Improved clinical outcome was recently reported with a dual-receptor CAR-T (CD33 and CLL1), reaching ~80% CR for R/R AML patients. However, CD33 is also expressed in normal hematopoietic stem cells (HSC) and patients need allogeneic hematopoietic stem cell transplantation (HSCT) following CAR-T therapy. Notably, AML mainly affects the elder population, and patients more than 65 years old are usually not suitable for HSCT. To address these challenges, we aim to find an effective target for AML without the need for the HSCT. In our study, CLL1 is chosen as a promising target as it is not expressed on normal HSCs, but highly expressed on AML blasts cells and leukemia stem cells (LSCs), which is a small population that plays an important role in disease progression and relapse. Here we report the results from a Phase I clinical trial to evaluate the toxicity and efficacy of the CLL1 CAR-T in the treatment of pediatric R/R AML. Methods We have generated a 2nd generation of CLL1 CAR-T, the extracellular scFv was derived from a murine CLL1 monoclonal antibody, which was generated by hybridoma technology. Autologous CAR-T cells were manufactured in a cGMP facility. Between Oct 2019 and Mar 2020, 3 pediatric R/R AML patients were infused. CAR-T cells were given by a dose at 0.2-1x106/kg with a single dose. Results Of the 3 patients infused, cytokine release syndrome (CRS) occurred in 3 patients (2 grade Ⅰ, 1grade II), no neurotoxicity occurred. All patients suffered pancytopenia, granulocytopenia and monocytopenia. All the adverse effects were resolved after treatment. Patient 1 is a refractory AML patient with more than 95% of AML blasts being CLL1 positive. The infused CAR-T cells showed typical clonal expansion peaking at Day 8. The patient reached CR/MRD- when evaluated at Day 21 post infusion. The patient received HSCT at Day 35, and remained CR/MRD- till now (Jul 2020, 8 months post CAR-T infusion). Patient 2 is a relapsed patient after HSCT and showed severe bone marrow necrosis (BMN). Therefore, we only generated a dose 0.35-1x106/kg CAR-T cells. The patient reached CR/MRD- when evaluated at Day 14 post infusion. The patient went through a second HSCT at Day 38. However, the patient passed away due to GVHD two months after the second HSCT. Patient 3 is a refractory AML patient with about 85% of AML blasts being CLL1 positive. The patient reached CR/MRD+ (1%) when evaluated at Day 14 post infusion. However, AML blast increased to 11% when evaluated at Day 30, a majority of them were CLL1 negative. The patient received Azacitidine treatment at Day 30-34, and AML blast decreased to 2.8% at Day 45. Notably this patient was refractory to Azacitidine treatment previously, suggesting that CLL1 CAR-T could eradicate LSCs, making the left AML tumor cells sensitive to chemotherapy. This patient received HSCT at Day 75, and remained CR/MRD- till now (Jul 2020, 7 months post CAR-T infusion). Conclusion Our study suggested that CLL1 CAR-T is a therapy with high efficacy and manageable toxicity in R/R AML patients. All patients in this study could reach CR within one month and only experienced 1-2 grade CRS. For patients with CLL1 negative AML blast, the CLL1- cells may take over after CLL1 CAR-T therapy. Combination with chemotherapy like Azacitidine may help patients reach complete response. Figure Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 3
    In: Revista de Chimie, Revista de Chimie SRL, Vol. 71, No. 8 ( 2020-8-31), p. 344-352
    Abstract: Acute myeloid leukemia (AML) is a malignant hematological disease caused by the abnormal hematopoietic system. Its specific pathogenesis is still unclear. Therefore, we have carried out a series of related studies. Firstly, co-expression analysis of acute myeloid leukemia related genes in the Human Mendelian Genetic Database (OMIM) was carried out, and a co-expression module was constructed. Further enrichment analysis of module-related genes with Go and KEGG was carried out. Subsequently, the modules are analyzed by Crosstalk to show their interaction. Also, pivot prediction is used to identify critical factors in the regulatory module and potential target drugs. Results A total of 14 co-expression modules were obtained, which were found to be significantly involved in cell proliferation and apoptosis, Ras and Wnt signaling pathways. The modules with higher connectivity (UBB, RAC1, TP53, PIK3CA) were also counted. Also, it is found that there is significant crosstalk between these modules. On the other hand, we screened 2815 drivers of regulatory modules, including TP53, E2F1, MYC-based transcription factors, and non-coding RNA (ncRNA) dominated by microRNA-320a, microRNA-193b-3p, and microRNA-93-5p. Finally, many regulatory drugs (Copper, Artenimol, Indomethacin, etc.) with targeted pathogenic genes were predicted. Overall, this study explores the underlying pathogenesis of acute myeloid leukemia and predicts the related regulatory drugs. The results of this study provide a new method and theoretical basis for follow-up mechanism research and treatment strategy.
