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1.
Nat Commun ; 12(1): 865, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558546

RESUMO

Chimeric antigen receptor T cell (CAR-T) targeting the CD19 antigen represents an innovative therapeutic approach to improve the outcome of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Yet, despite a high initial remission rate, CAR-T therapy ultimately fails for some patients. Notably, around half of relapsing patients develop CD19 negative (CD19neg) B-ALL allowing leukemic cells to evade CD19-targeted therapy. Herein, we investigate leukemic cells of a relapsing B-ALL patient, at two-time points: before (T1) and after (T2) anti-CD19 CAR-T treatment. We show that at T2, the B-ALL relapse is CD19 negative due to the expression of a non-functional CD19 transcript retaining intron 2. Then, using single-cell RNA sequencing (scRNAseq) approach, we demonstrate that CD19neg leukemic cells were present before CAR-T cell therapy and thus that the relapse results from the selection of these rare CD19neg B-ALL clones. In conclusion, our study shows that scRNAseq profiling can reveal pre-existing CD19neg subclones, raising the possibility to assess the risk of targeted therapy failure.


Assuntos
Antígenos CD19/metabolismo , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Análise de Célula Única , Criança , Células Clonais , Humanos , Recidiva
2.
Lancet Haematol ; 8(1): e55-e66, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357483

RESUMO

BACKGROUND: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era. METHODS: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model. FINDINGS: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10-2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10-2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10-2vs those with a MRD of <10-2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups. INTERPRETATION: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. FUNDING: The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-abl/genética , Adolescente , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases
3.
Ann Agric Environ Med ; 27(4): 713-716, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33356083

RESUMO

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood cancer. A special subtype of high risk BCP-ALL is Philadelphia-like ALL (Ph-like ALL), in which the gene expression profile is similar to BCR-ABL1-positive leukemia; however, fusion of the mentioned genes does not occur. The unfavourable clinical course and incidence of 15% of cases means that the diagnosis and therapeutic strategy of Ph-like ALL must be carefully developed and implemented into clinical practice. The study presents the case of a patient with diagnosed Ph-like ALL. The use of molecular analytical techniques has made it possible to identify a patient who is likely to relapse and who may benefit from personalized therapy This study shows the advantages of using genomic analyses to identify therapeutic targets, which is especially important for patients with high-risk disease. This model of management could be extended to other cancer subtypes, allowing for tailored diagnosis.


Assuntos
Análise em Microsséries/estatística & dados numéricos , Reação em Cadeia da Polimerase Multiplex/estatística & dados numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Doença Aguda/terapia , Criança , Humanos , Masculino , Polônia , Resultado do Tratamento
4.
Ann Hematol ; 99(10): 2215-2229, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32856140

RESUMO

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Subpopulações de Linfócitos B/imunologia , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/economia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Análise Custo-Benefício , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Custos de Medicamentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/economia , Infusões Intravenosas , Injeções Subcutâneas , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Pré-Medicação , Qualidade de Vida , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Carga Tumoral , Evasão Tumoral
5.
Medicine (Baltimore) ; 99(18): e18639, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358340

RESUMO

RATIONALE: Chimeric antigen receptor-modified T-cell (CART) therapy has revolutionized the treatment of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). However, the capacity of CART therapy has not yet been fully elucidated. PATIENT CONCERNS: An 18-year-old Chinese male patient presented with multiple firm masses on the skin all over his body following regular chemotherapy. DIAGNOSES: Bone marrow smear and skin biopsy confirmed that it was a bone marrow and skin relapse from the initial B-cell ALL. INTERVENTIONS: CD19 CART-cell therapy was performed to manage the bone marrow and skin of the relapsed B-cell ALL. OUTCOMES: During CART-cell therapy, cytokine release syndrome and central nervous encephalopathy occurred. Eventually, the lesions disappeared, and the bone marrow and skin tested minimal residual disease (MRD) negative. The patient achieved complete remission (CR). Fourteen days after testing MRD negative, he received allogeneic hematopoietic stem-cell transplantation and has remained disease free to date. LESSONS: The CR of this patient with leukemia cutis demonstrated that CART exhibited efficacy in this case. While further research is still required, this treatment could potentially be used as a therapy for skin leukemia, lymphoma, and other primary skin cancers.


