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1.
Haematologica ; 109(6): 1668-1676, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38832422

RESUMO

Immunotherapy has revolutionized treatment for a wide variety of cancers yet its use has been relatively limited in childhood malignancies. With the introduction of bispecific T-cell engagers (BiTE®) and chimeric antigen T-cell receptor technologies, previously refractory patients have attained remission, including molecularly negative states of disease, thus providing the possibility of long-term cure. Blinatumomab is a widely available CD3-CD19 BiTE that has dramatically changed the landscape of therapy for some children with precursor-B acute lymphoblastic leukemias (B-ALL) and lymphoblastic lymphomas. Challenges remain with using BiTE in a broader population although the appeal of now-confirmed reduced toxicity and deeper molecular remissions suggests that this approach will be an essential part of future treatment of childhood B-ALL. Herein, we review some of the pertinent literature covering clinical trials with blinatumomab and address future approaches and combination trials including BiTE.


Assuntos
Anticorpos Biespecíficos , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Linfócitos T , Humanos , Anticorpos Biespecíficos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Criança , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ensaios Clínicos como Assunto , Antígenos CD19/imunologia , Resultado do Tratamento , Antineoplásicos Imunológicos/uso terapêutico
2.
J Immunother Cancer ; 12(6)2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844406

RESUMO

The bispecific T cell-binding antibody blinatumomab (CD19/CD3) is widely and successfully used for the treatment of children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here, we report the efficacy of a single course of blinatumomab instead of consolidation chemotherapy to eliminate minimal residual disease (MRD) and maintain stable MRD-negativity in children with primary BCP-ALL.Between February 2020 and November 2022, 177 children with non-high-risk BCP-ALL were enrolled in the ALL-MB 2019 pilot study (NCT04723342). Patients received the usual risk-adapted induction therapy according to the ALL-MB 2015 protocol. Those who achieved a complete remission at the end of induction (EOI) received treatment with blinatumomab immediately after induction at a dose of 5 µg/m2/day for 7 days and 21 days at a dose of 15 µg/m2/day, followed by 12 months of maintenance therapy. MRD was measured using multicolor flow cytometry (MFC) at the EOI, then immediately after blinatumomab treatment, and then four times during maintenance therapy at 3-month intervals.All 177 patients successfully completed induction therapy and achieved a complete hematological remission. In 174 of these, MFC-MRD was measured at the EOI. 143 patients (82.2%) were MFC-MRD negative and the remaining 31 patients had varying degrees of MFC-MRD positivity.MFC-MRD was assessed in all 176 patients who completed the blinatumomab course. With one exception, all patients achieved MFC-MRD negativity after blinatumomab, regardless of the MFC-MRD score at EOI. One adolescent girl with high MFC-MRD positivity at EOI remained MFC-MRD positive. Of 175 patients who had completed 6 months of maintenance therapy, MFC-MRD data were available for 156 children. Of these, 155 (99.4%) were MFC-MRD negative. Only one boy with t(12;21) (p13;q22)/ETV6::RUNX1 became MFC-MRD positive again. The remaining 174 children had completed the entire therapy. MFC-MRD was examined in 154 of them, and 153 were MFC-MRD negative. A girl with hypodiploid BCP-ALL showed a reappearance of MFC-MRD with subsequent relapse.In summary, a single 28-day course of blinatumomab immediately after induction, followed by 12 months of maintenance therapy, is highly effective in achieving MRD-negativity in children with newly diagnosed non-high risk BCP-ALL and maintaining MRD-negative remission at least during the treatment period.


Assuntos
Anticorpos Biespecíficos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/farmacologia , Quimioterapia de Consolidação/métodos , Quimioterapia de Manutenção/métodos , Neoplasia Residual/tratamento farmacológico , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico
3.
Math Biosci Eng ; 21(4): 5164-5180, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38872531

RESUMO

B-cell acute lymphoblastic leukemia (B-ALL) is a malignant blood disorder, particularly detrimental to children and adolescents, with recurrent or unresponsive cases contributing significantly to cancer-associated fatalities. IKBKE, associated with innate immunity, tumor promotion, and drug resistance, remains poorly understood in the context of B-ALL. Thus, this research aimed to explore the impact of the IKBKE inhibitor MCCK1 on B-ALL cells. The study encompassed diverse experiments, including clinical samples, in vitro and in vivo investigations. Quantitative real-time fluorescence PCR and protein blotting revealed heightened IKBKE mRNA and protein expression in B-ALL patients. Subsequent in vitro experiments with B-ALL cell lines demonstrated that MCCK1 treatment resulted in reduced cell viability and survival rates, with flow cytometry indicating cell cycle arrest. In vivo experiments using B-ALL mouse tumor models substantiated MCCK1's efficacy in impeding tumor proliferation. These findings collectively suggest that IKBKE, found to be elevated in B-ALL patients, may serve as a promising drug target, with MCCK1 demonstrating potential for inducing apoptosis in B-ALL cells both in vitro and in vivo.