    Type of Medium: Online Resource
    ISSN: 0034-7752 , 2668-8212
    URL: Issue
    Language: English
    Publisher: Revista de Chimie SRL
    Publication Date: 2020
    detail.hit.zdb_id: 2488208-2
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  • 4
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2022-12-21)
    Abstract: Many cytogenetic changes and gene mutations are associated with acute myeloid leukemia (AML) survival outcomes. CD56 is related to poor prognosis when expressed in adult AML patients. However, the prognostic value of CD56 in children with AML has rarely been reported. In this research, we aimed to evaluate the prognostic value of CD56 in childhood AML. Methods The present retrospective study included 145 newly diagnosed pediatric patients with de novo AML (excluding AML-M3) in two hospitals between January 2015 and April 2021. Results The total median (range) age was 75 (8–176) months, and the median follow-up time was 35 months. No significant difference in the 3-year overall survival rate was noted between the CD56-positive and CD56-negative groups (67.0% vs. 79.3%, P  = 0.157) who received chemotherapy. However, among high-risk patients, the CD56-positive group had a worse overall survival rate and event-free survival rate ( P   〈  0.05). Furthermore, among high-risk patients, the CD56-positive group had higher relapse and mortality rates than the CD56-negative group ( P   〈  0.05). Conclusions CD56 represents a potential factor of poor prognosis in specific groups of children with AML and should be considered in the risk stratification of the disease. Given the independent prognostic value of CD56 expression, we should consider integrating this marker with some immunophenotypic or cytogenetic abnormalities for comprehensive analysis.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041352-X
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  • 5
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4617-4617
    Abstract: Background: Unrelated cord blood (UCB) transplant (UCBT) is not recommended in patients with thalassemia major (TM) so far. Post-transplant (PT) Cyclophosphamide (PTCy) with long pre-transplant immunosuppression therapy have improved haploidentical peripheral blood (PB) stem cell transplant (haplo-SCT) survival in TM patients but with 2/31 primary rejection. So, we designed a novel dual transplantation of UCBT following haplo-SCTwith PTCy(NF-14-TM-CT protocol). Aim:To improve results of haplo-SCT and UCBT in patients with TM. Patients and method: NF-14-TM -CT protocol was termed as double-insurance dual transplantsincluding a haplo-SCT and an UCBT, in which conditioning regimen consisted of ATG (at -10 to -8 day), Cy (-7), Fludarabine (-6 to -2), Busulfan (-6 to -4) Thiotepa (-3), haplo-PB (0), PTCy (+3, +4) and UCB (+6). PTCy serve as GVHD prophylaxes after haplo-SCT and as conditioning before UCBT. In total 131 patients with TM from three pediatric center in China received NF-14-TM-CT protocolfrom June, 2014 to April, 2019, with a median follow-up of 13 (2-59) months and a median age of 8 (3.5-17) years. Results Final haplo-PB engrafted(group1)in 76 patients with mean PBSC-MNCof 22.49 (±5.36) x108/kgand UCB nuclear cells (NC) of 5.95 (±3.39) x107/kg and final UCB engrafted (group 2) in 55 patients with mean PBSC-MNC of 21.78 (±5.68) x108/kg and mean UCB-NC of. 5.43 (±2.32) x107/kg. The 4-year overall survival (OS), thalassemia-free survival (TFS), graft rejection (GR), and transplant related mortality (TRM) were 97.6%, 96.0%, 1.5%, and 2.4%, respectively (Fig. A), in total. The corresponding rates for group 1 were 98.3%, 96.9%, 1.7% and 1.8% and for group 2 were 95.5%, 93.8%, 4.5% and 1.4%, respectively. No statistic significant difference was found in OS, TFS, GR and TRM, respectively, when comparing group 1 with group 2 (Fig. B. C, D, E).The incidence of grade II-IV acute GVHD, III-IV acute GVHD, mild chronic GVHD, moderate/severe chronic GVHD, VOD, PT cystitisand PT hemolysis of the entire cohort was 16.8%, 6.87%, 9.92%, 1.52%, 4.60%, 31.3% and 14.5, respectively. Summary:Current study proved that the novel CT improved the results of haplo-SCT and UCBT in patients with TM. Disclosures Wing: Miltenyi Biotec: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