Assuntos
Neoplasias da Medula Óssea/terapia , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Neoplasias Cutâneas/terapia , Adolescente , Neoplasias da Medula Óssea/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Indução de Remissão
6.
Cancer Cell ; 37(6): 867-882.e12, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32470390

RESUMO

A subset of B cell acute lymphoblastic leukemia (B-ALL) patients will relapse and succumb to therapy-resistant disease. The bone marrow microenvironment may support B-ALL progression and treatment evasion. Utilizing single-cell approaches, we demonstrate B-ALL bone marrow immune microenvironment remodeling upon disease initiation and subsequent re-emergence during conventional chemotherapy. We uncover a role for non-classical monocytes in B-ALL survival, and demonstrate monocyte abundance at B-ALL diagnosis is predictive of pediatric and adult B-ALL patient survival. We show that human B-ALL blasts alter a vascularized microenvironment promoting monocytic differentiation, while depleting leukemia-associated monocytes in B-ALL animal models prolongs disease remission in vivo. Our profiling of the B-ALL immune microenvironment identifies extrinsic regulators of B-ALL survival supporting new immune-based therapeutic approaches for high-risk B-ALL treatment.


Assuntos
Monócitos/imunologia , Recidiva Local de Neoplasia/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Microambiente Tumoral/imunologia , Adolescente , Adulto , Animais , Antineoplásicos/farmacologia , Transplante de Medula Óssea , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prognóstico , Proteoma/análise , RNA-Seq , Estudos Retrospectivos , Análise de Célula Única , Taxa de Sobrevida , Adulto Jovem
7.
Zhonghua Xue Ye Xue Za Zhi ; 41(3): 239-244, 2020 Mar 14.
Artigo em Chinês | MEDLINE | ID: mdl-32311895

RESUMO

Objective: To investigate the efficacy and side effects of anti-CD19 CAR-T cell bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) regimen for refractory B-lymphoblastic leukemia. Methods: 10 patients with refractory B-lymphoblastic leukemia with minimal residual disease (MRD) negative after anti-CD19 CAR-T cell treatment, then bridging to allo-HSCT from November 2017 to March 2019 in the Affiliated Cancer Hospital of Zhengzhou University were retrospectively analyzed. Results: ①Among 10 patients, 5 were males and 5 females, with a median age of 23.6 (10-31) years. 9 patients were diagnosed refractory acute lymphoblastic leukemia and the other one was chronic lymphoblastic leukemia. 10 patients reached MRD negative 30 days after anti-CD19 CAR-T cell. ②The donors were identical sibling (2 cases) and haploidentical family member (8 cases) . The median time from MRD negative after CAR-T treatment to transplantation were 32.5 (20-60) days. ③10 patients obtained complete haploidentical engraftment. The median time of neutrophil implantation was 15 (15-21) days, and 19 (17-30) days of platelet implantation. ④ After conditioning, no hepatic venoocclusive disease and hemorrhagic cystitis occurred. One patient had leakage syndrome and got improved after intervention such as limited water entry, albumin supplementation and diuresis. 8 (80%) patients had fever, 2 cases experienced acute graft-versus-host disease (GVHD) grade Ⅱ, 1 case with aGVHD grade Ⅲ. Among 9 survivals, localized chronic GVHD occurred in 8 patients. ⑤The median follow-up was 262 (150-540) days and the estimated 1-years overall survivaln (OS) and disease free survival (DFS) were (90.0±1.0) % and (85.7±1.3) %, respectively. Conclusion: Anti-CD19 CAR-T cell bridging to allo-HSCT regimen is a feasible choice with favorable outcome for refractory B-lymphoblastic leukemia.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Adulto , Antígenos CD19 , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Linfócitos T , Condicionamento Pré-Transplante , Adulto Jovem
8.
Biol Blood Marrow Transplant ; 26(7): 1239-1246, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32298807

RESUMO

The SARS-CoV-2 coronavirus (COVID-19) pandemic has significantly impacted the delivery of cellular therapeutics, including chimeric antigen receptor (CAR) T cells. This impact has extended beyond patient care to include logistics, administration, and distribution of increasingly limited health care resources. Based on the collective experience of the CAR T-cell Consortium investigators, we review and address several questions and concerns regarding cellular therapy administration in the setting of COVID-19 and make general recommendations to address these issues. Specifically, we address (1) necessary resources for safe administration of cell therapies; (2) determinants of cell therapy utilization; (3) selection among patients with B cell non-Hodgkin lymphomas and B cell acute lymphoblastic leukemia; (4) supportive measures during cell therapy administration; (5) use and prioritization of tocilizumab; and (6) collaborative care with referring physicians. These recommendations were carefully formulated with the understanding that resource allocation is of the utmost importance, and that the decision to proceed with CAR T cell therapy will require extensive discussion of potential risks and benefits. Although these recommendations are fluid, at this time it is our opinion that the COVID-19 pandemic should not serve as reason to defer CAR T cell therapy for patients truly in need of a potentially curative therapy.


