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Blinatumomab, as a novel bispecific antibody targeting CD19 and CD3, can induce T lymphocytes to precisely target CD19 positive B lymphocytes to apoptosis. At present, it is the only bispecific antibody approved for the treatment of hematological malignancies in China. Blinatumomab is effective in the treatment of newly diagnosed, relapsed/refractory, minimal residual disease positive patients with B-cell acute lymphoblastic leukemia (B-ALL) . It can improve the survival of the patients and is well tolerated. The further study of blinatumomab can provide theoretical basis and new ideas for induction therapy, salvage therapy and subsequent hematopoietic stem cell transplantation in patients with B-ALL.
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OBJECTIVE@#To evaluate the prognosis value of average daily platelet amount increase in children with B-cell acute lymphoblastic leukemia(B-ALL) treated by CCCG-ALL-2015 regimen.@*METHODS@#106 children with primary B-ALL were retrospective analyzed, standardized MRD test protocol was used to detect the MRD level (19 d and 46 d) after chemotherapy. The platelet count was measured by Sysmex XE-2100. Kaplan-Meier survival curve statistics was used to analyze the event free survival(EFS) rate of the children.@*RESULTS@#The trend of negative correlation existed between PPC and TPR (rs=-0.519, P=0.021). The 3-year EFS rate of the patients in Ap>5.4×109/L group was 95.7%, which was significantly higher than those in Ap≤5.4×109/L group(79.5%) (χ2=5.236, P=0.035); multivariate analysis showed that Ap≤5.4×109/L was the independent prognostic factor affecting survival of the patients (RR=3.978; 95%CI: 1.336-11.523, P=0.041). With both MRD and Ap≤5.4×109/L as candidate variables, Ap≤5.4×109/L lost its independent prognostic value (RR=1.225; 95%CI: 0.892-13.696, P=0.089), the correlation between d 19/d 46 MRD levels and Ap>5.4×109/L (χ2=4.318, P=0.038) could explain the phenomenon.@*CONCLUSION@#Ap can reflect the effect of B-ALL chemotherapy and can be used to monitor the curative effect and prognosis of B-ALL children.
Subject(s)
Child , Humans , Blood Platelets , Burkitt Lymphoma , Disease-Free Survival , Neoplasm, Residual/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prognosis , Retrospective StudiesABSTRACT
The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.
Subject(s)
Humans , Antigens, CD19/therapeutic use , Antineoplastic Agents/pharmacology , Immunotherapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , T-LymphocytesABSTRACT
Objective:To investigate the expression and ratio of CD4 +CD25 +Foxp3 +regulatory T cells (Tregs) to helper T cells 17 (Th17) in the peripheral blood of children with B-cell acute lymphoblastic leukemia (B-ALL). Method:54 children with newly diagnosed B-ALL in Children′s Hospital Capital Institute of Pediatrics from February 2017 to October 2019 were selected as the research subjects, with a median age of 4.9 (3.1 to 7.4) years. These children were divided into a pre-treatment group and a post-treatment group. According to the disease outcome after treatment, they were further divided into a complete remission group (45 cases), and a relapse/refractory group (9 cases). 20 healthy children were selected as the control group. Flow cytometry (FCM) was used to detect the proportions of CD4 +CD25 +Foxp3 +Treg cells and Th17 cells. The ratio of Treg/Th17 cells was calculated. Result:Before treatment, the proportion of Treg cells in the relapse/refractory group and the complete remission group (respectively 6.11±0.48, 6.20±1.16) were higher than those in the control group (4.89±1.46) (P<0.05), and the ratio of Treg/Th17 cells in peripheral blood of children with B-ALL in relapse/refractory stage and complete remission stage (respectively 8.34±2.14, 5.91±1.92) were higher than those in the control group (3.55±1.68) (P<0.05); The ratio of Treg/Th17 cells in the relapsed/refractory group was higher than that in the complete remission group (P<0.05). After treatment, the proportion of Treg cells and ratio of Treg/Th17 cells in peripheral blood of children with B-ALL in relapse/refractory stage (respectively 6.09±0.80, 7.37±1.19) were higher than those in complete remission stage (respectively 5.25±0.87, 4.22±1.50) and control group (respectively 4.89±1.46, 3.55±1.68) (P<0.05). Compared with that before treatment, children in complete remission stage after treatment had lower proportions of Treg cells and the ratio of Treg/Th17 cells, as well as higher proportions of Th17 cells in the peripheral blood (P<0.05). There were no significant differences in the proportions of Treg cells and Treg/Th17 ratio between the pre-treatment group and the post-treatment group of children in relapse/refractory stage (P>0.05).Conclusion:In peripheral blood of children with B-ALL, there is a ratio change of Treg/Th17 cells caused by the increase of CD4 +CD25 +Foxp3 +Treg cells and the decrease of Th17 cells, which tends to be normal with the remission of the disease. Regular detection of Treg and Th17 cells helps to monitor the immune status and provide prognosis of children with B-ALL, and may provide a basis for the immunotherapy of B-ALL.