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  • 6
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 10000-10000
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 10000-10000
    Abstract: 10000 Background: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in treating a variety of blood cancers, such as CD19 CAR-T for B-cell malignancies and BCMA CAR-T for myeloid myeloma (MM). However, similar achievement has yet to be replicated in patients with relapsed and refractory acute myeloid leukemia (R/R AML), primarily due to the AML heterogeneity, making it difficult to find an ideal CAR-T target. Previous efforts have targeted single CD33, CD123, LeY, NKG2D, or CD70 receptors, but the overall response rate is very disappointed. To address these challenges, we aim to find an effective target for AML without the need for the hematopoietic stem cells transplant (HSCT). In our study, CLL1 is chosen as a promising target as it is not expressed on normal HSCs, but highly expressed on AML blasts cells and leukemia stem cells (LSCs). Here we report the interim analysis from a Phase I clinical trial using anti-CLL1 based CAR-T cells to treat children with R/R AML. The primary and secondary objectives were to evaluate the safety and anti-AML responses, respectively, with long-term prognosis within those patients who did not receive allogeneic HSCT (allo-HSCT) as an additional objective. Methods: We have generated a 2nd generation of CLL1 CAR-T, the extracellular scFv was derived from a murine CLL1 monoclonal antibody, which was generated by hybridoma technology. Autologous CAR-T cells were manufactured in a cGMP facility. Between Oct 2019 and Jan 2021, 11 pediatric R/R AML patients were infused. CLL1 or CLL1-CD33 dual CAR-T cells were given by a dose at 0.3-1x10 6 /kg with a single dose after lymphodepleting conditioning with cyclophosphamide/fludarabine(Cy/Flu). Results: Of the 11 patients infused, Grade 3-4 hematologic adverse events were observed before and during CAR-T cell infusion, and no dose-limiting toxicities were observed. Meanwhile, grade 1-3 cytokine release syndrome was observed but without any lethal events. All the adverse effects were resolved after guideline-directed intervention. Anti-CLL1 CAR-T cells efficiently expanded in vivo, the median expansion peaking time was at Day 8. For these 11 R/R-AML patients, 10 patients completely responded to anti-CLL1 based CAR-T cell therapy, with CLL1 positive AML blast eliminated within one month. Among the responded 10 patients, 5 patients reached CR/MRD-, 3 patients reached CR/MRD+, 1 patient reached PR and 1 patient showed SD, with only CLL1 negative AML cells. Conclusions: Our study demonstrated that 10/11 patients responded to CLL1 CAR-T cell therapy within one month. For patients showing MRD+ with CLL1 negative AML blast, chemotherapy like Azacitidine, and combined with HSCT may help those patients to reach complete response. These initial results suggested that anti-CLL1 base CAR-T cells can be a well-tolerated and candidate option for treating children with R/R-AML. Clinical trial information: ChiCTR1900027684.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 7
    Online Resource
    Online Resource
    Termedia Sp. z.o.o. ; 2019
    In:  Archives of Medical Science Vol. 15, No. 6 ( 2019), p. 1530-1538
    In: Archives of Medical Science, Termedia Sp. z.o.o., Vol. 15, No. 6 ( 2019), p. 1530-1538
    Type of Medium: Online Resource
    ISSN: 1734-1922
    Language: Unknown
    Publisher: Termedia Sp. z.o.o.