Assuntos
Apoptose , Proliferação de Células , Quinase I-kappa B , Animais , Humanos , Camundongos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/metabolismo , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Sobrevivência Celular/efeitos dos fármacos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Criança , Adolescente , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Proteínas Quinases/farmacologia
4.
Nat Commun ; 15(1): 4557, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811530

RESUMO

Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.


Assuntos
Dexametasona , Resistencia a Medicamentos Antineoplásicos , Glucocorticoides , Receptores CXCR4 , Transdução de Sinais , Fosfolipases Tipo C , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Humanos , Animais , Transdução de Sinais/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Dexametasona/farmacologia , Fosfolipases Tipo C/metabolismo , Linhagem Celular Tumoral , Glucocorticoides/farmacologia , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Camundongos Endogâmicos NOD , Sobrevivência Celular/efeitos dos fármacos
5.
BMC Med Genomics ; 17(1): 149, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811988

RESUMO

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be divided into more than 10 subgroups. However, many genomic defects associated with resistance mechanisms have not yet been identified. As an individual clinical tool for molecular diagnostic risk classification, RNA-seq and gene expression pattern-based therapy could be potential upcoming strategies. In this study, we retrospectively analyzed the RNA-seq gene expression profiles of 45 children whose molecular diagnostic classifications were inconsistent with the response to chemotherapy. The relationship between the transcriptome and chemotherapy response was analyzed. Fusion gene identification was conducted for the included patients who did not have known high-risk associated fusion genes or gene mutations. The most frequently detected fusion gene pair in the high-risk group was the DHRSX duplication, which is a novel finding. Fusions involving ABL1, LMNB2, NFATC1, PAX5, and TTYH3 at onset were more frequently detected in the high-risk group, while fusions involving LFNG, TTYH3, and NFATC1 were frequently detected in the relapse group. According to the pathways involved, the underlying drug resistance mechanism is related to DNA methylation, autophagy, and protein metabolism. Overall, the implementation of an RNA-seq diagnostic system will identify activated markers associated with chemotherapy response, and guide future treatment adjustments.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , Masculino , Feminino , Pré-Escolar , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Análise de Sequência de RNA , Adolescente , Resistencia a Medicamentos Antineoplásicos/genética , Lactente , Estudos Retrospectivos , Proteínas de Fusão Oncogênica/genética
6.
J Assoc Physicians India ; 72(3): 97-99, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38736127

RESUMO

We present a case of a 24-year-old female recently diagnosed with acute leukemia who came with complaints of fever for 14 days, progressive lower limb weakness, and multiple episodes of vomiting in the last 1 day. In nerve conduction studies, a diagnosis of Guillain-Barré syndrome (GBS) was established. Fever with thrombocytopenia workup revealed a positive dengue nonstructural protein 1 (NS1) and immunoglobulin M (IgM) report. Immunophenotyping confirmed pre-B acute lymphoblastic leukemia (ALL). As leukemia is an immunocompromised state, the peripheral nervous system vulnerability is increased, or infection could precipitate an immune neuropathy. About 10% of adult ALL presents with central nervous system (CNS) leukemias; a higher incidence is seen in mature B ALL. There is some evidence to suggest immunosuppression secondary to intensive chemotherapy (vincristine-induced dying back neuropathy), which was not started in our case. This rare combination in a short period of time with a worsening situation paralyzed the line of management. Few reports described GBS in patients with dengue in adults. The association of Guillan-Barre syndrome and ALL could be coincidental or has a pathophysiological basis and is under basic investigation.