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Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.
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RESUMEN La mucormicosis es una infección fúngica oportunista, poco común causada por hongos del orden de los mucorales. Ocurre a una tasa anual de 1.7 casos por cada millón de personas y presenta una tasa de mortalidad alta que oscila desde el 30 hasta el 90% de acuerdo con el estado sistémico del paciente. Los escenarios más complejos se observan en pacientes inmunosuprimidos, mientras que, en pacientes competentes, la invasión fúngica es bien controlada por el sistema inmune del huésped. La infección comienza luego de la ex-posición, inhalación e invasión de esporas dentro de la cavidad oral y nasal desde donde se puede diseminar a otras partes del cuerpo, permitiendo diferentes presentaciones clínicas en pacientes susceptibles. Actualmente, los registros internacionales de mortalidad de mucormicosis en niños con neoplasias van desde 41.3 a 66.6, por lo que el objetivo de este estudio es presentar un caso raro de mu-cormicosis rinocerebral en un paciente masculino de 4 años quien además presentó como enfermedad base una leucemia linfoblástica aguda B común, tratado con anfotericina B liposomal y debridación quirúrgica de las zonas afectadas. Finalmente, se realizó una revisión sistemática de la literatura disponible con el afán de determinar y describir los signos, síntomas, diagnóstico, tratamiento disponible y pronóstico de esta enfermedad.
ABSTRACT Mucormycosis is an uncommon opportunistic fungal infection caused by fungi of the mucoral order. Occurs at an annual rate of 1.7 cas-es per million people. It has a high mortality rate ranging from 30 to 90% according to the patient's systemic status. The most complex scenarios are observed in immunosuppressed patients, whereas, in competent patients, the fungal invasion is well controlled by the host's immune system. The infection begins after exposure, inhalation and invasion of spores into the oral and nasal cavity from where it can spread to other parts of the body, allowing different clinical presentations in susceptible patients. Currently, international records of mortality of mucormycosis in children with neoplasms range from 41.3 to 66.6. The objective of this study is to present a rare case of rhi-nocerebral mucormycosis in a 4-year-old male patient who also presented as a base disease a leukemia acute B-lymphoblastic disease. Our patient was treated with liposomal amphotericin B and surgical debridement of affected areas. In addition, a systematic review of the available literature was carried out with the aim of determining and describing the signs, symptoms, diagnosis, available treatment and prognosis of this disease.
Subject(s)
Humans , Male , Child, Preschool , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Mucormycosis , Nasal Cavity , Amphotericin B , Immune System , NeoplasmsABSTRACT
Objective To investigate the expression profiles and chromosome distribution characteristics of miRNA in bone marrow samples between the patients with adult B-cell acute lymphoblastic leukemia (B-ALL) and their controls. Methods Illumina sequencing technology was applied to perform global miRNA expression analysis and chromosome distribution analysis in the bone marrow samples of 15 adult B-ALL patients relative to a control group of 10 patients without hematologic malignancies. Then, qPCR was carried out to validate the reliability of the se-quencing data. Results In total,291 differentially expressed miRNAs including 168 up-regulated and 123 down-regulated miRNAs were indentified in adult B-ALL patients as compared with their controls. Despite the distribution of miRNA genes in chromosome was similar in both samples, the distribution of miRNA expression abundance in chromosome show obvious differences. B-ALL group was mainly located in the chromosome 1, 2, 5 and 9, while the control group was mainly located in the chromosome 3,7,9,17 and X. Conclusions The altered expression profile of miRNA in bone marrow samples of adult B-ALL patients implies that aberrantly expressed miRNAs maybe plays roles in the occurrence and development of B-ALL.
