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  • 1
    Language: English
    In: The New England journal of medicine, 2013-04-18, Vol.368 (16), p.1509-1518
    Description: Chimeric antigen receptor–modified T cells have demonstrated efficacy in chronic lymphoid leukemia, an indolent disease. They have now been shown to have efficacy in two patients with rapidly progressive, treatment-refractory acute lymphoid leukemia. Patients with relapsed and chemotherapy-refractory pre–B-cell ALL have a poor prognosis despite the use of aggressive therapies such as allogeneic hematopoietic stem-cell transplantation 1 , 2 and bispecific CD19 antibody fragments. 3 Chimeric antigen receptor–modified T cells that target the lineage-specific antigens CD19 and CD20 have been reported to be effective in adults with CLL and B-cell lymphomas. 4 – 9 However, the effects of chimeric antigen receptor T cells on ALL blasts, a more immature leukemia that progresses more rapidly, have not been fully investigated. In particular, there has been uncertainty about whether chimeric antigen receptor T cells would expand in vivo in patients . . .
    Subject(s): Hematologic and hematopoietic diseases ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Biological and medical sciences ; General aspects ; Medical sciences ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy ; Humans ; Immunotherapy ; Antigens, CD19 ; Female ; T-Lymphocytes - immunology ; Receptors, Antigen, T-Cell ; Child ; Remission Induction ; Chimera ; Regression (Disease) ; Care and treatment ; Immune response ; Acute lymphocytic leukemia ; Research ; T cells ; Pediatrics ; Laboratories ; Leukemia ; Body weight ; Cytotoxicity ; Lymphocytes T ; Cerebrospinal fluid ; Etanercept ; Lymphocytes ; Bone marrow ; Remission ; Children ; Blast cells ; Antigens ; Chronic lymphatic leukemia ; CD19 antigen ; Acute lymphatic leukemia ; Cytokines ; Tumor cells ; T cell receptors ; Lymphatic leukemia ; Patients ; Lymphoma ; Fever ; Children & youth ; Chimeric antigen receptors ; Chemotherapy ; Aplasia ; Lymphocytes B ; Index Medicus ; Abridged Index Medicus
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Source: Single Journals
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: The New England journal of medicine, 2014-10-16, Vol.371 (16), p.1507-1517
    Description: In this study, adoptively transferred T cells transfected with anti-CD19 and activating signal–generating molecules led to complete remission in 90% of patients with relapsed and refractory acute leukemia, and overall survival at 6 months was 78%. Engineered T-cell therapy is a new strategy for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL), which is associated with an extremely poor prognosis in adults and remains a leading cause of death from childhood cancer. 1 – 3 In initial proof-of-principle clinical trials involving patients with chronic lymphocytic leukemia (CLL), chimeric antigen receptor–modified T cells that target CD19 produced a durable complete remission in a small number of patients. 4 – 6 Our group and others then extended these findings to relapsed and refractory B-cell ALL, and we found profound responses in a small number of children and adults. 7 , 8 Chimeric . . .
    Subject(s): Hematologic and hematopoietic diseases ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Biological and medical sciences ; General aspects ; Medical sciences ; Genetic Therapy ; Recurrence ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology ; Humans ; Middle Aged ; Receptors, Antigen, T-Cell - therapeutic use ; Child, Preschool ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality ; Young Adult ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy ; Immunotherapy ; Adult ; Female ; Lentivirus - genetics ; Child ; Cytokines - blood ; Antibodies, Monoclonal, Humanized - therapeutic use ; Survival Rate ; Remission Induction ; Genetic Engineering ; Adolescent ; Antigens, CD19 ; T-Lymphocytes - immunology ; Receptors, Antigen, T-Cell - genetics ; Genetic Vectors ; Chimera ; Development and progression ; Care and treatment ; Research ; Leukemia ; Autografts ; CD19 antigen ; Acute lymphatic leukemia ; Body weight ; Stem cell transplantation ; Clinical trials ; T cell receptors ; Lymphocytes T ; Cerebrospinal fluid ; Lymphatic leukemia ; Patients ; Children & youth ; Interleukin 6 ; Chimeric antigen receptors ; Aplasia ; Lymphocytes B ; Lymphocytes ; Bone marrow ; Remission ; Children
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Source: Single Journals
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: Blood cancer journal (New York), 2019-01-22, Vol.9 (2), p.10-10
    Description: Outcomes of pediatric and young adult patients diagnosed with acute lymphoblastic leukemia (ALL) have improved significantly in the past few decades. Treatment advances have provided 5-year survival rates ranging from 78 to 91% depending on the age at diagnosis. However, approximately 2-3% of patients will present with refractory disease that is unresponsive to chemotherapy, and 10-15% of patients will relapse. Outcomes post-relapse show significantly reduced 5-year survival rates that continue to decrease with each subsequent relapse. Despite our increased understanding of risk factors and disease predictors, treatment strategies for patients with relapsed or refractory (r/r) disease, including variations of chemotherapy and stem cell transplant, remain ineffective for many patients. To improve outcomes of patients with r/r disease, immunotherapies targeting specific B cell antigens are being developed. Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy recently approved by the US Food and Drug Administration for patients with refractory leukemia or those with second or later relapse. In this treatment strategy, a patient's own T cells are transduced to express an anti-CD19 CAR that, when reintroduced into the patient, directs specific binding and killing of CD19+ B cells. In a phase 2, single-arm, multicenter, global study, tisagenlecleucel resulted in a remission rate of 81% in pediatric and adolescent patients with r/r B cell ALL. This review article summarizes four typical cases of pediatric and adolescent r/r B-cell ALL, focusing on the patient's journey from initial diagnosis to treatment with CAR T cell therapy.