Assuntos
Síndrome de Guillain-Barré , Humanos , Feminino , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamento farmacológico , Adulto Jovem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Dengue/diagnóstico , Dengue/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico
7.
Invest New Drugs ; 42(3): 299-308, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38662275

RESUMO

Blinatumomab is efficacious in patients with B-cell acute lymphoblastic leukemia (B-ALL), yet limited real-world data exists in this context. This retrospective study provided real-world data on the treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with newly diagnosed (ND) and relapsed/refractory (R/R) B-ALL. Patients with B-ALL who received at least one dose of blinatumomab in frontline or R/R settings between August 2021 and June 2023 were included. The primary outcome was the treatment pattern of blinatumomab. Key secondary outcomes included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity, median event-free survival (EFS), and safety. The study included 96 patients with B-ALL; 53 (55.2%) patients were in the ND group and 43 (44.8%) patients were in the R/R group. The median treatment duration was one cycle (range: 1-5). Most patients underwent chemotherapies, allo-HSCT, or experimental CAR-T following blinatumomab. The ND patients using blinatumomab induction therapy achieved 100% CR/CRi rate; 87.2% achieved MRD negativity within two cycles of blinatumomab. In R/R re-induction patients, the CR/CRi rate was 50%; MRD negativity rate was 64.2%. In R/R patients using blinatumomab for consolidation, MRD negativity rate was 90.9%. The median EFS was not reached in both ND and R/R patients; 1-year EFS rate was 90.8% (95% CI: 67%, 97%) and 55.1% (95% CI: 30%, 74%), respectively. Grade ≥ 3 adverse events were observed in 12.5% patients. Blinatumomab was found to be effective with a tolerable safety profile in real world setting.


Assuntos
Anticorpos Biespecíficos , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/administração & dosagem , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Adolescente , Adulto Jovem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Idoso , Criança , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , China , Resultado do Tratamento , Neoplasia Residual , Pré-Escolar , Indução de Remissão , População do Leste Asiático
8.
Leuk Res ; 141: 107506, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38663165

RESUMO

Significant heterogeneity has been reported in outcome of Acute lymphoblastic leukemia with t(1;19)(q23;p13)/TCF3::PBX1 in adolescents and adults leading to a lack of consensus on precise risk stratification. We evaluated clinical outcome of 17 adult ALL cases (≥15 years) with this genotype treated on intensive regimes.13/17 received COG0232 and 4/17 cases received UK-ALL protocol. All achieved CR (100%) with above treatment. End of induction MRD was evaluated in 14/17 cases of which 11 (78.5%) achieved MRD negativity. Total nine patients relapsed (7 marrows, 2 CNS). Overall survival at 2 years was 53.3%. The 2 year estimated PFS was 42.9%. The 2 years CIR was 54.2%. Adults with this genotype perform poorly despite early favorable response. Incorporation of novel immunotherapies and prompt HSCT should be strongly considered with this genotype. Targeted NGS panels for additional genetic aberrations can further help in risk stratifying and guiding therapy for this genotype.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Masculino , Adulto , Feminino , Adolescente , Pessoa de Meia-Idade , Adulto Jovem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Cromossomos Humanos Par 19/genética , Taxa de Sobrevida , Prognóstico , Resultado do Tratamento
9.
Cancer Med ; 13(8): e7172, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38651186

RESUMO

BACKGROUND: Quantitative measurement of minimal residual disease (MRD) is the "gold standard" for estimating the response to therapy in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Nevertheless, the speed of the MRD response differs for different cytogenetic subgroups. Here we present results of MRD measurement in children with BCP-ALL, in terms of genetic subgroups with relation to clinically defined risk groups. METHODS: A total of 485 children with non-high-risk BCP-ALL with available cytogenetic data and MRD studied at the end-of-induction (EOI) by multicolor flow cytometry (MFC) were included. All patients were treated with standard-risk (SR) of intermediate-risk (ImR) regimens of "ALL-MB 2008" reduced-intensity protocol. RESULTS AND DISCUSSION: Among all study group patients, 203 were found to have low-risk cytogenetics (ETV6::RUNX1 or high hyperdiploidy), while remaining 282 children were classified in intermediate cytogenetic risk group. For the patients with favorable and intermediate risk cytogenetics, the most significant thresholds for MFC-MRD values were different: 0.03% and 0.04% respectively. Nevertheless, the most meaningful thresholds were different for clinically defined SR and ImR groups. For the SR group, irrespective to presence/absence of favorable genetic lesions, MFC-MRD threshold of 0.1% was the most clinically valuable, although for ImR group the most informative thresholds were different in patients from low-(0.03%) and intermediate (0.01%) cytogenetic risk groups. CONCLUSION: Our data show that combining clinical risk factors with MFC-MRD measurement is the most useful tool for risk group stratification of children with BCP-ALL in the reduced-intensity protocols. However, this algorithm can be supplemented with cytogenetic data for part of the ImR group.