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Objective To investigate the expression profiles and chromosome distribution characteristics of miRNA in bone marrow samples between the patients with adult B-cell acute lymphoblastic leukemia (B-ALL) and their controls. Methods Illumina sequencing technology was applied to perform global miRNA expression analysis and chromosome distribution analysis in the bone marrow samples of 15 adult B-ALL patients relative to a control group of 10 patients without hematologic malignancies. Then, qPCR was carried out to validate the reliability of the se-quencing data. Results In total,291 differentially expressed miRNAs including 168 up-regulated and 123 down-regulated miRNAs were indentified in adult B-ALL patients as compared with their controls. Despite the distribution of miRNA genes in chromosome was similar in both samples, the distribution of miRNA expression abundance in chromosome show obvious differences. B-ALL group was mainly located in the chromosome 1, 2, 5 and 9, while the control group was mainly located in the chromosome 3,7,9,17 and X. Conclusions The altered expression profile of miRNA in bone marrow samples of adult B-ALL patients implies that aberrantly expressed miRNAs maybe plays roles in the occurrence and development of B-ALL.
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An 11 year old, hispanic girl with a history of B-cell acute lymphoblastic leukemia was admitted to the hospital for symptoms compatible with Bartonella henselae infection. The first molecularly diagnosed case of disseminated Bartonella henselae infection was reported in an immunocompromised patient in Lima, Peru. The analysis was confirmed by Polymerase Chain Reaction and automated sequencing of a liver biopsy sample, even though the serologic tests were negative. In conclusion, Bartonella spp. infection should have a particular diagnostic consideration in immunocompromised patients with fever of unknown origin and further investigation regarding the patient's past exposures with cats should also be elicited.
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An 11 year old, hispanic girl with a history of B-cell acute lymphoblastic leukemia was admitted to the hospital for symptoms compatible with Bartonella henselae infection. The first molecularly diagnosed case of disseminated Bartonella henselae infection was reported in an immunocompromised patient in Lima, Peru. The analysis was confirmed by Polymerase Chain Reaction and automated sequencing of a liver biopsy sample, even though the serologic tests were negative. In conclusion, Bartonella spp. infection should have a particular diagnostic consideration in immunocompromised patients with fever of unknown origin and further investigation regarding the patient's past exposures with cats should also be elicited.
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The cause of B-cell Acute Lymphoblastic Leukemia (B-ALL) is unknown. Some studies suggested that the cause might be a deficiency in certain transcription factors due to a genetic deletion. We would like to propose a different event that might cause such deficiency. This event is the presence of certain latent viruses in infected cells. The event and its molecular, cellular and clinical consequences have been described by Hanan Polansky in 2003 in his book on Microcompetition.