Assuntos
Infecções por Coronavirus/epidemiologia , Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Pandemias , Pneumonia Viral/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Linfócitos T/transplante , Anticorpos Monoclonais Humanizados/uso terapêutico , Controle de Doenças Transmissíveis , Infecções por Coronavirus/imunologia , Alocação de Recursos para a Atenção à Saúde/ética , Alocação de Recursos para a Atenção à Saúde/organização & administração , Humanos , Imunoterapia Adotiva/ética , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Pneumonia Viral/imunologia , Guias de Prática Clínica como Assunto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Doadores de Tecidos/provisão & distribução , Estados Unidos/epidemiologia
9.
Pediatr Blood Cancer ; 67(5): e28249, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32159278

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, this new paradigm has introduced unique considerations specific to the patients receiving CAR T-cell therapy, including prognostic uncertainty, symptom management, and psychosocial support. With increasing availability, there is a growing need for evidence-based recommendations that address the specific psychosocial needs of the children who receive CAR T-cell therapy and their families. To guide and standardize the psychosocial care offered for patients receiving CAR T-cell therapy, we propose the following recommendations for addressing psychosocial support.


Assuntos
Imunoterapia Adotiva/psicologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/psicologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos , Criança , Humanos
10.
Postgrad Med ; 132(5): 485-488, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32148146

RESUMO

Acute demyelinating myelopathy after allogeneic hematopoietic stem cell transplantation (HSCT) is rare, and the exact pathogenesis remains unclear. Here, we report the case of a 20-year-old patient with B-cell acute lymphocyte leukemia (B-ALL) who developed acute demyelinating myelopathy approximately 10 months after HSCT. Magnetic resonance imaging revealed high T2 signal intensity lesions from the C2-T4 levels of the spinal cord. Treatments with high doses of corticosteroids, immunoglobulins, and rituximab improved his neurologic symptoms, and he achieved 44 months of leukemia-free and graft-versus-host disease (GVHD)-free survival, with no recurrence of the demyelination myelopathy. An understanding of the contribution of immune reconstitution to the pathogenesis of demyelinating myelopathy after HSCT and the association of this disease with GVHD will require more clinical cases.


Assuntos
Doenças Desmielinizantes/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Doenças Desmielinizantes/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adulto Jovem
12.
Leuk Res ; 91: 106334, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32135394

RESUMO

OBJECTIVES: To describe real-world management and clinical and economic outcomes of patients with B-cell precursor acute lymphoblastic leukemia (ALL) in Belgium, Greece and Switzerland. METHODS: This descriptive, retrospective medical chart review collected patient-level data in 2018 from adults with ≥1 minimal residual disease (MRD) test during front-line ALL treatment. Data were stratified by MRD status. RESULTS: Eighty-two patients were included (median age 44 years, 23 % Philadelphia chromosome-positive; MRD-positive: n = 17, MRD-negative: n = 50, MRD result unknown: n = 15). HyperCVAD (32 %) and HOVON (26 %) were the most frequently used front-line treatment protocols; 22 % of patients received stem cell transplantation. Overall, 76 % of ALL patients were hospitalized (mean 1.1 hospitalization/month). Complete hematological response (CRh) occurred in 66/82 patients (80 %). Median relapse-free survival from CRh was 32.7 months (MRD-positive: 11.7 months; MRD-negative: 33.3 months). Median overall survival from diagnosis was 28.9 months (MRD-positive: 15.3 months; MRD-negative: not reached). Most patients (88 %) were MRD tested during induction; testing rates considerably decreased thereafter (39 % during consolidation). CONCLUSIONS: B-cell precursor ALL represents a clinical burden and impacts healthcare resources; MRD-positive patients have worse prognosis than MRD-negative patients. Efforts should be made to adhere to recommendations for MRD testing in clinical guidelines.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bélgica , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Gerenciamento Clínico , Doxorrubicina/uso terapêutico , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Recidiva , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Suíça , Transplante Homólogo , Vincristina/uso terapêutico
13.
Ann Hematol ; 99(4): 835-838, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32076826