Assuntos
Citometria de Fluxo , Neoplasia Residual , Humanos , Neoplasia Residual/genética , Criança , Citometria de Fluxo/métodos , Masculino , Feminino , Pré-Escolar , Adolescente , Lactente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Análise Citogenética/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Subunidade alfa 2 de Fator de Ligação ao Core/genética
10.
Cancer Cell ; 42(4): 552-567.e6, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38593781

RESUMO

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.


Assuntos
Leucemia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Asparaginase/farmacologia , Farmacologia em Rede , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transdução de Sinais , Leucemia/tratamento farmacológico
11.
Hematology ; 29(1): 2344998, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38666535

RESUMO

OBJECTIVES: Relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) often responds poorly to induction chemotherapy. However, recent research has shown a novel and effective drug treatment for R/R B-ALL. METHODS: A total of eight patients with R/R B-ALL were enrolled in the study from November 2021 to August 2022. All patients received chemotherapy based on a combination regimen of venetoclax and azacitidine. The regimen was as follows venetoclax 100 mg d1, 200 mg d2, 400 mg d3-14, azacitidine 75 mg/m2 d1-7. RESULTS: Five of eight patients achieved very deep and complete remission (CR) with minimal residual disease (MRD) less than 0.1%. One patient achieved partial remission. Two patients did not achieve remission. There were no serious adverse events and all patients were well tolerated. Three patients were eligible for consolidation chemotherapy and were bridged to CAR-T therapy. CONCLUSIONS: The combined regimen of venetoclax and azacitidine may be beneficial for patients with R/R B-ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Sulfonamidas , Humanos , Azacitidina/uso terapêutico , Azacitidina/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Feminino , Masculino , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Idoso , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico
12.
J Oncol Pharm Pract ; 30(4): 780-782, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38545702

RESUMO

INTRODUCTION: Cytarabine (ARA-C) is an antimetabolite agent used especially in the treatment of hematologic malignancies. Infusion reactions have an important place among the side effects that may occur due to treatment. Clinical findings of infusion reactions resemble allergic reactions. CASE REPORT: 47-year-old male patient with a diagnosis of B-cell Acute Lymphoblastic Leukaemia developed infusion reaction during ARA-C treatment. MANAGEMENT & OUTCOME: There was no alternative treatment option for his existing malignant disease, we decided ARA-C desensitization. DISCUSSION: We would like to describe a successful desensitization protocol in an adult patient who experienced a reaction during ARA-C infusion.


Assuntos
Citarabina , Dessensibilização Imunológica , Hipersensibilidade a Drogas , Humanos , Masculino , Citarabina/efeitos adversos , Citarabina/administração & dosagem , Pessoa de Meia-Idade , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/terapia , Hipersensibilidade a Drogas/etiologia , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Infusões Intravenosas , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia
13.
Chemotherapy ; 69(2): 104-107, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38508148

RESUMO

INTRODUCTION: With the increasing use of blinatumomab in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), including minimal residual disease (MRD)-positive cases, awareness of its adverse effects has gradually improved. Pneumocystis jirovecii pneumonia (PCP) associated with blinatumomab therapy is rare. CASE PRESENTATION: We present a case of PCP in a patient undergoing blinatumomab therapy. A 70-year-old female diagnosed with Philadelphia-like CRLF2 overexpression B-cell precursor ALL received blinatumomab as consolidation therapy after achieving complete remission with prior induction chemotherapy. On the second day of blinatumomab infusion, she developed intermittent low-grade fever, and chest computed tomography (CT) revealed subtle infiltrates and nodules. Despite empiric trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, she progressed to significant shortness of breath and type I respiratory failure, with increased lactate dehydrogenase and ß-D-glucan assays. Chest CT showed diffuse ground-glass opacities with scattered small nodules. The dry cough prompted next-generation sequencing of peripheral blood, which tested positive for pneumocystis jirovecii without evidence of other pathogens. Consequently, the patient was diagnosed with PCP. The first cycle of blinatumomab had to be discontinued, and therapeutic dosages of TMP-SMX and dexamethasone were administered, resulting in full recovery and stable condition during follow-ups. CONCLUSION: PCP is rare in B-cell precursor ALL patients receiving blinatumomab therapy but manifests with early onset and rapid disease progression. Despite prophylaxis, PCP infection cannot be ignored during blinatumomab therapy. Therefore, heightened attention is warranted when using blinatumomab therapy.