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Objective To evaluate the outcomes of mature B-cell acute lymphoblastic leukemia(mature B-ALL) and to assess the safety and efficacy of the treatment protocol.Methods From February of 2003 to December of 2012,15 children were diagnosed as mature B-cell acute lymphoblastic leukemia/lymphoma possible (mature B-ALL/NHLp) in Shanghai Children's Medical Center(SCMC) were enrolled,and they were treated with SCMC-mature B-ALL/NHLp-2003 protocol.All of the clinical characteristics,therapeutic effects and long-term outcomes were analyzed.The statistical data were processed by SPSS 21.0.Results The median age on diagnosis was 8.7 years (1 year and 5 months to 14 years and 4 months).Among them,4 cases presented with local mass including maxillofacial tumors,neck and abdominal mass.The others had systemic manifestations such as fever and pale face.These neoplastic cells retained the expressions of surface membrane immunoglobulin M,terminal deoxynucleotidyl transferase,Cμ,CD10,CD19,cCD79 a differently.Follow-up was updated to November 30,2013.The median follow-up period was 80 months (39-128 months).Theestimated 5-year event free survival rate was (80.0 ± 10.3) ％.According to univariate analysis,increased lactate dehydrogenase level (＞ 4-times the normal value),increased serum ferritin level (＞ 2-times the normal value),no small residual disease markers were indepen-dent poor prognostic factors(x2 =5.49,4.89,5.49,all P ＜ 0.05).Conclusions SCMC-mature B-NHL/ALLp-2003 protocol is feasible and safe for children with mature B-ALL/NHLp,but more sample cases need to be investigated.
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Objective To investigate the changes of CD4 +CD25highFoxp3 +regulatory T (Treg) cells and their significance in immune escape of childhood B-cell acute lymphocytic leukemia ( B-ALL ) . Methods Forty-two children with B-ALL and twenty-eight age-matched healthy children were enrolled in this study.Flow cytometry analysis was performed to evaluate the proportion of CD 4 +CD25high Foxp3 +Treg cells as well as CD4 +CD25high ICOS+Foxp3 +and CD4 +CD25high ICOS-Foxp3 +subsets in peripheral blood samples.The expression of associated molecules including IL-10, TGF-β, IL-35, TGF-βRII, ICOS and CD28 at protein level were also measured by flow cytometry analysis .The transcription level of Smad3/4, TIEG1 and Itch by CD4 +T cells were determined by quantitative real-time PCR.The concentration of TGF-βin plasma was detected by enzyme-linked immunosorbent assay.Results (1)The proportion of CD4 +CD25highFoxp3 +Treg cells in children with B-ALL were significantly higher than those of health subjects (P0.05).(3)The concentra-tion of TGF-βin plasma from children with B-ALL were higher than those from control group [ ( 25 .83 ± 12.65) ng/ml vs (8.59 ±5.73) ng/ml, P<0.05].The expression of TGF-βRII and its associated mole-cules (Smad3/4, TIEG1 and Itch) by CD4 +T cells were significantly up-regulated.Moreover, an increased expression of ICOS and CD28 by CD4 +CD25highFoxp3 +Treg cells were also observed in children with B-ALL (P<0.05).Conclusion The hyper-activity of TGF-β, ICOS and CD28 signaling might be closely associ-ated with the increased proportion of CD4 +CD25high Foxp3 +Treg cells and the imbalance of its subsets in children with B-ALL.
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Therapy-related myeloid neoplasms have been well characterized. However, precursor B-cell acute lymphoblastic leukemia in patients with prior malignancies is uncommon, and the effect of prior cytotoxic therapy on development of precursor B-cell acute lymphoblastic leukemia is controversial. Therapy-related precursor B-cell acute lymphoblastic leukemia has been reported occasionally. However, cytotoxic therapy-related precursor B-cell acute lymphoblastic leukemia has been reported in Korea only rarely. We herein describe two cases of therapy-related precursor B-cell acute lymphoblastic leukemia.
Subject(s)
Humans , Korea , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor Cells, B-LymphoidABSTRACT
MYC rearrangement, a characteristic cytogenetic abnormality of Burkitt lymphoma and several subsets of other mature B-cell neoplasms, typically involves an immunoglobulin gene partner. Herein, we describe a case of precursor B-cell lymphoblastic leukemia harboring a MYC rearrangement with a novel non-immunoglobulin partner locus. The patient was a 4-yr-old Korean boy with ALL of the precursor B-cell immunophenotype. At the time of the second relapse, cytogenetic analyses revealed t(4;8)(q31.1;q24.1) as a clonal evolution. The MYC rearrangement was confirmed by FISH analysis. He died 3 months after the second relapse without achieving complete remission. To our knowledge, this is the first report of a case of MYC rearrangement with a non-immunoglobulin partner in precursor B-cell lymphoblastic leukemia.