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1.
JAMA ; 325(9): 833-842, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33651090

RESUMO

Importance: Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile. Objective: To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL. Design, Setting, and Participants: This trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669). Interventions: All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant. Main Outcome and Measures: The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025. Results: Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group. Conclusions and Relevance: Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point. Trial Registration: ClinicalTrials.gov Identifier: NCT02101853.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunoterapia , Leucemia de Células B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Quimioterapia de Consolidação/efeitos adversos , Intervalo Livre de Doença , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Adulto Jovem
2.
JAMA ; 325(9): 843-854, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33651091

RESUMO

Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. Design, Setting, and Participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization. Intervention: Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 µg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation. Main Outcomes and Measures: The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events. Results: A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group. Conclusions and Relevance: Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT02393859.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunoterapia , Leucemia de Células B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Quimioterapia de Consolidação/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia de Células B/mortalidade , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Fatores de Risco , Taxa de Sobrevida
3.
Ann Hematol ; 100(4): 1003-1012, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33587155

RESUMO

Chimeric antigen receptor (CAR) T cell therapy improves the remission rate of refractory/relapsed B-acute lymphoblastic leukemia (R/R B-ALL) patients, but the relapse rate remains high. Recent studies suggest patients who underwent post-chimeric antigen receptor T cell therapy hematopoietic stem cell transplantation (post- HSCT) would achieve durable remission and better survival, but this remains controversial. To this end, we conducted a meta-analysis to assess the role of post-HSCT in R/R B-ALL. The Cochrane Library, Embase, and PubMed were used to identify relevant studies; the latest search update was on July 05, 2020. We used the Cochran Q test and I-squared statistics to test for heterogeneity among the studies analyzed. The fixed model and random model were used to combine results when appropriate. We performed all statistical analyses with Stata 12, and P < 0.05 was considered statistically significant. We included 18 studies with 758 patients in the meta-analysis. Our results indicated that post-HSCT was associated with lower relapse rate (RR: 0.40, 95% CI: 0.32-0.50, P = 0.000), better overall survival (HR: 0.37, 95% CI: 0.19-0.71, P = 0.003), better leukemia-free survival (HR: 0.20, 95% CI: 0.10-0.40, P = 0.000). However, post-HSCT did not influence OS in Caucasians, and CAR-T cells with CD28 co-stimulation factor bridged to HSCT did not influence OS. Post-HSCT decreased the relapse rate and improved the long-term survival of R/R B-ALL patients. R/R B-ALL patients would benefit from post-HSCT after CAR-T cell therapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia de Salvação , Antígenos CD19/imunologia , Grupo com Ancestrais do Continente Asiático , Intervalo Livre de Doença , Estudos Epidemiológicos , Grupo com Ancestrais do Continente Europeu , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Recidiva , Indução de Remissão , Resultado do Tratamento
4.
Cancer Sci ; 112(3): 1150-1160, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33428808

RESUMO

This study focused on children as well as adolescents and young adults (AYAs) and aimed to examine trends in survival of leukemia over time using population-based cancer registry data from Osaka, Japan. The study subjects comprised 2254 children (0-14 years) and 2,905 AYAs (15-39 years) who were diagnosed with leukemia during 1975-2011. Leukemia was divided into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias. We analyzed 5-year overall survival probability (5y-OS), using the Kaplan-Meier method and expressed time trends using the joinpoint regression model. For recently diagnosed (2006-2011) patients, a Cox proportional hazards model was applied to determine predictors of 5y-OS, using age group, gender, and treatment hospital as covariates. Over the 37-year period, 5y-OS greatly improved among both children and AYAs, for each leukemia type. Among AYAs, 5y-OS of ALL improved, especially after 2000 (65% in 2006-2011), when the pediatric regimen was introduced but was still lower than that among children (87% in 2006-2011, P < .001). Survival improvement was most remarkable in CML, and its 5y-OS was over 90% among both children and AYAs after the introduction of molecularly targeted therapy with tyrosine kinase inhibitors. Among patients with recently diagnosed AML, the risk of death was significantly higher for patients treated at nondesignated hospitals than those treated at designated cancer care hospitals. The changes in survival improvement coincided with the introduction of treatment regimens or molecularly targeted therapies. Patient centralization might be one option which would improve survival.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide Aguda/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Adulto , Fatores Etários , Institutos de Câncer/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/estatística & dados numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/uso terapêutico , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Fatores Sexuais , Adulto Jovem
5.
PLoS One ; 15(12): e0243657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338050