    Publication Date: 2019
    detail.hit.zdb_id: 2203781-0
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  • 8
    In: Leukemia, Springer Science and Business Media LLC, Vol. 36, No. 11 ( 2022-11), p. 2596-2604
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2008023-2
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  • 9
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 970-970
    Abstract: Sibling donor transplantation (SDT) is a proven curative therapy for patients with thalassemia major (TM), NF-08-TM protocol improved the outcomes of unrelated donor transplantation (UDT) in single-center. This study aim was to determine whether outcomes of NF-08-TM protocol could be proved in multicenter and long-term follow-up and to compare the outcomes of full-matched (FM) and one-locus mismatch (WM) UDT. 586 patients from 4 pediatric BMT centers in China from Dec. 2008 to Jun. 2016 received NF-08-TM protocol, a newly designed Busulfan following Cyclophosphamide and constant cell dose protocol. With a median follow-up of 57 months (range, 21-116), the 9-year OS, TFS, GR, and TRM were 94.4%, 92.8%, 2.7%, and 5.6%, respectively, in total. The corresponding rates for SDTs (n=224) were 95.9%, 95.5%, 1.4% and 4.1%; for UDTs (n=275) were 92.4%, 89.9%, 4.3% and 7.6%; for parental donor transplantation (PDT, n=40) were 95.0%, 95.0%, 0% and 5.0%; and for cord blood transplantation (CBT, n=47) were 97.9%, 95.4%, 2.6% and 2.1%, respectively.The incidence of grade II-IV aGVHD, III-IV aGVHD, mild cGVHD and moderate/severe cGVHD of the entire cohort was 8.9%, 4.6%, 3.7%, and 1.4%, respectively. There was no statistically significant difference (SSD) in OS, TFS, TRM, and GR when comparing FM-SDTs with those of FM-PDTs, FM-UDTs or FM-CBTs. Among PDTs, no SSD was found in OS, TFS, TRM, GR, and GVHD in comparison of FM-PDTs and WM-PDTs. More moderate/severe cGVHD occurred in WM-UDTs than FM-UDTs. Compared FM-SDTs, WM-UDTs had worse OS, TFS, TRM, and a higher rate of grade II-IV aGVHD and cGVHD. Current study proved that Good outcomes of NF-08-TM protocol in single-center be proved in multicenter and long-term follow-up. Compared to the outcomes of FM-UDT) those of well-UDT was worse and was not recommended to thalassemia patients. Disclosures Wing: Miltenyi Biotec: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
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  • 10
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4181-4181
    Abstract: Background At present, allogeneic-HSCT is still the only proven potentially curative strategy for Juvenile myelomonocytic leukemia(JMML) children, being only able to cure about 50% of patients by either a relative donnor or an unrelated volunteer. Relapse represented the main causes of treatment failure. The data of HLA-haploidentical transplantation is poorly reported so far. But we have reported an encouraging result in the treatment of leukemia and Thalassemia with complementary transplantation(CT), i.e. unrelated umbilical cord blood(UCB) following haploidentical stem cells transplantation(see blood 2016 128:1235). The evidence of aberrant DNA methylation in JMML provided a rationale for the use of the DNA hypomethylating agent 5-azacytidine or Decitabine(DAC). Recent studies have indicated hypomethylating agent maybe reduce the disease burden in the pretransplant window with minimal toxicity and play an immunomodulatory role after transplantation. Therefore, we developed a novel CT strategy combinated with hypomethylation agent for children with JMML. Patients and method 48 patients received CT combined with DAC from December 2014 to April 2019 in two independent HSCT-centers. Of them, 44 patients had molecular genetics mutation(including NF1, PTPN11,Kras,Nras),and 6 patients had cytogenetic abnormalities with monosomy 7. The median age at diagnosis was 22 (1 to 90) ms. (Table.1). 