Assuntos
Anticorpos Biespecíficos , Pneumocystis carinii , Pneumonia por Pneumocystis , Humanos , Feminino , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/diagnóstico , Idoso , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/efeitos adversos , Pneumocystis carinii/isolamento & purificação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Tomografia Computadorizada por Raios X , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos
16.
Cancer Biol Ther ; 25(1): 2323765, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38465622

RESUMO

Adipocyte is a unique and versatile component of bone marrow microenvironment (BMM). However, the dynamic evolution of Bone Marrow (BM) adipocytes from the diagnosis of B cell Acute Lymphoblastic Leukemia (B-ALL) to the post-treatment state, and how they affect the progression of leukemia, remains inadequately explicated. Primary patient-derived xenograft models (PDXs) and stromal cell co-culture system are employed in this study. We show that the dynamic evolution of BM adipocytes from initial diagnosis of B-ALL to the post-chemotherapy phase, transitioning from cellular depletion in the initial leukemia niche to a fully restored state upon remission. Increased BM adipocytes retards engraftment of B-ALL cells in PDX models and inhibits cells growth of B-ALL in vitro. Mechanistically, the proliferation arrest of B-ALL cells in the context of adipocytes-enrichment niche, might attribute to the presence of adiponectin secreted by adipocytes themselves and the absence of cytokines secreted by mesenchymal stem cell (MSCs). In summary, our findings offer a novel perspective for further in-depth understanding of the dynamic balance between BMM and B-ALL.


Assuntos
Leucemia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Medula Óssea , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Células Estromais , Adipócitos , Células da Medula Óssea , Microambiente Tumoral
17.
Br J Haematol ; 204(4): 1367-1374, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38444113

RESUMO

Literature regarding prognostic relevance of CD20 antigen expression among paediatric B-lineage acute lymphoblastic leukaemia (B-ALL) patients is sparse and contradictory. We analysed clinical laboratory parameters and survival characteristics pertinent to CD20 expression among 224 treatment-naïve paediatric B-ALL patients. 50% patients had CD20 expression (CD20+ B-ALL). There was no difference in the clinical & laboratory presentation and end of induction measurable residual disease (EOI-MRD) status according to CD20 expression. As compared to CD20- B-ALL patients, CD20+ B-ALL patients had two times more relapse (16% vs. 29%, p = 0.034), inferior relapse-free survival (79% vs. 66%, p = 0.025) but no difference in overall survival (75% vs. 69%, p = 0.126). Similar to high-risk NCI status and EOI-MRD positivity, CD20 expression was an independent predictor for inferior relapse-free survival (HR: 1.860, 95% CI: 1.008-3.432, p = 0.047). Compared to baseline, there was a significant increase in CD20-expressing EOI-residual blasts among CD20- B-ALL patients (5% vs. 13%, p = 0.001). EOI residual blasts of both CD20+ and CD20- patients had three times increased normalized CD20 expression intensity (nCD20), with the intensity among CD20- B-ALL patients reaching the pretreatment nCD20 of CD20+ B-ALL patients (4.9 vs. 3.6, p = 0.666). Rituximab can be considered in managing EOI-MRD-positive CD20- B-ALL patients as the residual blasts of these patients have quantitative and qualitative increases in CD20 expression.


Assuntos
Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Antígenos CD20 , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Rituximab/uso terapêutico , Neoplasia Residual
18.
Cancer Med ; 13(5): e7062, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38491815

RESUMO

BACKGROUND: Blinatumomab early-line treatment in B-cell precursor acute lymphoblastic leukemia (B-ALL) might improve clinical outcomes. METHODS: We conducted a retrospective real-world cohort analysis in 20 newly diagnosed B-ALL patients who received reduced-dose chemotherapy (idarubicin, vindesine, and dexamethasone) for 1-3 weeks, followed by blinatumomab for 1-4 weeks as an induction therapy. RESULTS: At the end of the induction therapy, a complete remission rate of 100% was achieved; 17 (85%) patients were minimal residual disease (MRD) negative (<1 × 10-4 ). Adverse events (AEs) were reported in 12 (60%) patients-43.8% were grade 1-2 and 56.2% were grade 3-4. No incidence of neurotoxicity or grade ≥3 cytokine release syndrome was reported. CONCLUSIONS: Blinatumomab demonstrated a significant improvement in clinical outcomes in patients with newly diagnosed B-ALL irrespective of their poor-risk factor status and the pretreatment blast burden.