RESUMO

Despite improvement in survival of newly diagnosed adult precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL), the results of relapsed/refractory disease are poor. Blinatumomab, a bispecific monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL and in minimal residual disease (MRD)-positive patients.We report our "real-world" experience with blinatumomab in patients with relapsed/refractory B-ALL.Twenty-one patients, at a median age 52 years with median disease duration of 10 months, were included. Indications for treatment were hematological relapse (n = 17), MRD positivity (n = 2), inability to continue intensive chemotherapy (n = 1), and bridging to a second alloSCT (n = 1). Blinatumomab was given as first salvage in 11 patients and after at least one prior salvage treatment in eight.Complete response (CR) was newly achieved in 47% and was maintained in 75% of patients with baseline CR. At a median follow-up of 12.4 months, 13 patients were alive, and 11 in CR. Median leukemia-free survival was 8.7 months, and median overall survival was 15.2 months. Median leukemia-free survival and overall survival were not reached in patients proceeding to alloSCT compared to 5.1 and 15.2 months, respectively, for patients who did not receive stem cell transplantation.Treatment was well tolerated with neurological events reported in two patients (10%) and GI events in three patients (14%). Cytokine storm was reported in four patients (19%).In conclusion, treatment with blinatumomab is effective and tolerable in adult patients with relapsed/refractory B-ALL outside of a clinical trial stetting.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Complexo CD3/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos/efeitos adversos , Especificidade de Anticorpos , Antineoplásicos Imunológicos/efeitos adversos , Terapia Combinada , Citocinas/metabolismo , Intervalo Livre de Doença , Feminino , Gastroenteropatias/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Doenças do Sistema Nervoso/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
Pediatr Blood Cancer ; 67(4): e28199, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020723

RESUMO

Chimeric antigen receptor T cells (CAR-T) are an effective and potentially durable treatment for refractory and multiply relapsed B-cell acute lymphoblastic leukemia. Neurotoxicity is frequent after CAR-T cell therapy. Mechanisms driving neurotoxicity are incompletely understood, and symptoms can range from transient and mild to severe and life-threatening. Providers have exercised caution in providing CAR-T to patients with neurological comorbidities or extramedullary disease. Here, we report three patients with prior significant neurologic morbidity who safely tolerated CAR-T cell infusion after bridging therapy with conventional chemotherapy.


Assuntos
Imunoterapia Adotiva/efeitos adversos , Doenças do Sistema Nervoso , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adolescente , Criança , Pré-Escolar , Comorbidade , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia
16.
BMC Cancer ; 20(1): 110, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041553

RESUMO

BACKGROUND: TP53 mutations occur in only about 3% of primary and 10-20% of relapse B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). However, alternative mechanisms may contribute to functionally impairing the p53 pathway in the absence of a mutation. Candidate mechanisms include overexpression of p53 mRNA variants encoding either dominant-negative p53 protein isoforms such as Delta40p53 and Delta133p53, or modulatory isoforms such as p53beta, which counteract the effects of Delta133p53 on replicative senescence in T-lymphocytes. METHODS: We used semi-quantitative reverse-transcriptase PCR (RT-PCR) and Western blot to investigate the expression of full length p53 (TAp53), Delta40p53, Delta133p53 or p53beta in diagnostic marrow from a clinical cohort of 50 BCP-ALL patients without TP53 mutation (29 males and 21 females, age range 2-14 years) and in the bone marrow cells of 4 healthy donors (used as controls). RESULTS: Irrespective of isoforms, levels of p53 mRNA were low in controls but were increased by 2 to 20-fold in primary or relapse BCP-ALL. TAp53 was increased in primary BCP-ALL, Delta40p53 was elevated in relapse BCP-ALL, whereas Delta133p53 and p53beta were increased in both. Next, mRNA levels were used as a basis to infer the ratio between protein isoform levels. This inference suggested that, in primary BCP-ALL, p53 was predominantly in active oligomeric conformations dominated by TAp53. In contrast, p53 mostly existed in inactive quaternary conformations containing ≥2 Delta40 or Delta133p53 in relapse BCP-ALL. Western blot analysis of blasts from BCP-ALL showed a complex pattern of N-terminally truncated p53 isoforms, whereas TAp53beta was detected as a major isoform. The hypothesis that p53 is in an active form in primary B-ALL was consistent with elevated level of p53 target genes CDKN1A and MDM2 in primary cases, whereas in relapse BCP-ALL, only CDKN1A was increased as compared to controls. CONCLUSION: Expression of p53 isoforms is deregulated in BCP-ALL in the absence of TP53 mutation, with increased expression of alternative isoforms in relapse BCP-ALL. Variations in isoform expression may contribute to functional deregulation of the p53 pathway in BCP-ALL, specifically contributing to its down-regulation in relapse forms.


Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Domínios e Motivos de Interação entre Proteínas/genética , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Mutação , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Isoformas de Proteínas/genética , Multimerização Proteica/genética , RNA Mensageiro , Recidiva , Proteína Supressora de Tumor p53/química
17.
Leuk Res ; 91: 106333, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32109757

RESUMO

B-cell acute lymphoblastic leukemia (B-ALL) with MLL-rearrangements (MLL-r) is rare in pediatric patients (aged >1 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 and <0.001, 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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Asparaginase/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Criança , Pré-Escolar , Ciclofosfamida/uso terapêutico , Daunorrubicina/uso terapêutico , Dexametasona/uso terapêutico , Esquema de Medicação , Feminino , Haplótipos , Humanos , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Recidiva , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Translocação Genética , Transplante Haploidêntico , Vincristina/uso terapêutico
18.
Cancer Immunol Immunother ; 69(5): 867-877, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31970440

RESUMO

Acute lymphoblastic leukaemia (ALL) in adults is a rare and difficult-to-treat cancer that is characterised by excess lymphoblasts in the bone marrow. Although many patients achieve remission with chemotherapy, relapse rates are high and the associated impact on survival devastating. Most patients receive chemotherapy and for those whose overall fitness supports it, the most effective treatment to date is allogeneic stem cell transplant that can improve overall survival rates in part due to a 'graft-versus-leukaemia' effect. However, due to the rarity of this disease, and the availability of mature B-cell antigens on the cell surface, few new cancer antigens have been identified in adult B-ALL that could act as targets to remove residual disease in first remission or provide alternative targets for escape variants if and when current immunotherapy strategies fail. We have used RT-PCR analysis, literature searches, antibody-specific profiling and gene expression microarray analysis to identify and prioritise antigens as novel targets for the treatment of adult B-ALL.


Assuntos
Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Imunoterapia/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Evasão Tumoral/efeitos dos fármacos , Adulto , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/isolamento & purificação , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Terapia de Alvo Molecular/métodos , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Indução de Remissão/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento , Evasão Tumoral/imunologia
19.
Pediatr Blood Cancer ; 67(4): e28149, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31981407

RESUMO

BACKGROUND: Accurate disease detection is integral to risk stratification in B-cell acute lymphoblastic leukemia (ALL). The gold standard used to evaluate response in the United States includes morphologic evaluation and minimal residual disease (MRD) testing of aspirated bone marrow (BM) by flow cytometry (FC). This MRD assessment is usually made on a single aspirate sample that is subject to variability in collection techniques and sampling error. Additionally, central nervous system (CNS) assessments for ALL include evaluations of cytopathology and cell counts, which can miss subclinical involvement. PROCEDURE: We retrospectively compared BM biopsy, aspirate, and FC samples obtained from children and young adults with relapsed/refractory ALL to identify the frequency and degree of disease discrepancies in this population. We also compared CNS FC and cytopathology techniques. RESULTS: Sixty of 410 (14.6%) BM samples had discrepant results, 41 (10%) of which were clinically relevant as they resulted in a change in the assignment of marrow status. Discrepant BM results were found in 28 of 89 (31.5%) patients evaluated. Additionally, cerebrospinal fluid (CSF) FC identified disease in 9.7% of cases where cytopathology was negative. CONCLUSIONS: These results support further investigation of the role of concurrent BM biopsy, with aspirate and FC evaluations, and the addition of FC to CSF evaluations, to fully assess disease status and response, particularly in patients with relapsed/refractory ALL. Prospective studies incorporating more comprehensive analysis to evaluate the impact on clinical outcomes are warranted.


Assuntos
Medula Óssea/patologia , Citometria de Fluxo/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Imunofenotipagem , Masculino , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
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