    Subject(s): Recurrence ; Immunotherapy, Adoptive - methods ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology ; Receptors, Antigen, T-Cell - metabolism ; Humans ; Treatment Outcome ; Combined Modality Therapy ; Stem Cell Transplantation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy ; T-Lymphocytes - metabolism ; Receptors, Chimeric Antigen - genetics ; T-Lymphocytes - immunology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Receptors, Chimeric Antigen - metabolism ; Pediatrics ; Chemotherapy ; Young adults ; Lymphocytes ; Patients ; Leukemia ; Index Medicus ; Review
    ISSN: 2044-5385
    E-ISSN: 2044-5385
    Source: Nature Open Access
    Source: PubMed Central
    Source: Directory of Open Access Journals
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 4
    Language: English
    In: Leukemia, 2018-12-28, Vol.33 (4), p.884-892
    Description: Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/ refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was welltolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.
    Subject(s): Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Antibodies, Monoclonal, Humanized - therapeutic use ; Prognosis ; Humans ; Salvage Therapy ; Child, Preschool ; Neoplasm Recurrence, Local - drug therapy ; Male ; Survival Rate ; Antineoplastic Agents - therapeutic use ; Remission Induction ; Neoplasm Recurrence, Local - pathology ; Young Adult ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Adolescent ; Adult ; Female ; Inotuzumab Ozogamicin ; Retrospective Studies ; Child ; Drug Resistance, Neoplasm - drug effects ; Cancer immunotherapy ; Acute lymphocytic leukaemia
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 5
    Language: English
    In: Frontiers in oncology, 2014, Vol.4, p.108-108
    Description: A complex interplay of intracellular signaling networks orchestrates normal cell growth and survival, including translation, transcription, proliferation, and cell cycle progression. Dysregulation of such signals occurs commonly in many malignancies, thereby giving the cancer cell a survival advantage, but also providing possible targets for therapeutic intervention. Activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway contributes to the proliferative advantage of malignant cells and may confer resistance to chemotherapy in various hematologic malignancies. The initial mTOR inhibitor, sirolimus (also known as rapamycin), was first discovered in 1975 in the soil of Easter Island. Sirolimus was originally developed as an anti-fungal agent given its macrolide properties, but was approved by the Food and Drug Administration (FDA) in 1999 as an immunosuppressive agent for renal transplantation patients once its T cell suppression characteristics were recognized. Shortly thereafter, recognition of sirolimus's ability to inhibit cellular proliferation and cell cycle progression brought sirolimus to the forefront as a possible inhibitor of mTOR. In the subsequent decade, the functional roles of the mTOR protein have been more fully elucidated, and this protein is now known to be a key regulator in a highly complex signaling pathway that controls cell growth, proliferation, metabolism, and apoptosis. This article discusses the dysregulation of PI3K/mTOR signaling in hematologic malignancies, including acute and chronic leukemias, lymphomas, and lymphoproliferative disorders. The current repertoire of PI3K/mTOR pathway inhibitors in development and clinical trials to date are described with emphasis upon pediatric hematologic malignancies (Figure 1). Investigation of small molecule inhibitors of this complex signaling network is an active area of oncology drug development.