RESUMO

BCR-ABL1 fusion gene is the driver mutation of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Although the prognostic value of BCR-ABL1 isoforms in Ph+ ALL patients has been investigated in numerous studies in the tyrosine kinase inhibitor (TKI) era, the results were still conflicting. Hence we performed herein the meta-analysis to comprehensively assess the impact of BCR-ABL1 isoforms on the clinical outcomes of Ph+ ALL patients. Systematic literature review was conducted in PubMed, Embase, and Cochrane databases with the data access date up to June 15, 2020. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Furthermore, subgroup analyses were performed to assess the robustness of the associations. Nine studies with a total number of 1582 patients were eligible for this meta-analysis. Combined HRs suggested that p210 was slightly associated with inferior event-free survival (EFS) (HR = 1.34, 95% CI 1.05-1.72). The overall survival (OS) was not significantly affected (HR = 1.15, 95% CI 0.92-1.45). In subgroup analyses, the HRs showed a trend toward adverse impact of p210 on clinical outcomes. However, the confidence intervals were not crossing the null value only in a minority of subgroups including Caucasian studies, first-generation TKI treated cohort and transplant cohort. Our findings suggested that p210 might pose a mild adverse impact on the EFS of Ph+ ALL patients. This effect might be compromised by the use of second- or third-generation TKIs. Further studies are needed to verify our conclusions.


Assuntos
Proteínas de Fusão bcr-abl/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Intervalo Livre de Doença , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Isoformas de Proteínas/genética
6.
Lancet Haematol ; 7(11): e816-e826, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33091355

RESUMO

BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in patients with refractory or relapsed acute lymphocytic leukaemia. Various anti-CD19 CAR T-cell constructs have been trialled and responses vary widely among different studies. We aimed to systematically analyse the outcomes of patients with acute lymphocytic leukaemia treated with anti-CD19 CAR T cells and identify factors associated with differences in outcomes. METHODS: We did a systematic review and meta-analysis of published and unpublished clinical trials that reported data on the outcomes of adult or paediatric patients that were treated with anti-CD19 CAR T cells for relapsed or refractory B-cell acute lymphocytic leukaemia, reported between Jan 1, 2012, and April 14, 2020. Studies with two patients or fewer were excluded and summary data were extracted from the reports. The primary outcome was the number of patients who had complete remission at any time after anti-CD19 CAR T-cell infusion. This study is not registered in PROSPERO. FINDINGS: From 1160 studies, we identified 40 potentially appropriate studies, 35 (88%) of which met the eligibility criteria and were included in the final analysis (n=953 patients). The pooled complete remission was 80% (95% CI 75·5-84·8) and heterogeneity between studies was moderate (I2=56·96%). In the prespecified subgroup analyses, 195 (75% [95% CI 66·9-82·9, I2=35·22%]) of 263 patients in adult studies and 242 (81% [72·9-87·2, I2=54·45%]) of 346 patients in paediatric studies achieved complete remission, p=0·24. The pooled complete remission did not significantly differ with anti-CD19 CAR T-cell construct type or single-chain variable fragment clone, but was higher with autologous T-cell origin (727 [83%, 78·5-86·5, I2=44·34%] of 901 patients), compared with allogeneic T-cell origin (29 [55%, 30·6-79·0, I2=62·64%] of 52 patients; p=0·018). 242 (26% [95% CI 18·5-34·1]) of 854 patients developed grade 3 or worse cytokine release syndrome and 97 (12% [6·6-19·2]) of 532 developed grade 3 or worse neurotoxicity. There was no difference in the proportion of patients who achieved complete remission or who had cytokine release syndrome or neurotoxicity between different anti-CD19 CAR T-cell constructs. The risk of bias was assessed as low in 17 studies and moderate in 18 studies. INTERPRETATION: The high response rates after anti-CD19 CAR T-cell therapy can be used to guide the use of therapy in patients with relapsed or refractory acute lymphocytic leukaemia. Comparison studies are required to further determine differences in efficacy between different anti-CD19 CAR T-cell constructs in the setting of relapsed or refractory acute lymphocytic leukaemia. FUNDING: National Cancer Institute, National Comprehensive Cancer Network, Mayo Clinic K2R Research Pipeline, and Mayo Clinic Center for Individualized Medicine.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Síndrome da Liberação de Citocina/etiologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/uso terapêutico , Indução de Remissão , Transplante Autólogo
7.
N Engl J Med ; 383(17): 1613-1623, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33085860

RESUMO

BACKGROUND: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment. METHODS: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment. RESULTS: Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%). CONCLUSIONS: A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).