47 of 48 patients received 2~6 courses of DAC therapy (20mg/m2/d ×5 days for each course with 4-weeks interval) and 1~2 courses of mild-moderate cytotoxic chemotherapy (according to the"A-triple-V"regimen from Korea or reduced-intensity FlAG regimen) as "Bridging therapy" in order to reduce the tumor burden prior to HSCT. There was only one patient who was accepted one course of DAC therapy prior to HSCT. In addition, low dose DAC was also administrated 2~6 courses (10mg/m2/day for 3 or 5 days for each course with the interval of 4~6 weeks) for all patients in order to overcome immune-escape of leukemia cells post HSCT. None of the patients underwent splenectomy. Conditioning regimen included DAC ,Cyclophosphamide(Cy) ,Busulfan,Fludarabine and Thiotepa (or replaced by Busulfan). GVHD prophylaxis consisted of Cy on day+3,+4, MMF and Tacrolimus from day+6. Noteworthily, UCB was infused on day+6 (Fig.1). Human leukocyte antigen of UCB-donor/recipient pairs had less than 3/10 loci incompatibility.The median number of infusion mononuclear cells from haploid-donor was 37.8×108/kg, and which of infusion nucleated cells from UCB was 8.8×107/kg(Table.1). Results The median and mean follow-up time was 13.5 and 16.2 (3 to 63)ms ,respectively. Full donor cells engrafted in all patients (donor cell engraftment in one case without any cytotoxic chemotherapy before HSCT, who was occurred in a salvaged HSCT from another haplo-donor and UCB-donor after primary failure of first CT ). 5-years OS, disease-free survival(DFS) and transplant-related mortality were 90.1%,86.9% and 4.4%, respectively(Fig.2). Haplo-cells and UCB-cells engrafted finally in 26 and 22 patients, respectively. The median times to neutrophil more than 0.5×109/L and platelet more than 20×109/L were 29 days and 24 days post-HSCT, respectively (Table.2). Platelets and neutrophi recovered earlier in patients with haplo-engrafted than those with UCB-engrafted (p=0.000)(Table.3). Five patients developed relapse after HSCT, who had PTPN11 mutation. 4 of them were Haplo-cells engraftment. The median time to relapse after HSCT was 5.5 (1.5 to 12 ) months. There ware no significant difference in the OS and DFS between UCB-engrafted group and Haplo-engrafted group(p=0.612 and p=0.227,respectively)(Fig.3).The cumulative incidences of grades Ⅱ-Ⅳ aGVHD was 38% (18 pts).The number of patients with grade III and Ⅳ aGVHD were 7 in total. Chronic GVHD occurred in 7 patients, and no chronic GVHD more than grade II (NIH criterion) occurred in all patients(Table.2).The most common complication associated CT was infection. The reactivation incidences of CMV, EBV and human herpes virus 6 were 27% ,13% and 5.0%, respectively. Recoverable serious pancytopenia occurred in four patients with DAC therapy post-HSCT. Summary CT have significantly improved the therapeutic effect in JMML-HSCT.Hypomethylation agent may play an important role in CT. Neither cord blood-engraftment nor haploid-engraftment demonstrated a clear superiority for CT. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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