    Subject(s): clinical trial ; tyrosine kinase inhibitors ; acute myeloid leukemia ; PI3K ; acute lymphoblastic leukemia ; mTOR ; Oncology ; non-Hodgkin lymphoma ; Hodgkin lymphoma ; pediatric ; acute myeloid leukemia (AML) ; Clinical Trial
    ISSN: 2234-943X
    E-ISSN: 2234-943X
    Source: PubMed Central
    Source: Directory of Open Access Journals
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 6
    Language: English
    In: Pediatric blood & cancer, 2020-09, Vol.67 (9), p.e28541-n/a
    Subject(s): blinatumomab ; acute lymphoblastic leukemia ; relapse ; continuous infusion ; immunotherapy ; pediatrics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Prognosis ; Antibodies, Bispecific - administration & dosage ; Humans ; Antineoplastic Agents - administration & dosage ; Infusions, Intravenous - standards ; Infusions, Intravenous - statistics & numerical data ; Index Medicus
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 7
    Language: English
    In: American journal of hematology, 2018-11, Vol.93 (11), p.E352-E355
    Subject(s): Analysis ; Leukemia ; B cells ; CD22 antigen ; CD19 antigen ; Lymphatic leukemia
    ISSN: 0361-8609
    E-ISSN: 1096-8652
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 8
    Language: English
    In: American journal of hematology, 2017-01, Vol.92 (1), p.E11-E13
    Subject(s): Antigens ; Immunotherapy ; Lymphomas ; Index Medicus
    ISSN: 0361-8609
    E-ISSN: 1096-8652
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 9
    Language: English
    In: Leukemia, 2018-11, Vol.32 (11), p.2316-2325
    Description: The survival of pediatric patients with multiply relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia has historically been very poor; however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply R/R childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean ± SE) were 51 ± 4% for patients with bone marrow R/R B-ALL who underwent a second salvage attempt, 37 ± 6% for a third attempt, and 31 ± 6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41 ± 6%, 13 ± 7%, and 27 ± 13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 10
    Language: English
    In: British journal of haematology, 2017-05, Vol.177 (3), p.467-474
    Description: Summary The phosphatidylinositol 3‐kinase (PI3K)/mammalian (or mechanistic) target of rapamycin (mTOR) signalling pathway is commonly dysregulated in acute lymphoblastic leukaemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus in combination with UKALL R3 re‐induction chemotherapy was conducted in children and adolescents with second or greater relapse of ALL. The initial temsirolimus dose level (DL1) was 10 mg/m2 weekly × 3 doses. Subsequent patient cohorts received temsirolimus 7·5 mg/m2 weekly × 3 doses (DL0) or, secondary to toxicity, 7·5 mg/m2 weekly × 2 doses (DL‐1). Sixteen patients were enrolled, 15 were evaluable for toxicity. Dose‐limiting toxicity (DLT) occurred at all three dose levels and included hypertriglyceridaemia, mucositis, ulceration, hypertension with reversible posterior leucoencephalopathy, elevated gamma‐glutamyltransferase or alkaline phosphatase and sepsis. The addition of temsirolimus to UKALL R3 re‐induction therapy resulted in excessive toxicity and was not tolerable in children with relapsed ALL. However, this regimen induced remission in seven of fifteen patients. Three patients had minimal residual disease levels 〈0·01%. Inhibition of PI3K signalling was detected in patients treated at all dose levels of temsirolimus, but inhibition at an early time point did not appear to correlate with clinical responses at the end of re‐induction therapy.
    Subject(s): mTOR inhibitor ; clinical trials ; relapse ; acute lymphoblastic leukaemia ; pharmacodynamics ; Recurrence ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Phosphatidylinositol 3-Kinase - antagonists & inhibitors ; Humans ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Child, Preschool ; Infant ; Male ; Protein Kinase Inhibitors - adverse effects ; Dose-Response Relationship, Drug ; Young Adult ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Female ; Phosphatidylinositol 3-Kinase - blood ; Child ; Sirolimus - adverse effects ; Sirolimus - analogs & derivatives ; Drug Administration Schedule ; Induction Chemotherapy - methods ; Treatment Outcome ; Sirolimus - pharmacology ; Protein Kinase Inhibitors - administration & dosage ; Sirolimus - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Adolescent ; Protein Kinase Inhibitors - pharmacology
    ISSN: 0007-1048
    E-ISSN: 1365-2141
    Source: Alma/SFX Local Collection
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