Assuntos
Anticorpos Biespecíficos , Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Estudos Retrospectivos , Quimioterapia de Indução , Anticorpos Biespecíficos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Linfoma de Burkitt/tratamento farmacológico
19.
Cell Death Dis ; 15(3): 216, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38485947

RESUMO

Despite progressive improvements in the survival rate of pediatric B-cell lineage acute lymphoblastic leukemia (B-ALL), chemoresistance-induced disease progression and recurrence still occur with poor prognosis, thus highlighting the urgent need to eradicate drug resistance in B-ALL. The 6-mercaptopurine (6-MP) is the backbone of ALL combination chemotherapy, and resistance to it is crucially related to relapse. The present study couples chemoresistance in pediatric B-ALL with histidine metabolism deficiency. Evidence was provided that histidine supplementation significantly shifts the 6-MP dose-response in 6-MP-resistant B-ALL. It is revealed that increased tetrahydrofolate consumption via histidine catabolism partially explains the re-sensitization ability of histidine. More importantly, this work provides fresh insights into that desuccinylation mediated by SIRT5 is an indispensable and synergistic requirement for histidine combination therapy against 6-MP resistance, which is undisclosed previously and demonstrates a rational strategy to ameliorate chemoresistance and protect pediatric patients with B-ALL from disease progression or relapse.


Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Sirtuínas , Humanos , Criança , Mercaptopurina/farmacologia , Mercaptopurina/uso terapêutico , Histidina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Linfoma de Burkitt/tratamento farmacológico , Recidiva , Progressão da Doença
20.
Transplant Cell Ther ; 30(5): 520.e1-520.e12, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38462215

RESUMO

BACKGROUND: Blinatumomab, a bispecific monoclonal antibody, effectively controls refractory B cell acute lymphoblastic leukemia (ALL) and promotes measurable residual disease (MRD) negativity. This study investigated the impact of pretransplant blinatumomab on allogeneic hematopoietic cell transplantation (HCT) outcomes in B cell ALL patients. METHODS: We analyzed the effect of pretransplant blinatumomab on transplant outcomes of 117 adults undergoing allogeneic HCT for B cell ALL at Princess Margaret Hospital, Toronto, between 2010 and 2021. Outcomes assessed included overall survival (OS), graft-versus-host disease and relapse-free survival (GRFS), cumulative incidences of relapse (CIR), and nonrelapse mortality (NRM). RESULTS: The median follow-up was 36 months. Thirty-one participants (26.5%) received blinatumomab. Blinatumomab group had higher proportions of individuals with high disease risk index, primary induction failure and was more likely to receive dual T cell depletion with antithymocyte globulin and post-transplant cyclophosphamide. Two-year OS, GRFS, NRM, and CIR in the blinatumomab and nonblinatumomab groups were, respectively: 65.4% versus 45.6% (P = .05), 42.2% versus 17.3% (P = .01), 3.2% versus 43.0% (P = .007) and 34.4% versus 14.4% (P = .02). Blinatumomab was associated with a lower incidence of day-100 grade 2 to 4 and grade 3 to 4 acute graft-versus-host disease (aGVHD): 27.5% versus 56.7% (P = .009), and 10.9% versus 34.7% (P = .04), respectively. Multivariate analysis confirmed the association between pretransplant blinatumomab and improved OS and NRM. CONCLUSIONS: Pretransplant blinatumomab is associated with improved OS and lower risk of NRM in B cell ALL patients undergoing allogeneic HCT, likely reflecting lower burden of treatment-related toxicity in this population. Larger prospective trials are warranted to validate our findings.


Assuntos
Anticorpos Biespecíficos , Transplante de Células-Tronco Hematopoéticas , Humanos , Anticorpos Biespecíficos/uso terapêutico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem , Resultado do Tratamento , Adolescente , Idoso , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Doença Enxerto-Hospedeiro , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
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