Assuntos
Anticorpos Biespecíficos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dasatinibe/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia de Consolidação , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Mutação , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento
8.
Ann Hematol ; 99(11): 2629-2637, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980890

RESUMO

Treatment of acute lymphoblastic leukemia (ALL) requires the combination of multiple drugs to integrate a complete remission. The different prognostic factors (age, leukocytes, risk, cytogenetic alterations) allow identifying those patients with a high risk of relapse, but there are few described factors that impact the induction response. The objective was to identify the utility of different risk factors (overexpression of the ABCB1 drug resistance gene, favorable response to steroids (FRS) and early response at day + 8 of treatment) on the percentage of complete remissions and overall survival. This is a prospective, observational study in adult patients with B-ALL without specific cytogenetic alterations, who started induction treatment based on a pretreatment with prednisone and subsequently vincristine (1.6 mg/m2 subcutaneous) plus daunorubicin (45 mg/m2 subcutaneously) on days + 1, + 8, + 15. The ABCB1 resistance gene was evaluated at diagnosis, the FRS at the end of the pretreatment and the early response during day + 8. A total of 53 adult patients diagnosed with ALL Philadelphia negative chromosome (Ph-), with immunophenotype B, with a normal karyotype, were studied. Cases with genetic abnormalities with a poor prognosis were excluded in order to reduce bias. The mean age was 48 years (range 17-68 years). 62.3% of patients were at high risk of relapse. When analyzing the risk factors, 30.2% showed high levels of the ABCB1 resistance gene, without showing an impact on the induction response (OR: 1.218, p = 0.743), but its overexpression was associated with a poor response to steroids as in the absence of early response. Individually, both the FRS (OR: 5.7, p = 0.004) and the absence of early response to day + 8 (OR: 6.42, p = 0.002) showed significance. By combining the different factors, having more than 2 was directly related to a failure (OR: 9.514, p = 0.000). The identification of factors such as FRS such as the persistence of blasts at the end of the first week of treatment is useful to identify patients at risk of failure in induction.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Quimioterapia de Indução , Proteínas de Neoplasias/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Adolescente , Adulto , Idoso , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisolona/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Vincristina/administração & dosagem
9.
Lancet Haematol ; 7(10): e715-e723, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32976751

RESUMO

BACKGROUND: The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. METHODS: We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. FINDINGS: We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset. INTERPRETATION: Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. FUNDING: The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Interleucinas/genética , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
10.
Ann Hematol ; 99(11): 2619-2628, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32960314

RESUMO

In the era of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended as a standard approach for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) achieving complete remission (CR). However, the role of autologous hematopoietic stem cell transplantation (auto-HSCT) in adult patients achieving complete molecular remission (CMR) is an alternative, less toxic treatment options, especially for the patients who lack suitable donors and are unfit for allo-HSCT. Thus, we conducted a systematic review and meta-analysis to compare the efficacy of allo-HSCT and auto-HSCT for the treatment of adult patients with Ph+ ALL. We searched the PubMed, Embase, Scopus, and Cochrane Library for studies published before June 2019 without language restriction. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for overall survival (OS) and relapse-free survival (RFS) and odds ratios (ORs) and 95% CIs for relapse rate (RR) and treatment-related mortality (TRM). Four prospective studies and one retrospective study were included with a total of 810 patients. We found auto-HSCT was superior to allo-HSCT in OS (HR = 1.42, 95% CI: 1.06-1.91, P = 0.02), and there was no difference between allo-HSCT and auto-HSCT for RFS (HR = 1.10, 95% CI: 0.86-1.40, P = 0.44) and RR (OR = 0.53, 95% CI: 0.22-1.26, P = 0.15). The risk of TRM for patients undergoing allo-HSCT was significantly higher than that of the patients who received auto-HSCT (OR = 5.06, 95% CI: 1.03-24.75, P = 0.05). Our meta-analysis shows that auto-HSCT may be an attractive and alternative treatment option for adult Ph+ ALL patients achieving CMR, with similar or better outcomes than allo-HSCT in the era of TKIs.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Aloenxertos , Autoenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Taxa de Sobrevida
11.
Ann Hematol ; 99(11): 2639-2648, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32889611

RESUMO

Extramedullary relapse (EMR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) continues to remain a clinical challenge. The data on EMR in acute lymphoblastic leukemia (ALL) are currently limited. Herein, a retrospective analysis of 268 adult ALL patients who underwent allo-HSCT in our center between March 2008 and December 2017 was performed to analyze post-HSCT EMR. Ninety patients (33.58%) experienced relapse; 51(19.03%) experienced bone marrow relapse (BMR), whereas 39 (14.55%) experienced EMR. The 5-year cumulative EMR incidence (CEMRI) revealed that matched sibling donor (MSD)-HSCTs were more likely to develop EMR than unrelated donor (URD)- and haploidentical-related donor (HRD)-HSCTs (CEMRI: 24.02%, 7.69%, and 14.69% for MSD, URD, and HRD, respectively). Notably, MSD-HSCTs (URD vs MSD hazard ratio (HR) = 0.26, p = 0.015; HRD vs MSD HR = 0.46, p = 0.032), history of extramedullary disease (EMD) (HR = 2.45, p = 0.041), and T cell ALL (HR = 2.80, p = 0.012) were independent risk factors for EMR in the multivariate analysis. The median overall survival (OS) for all patients was 15.23 months. However, the OS of EMR patients was significantly longer (19.50 months) than that of BMR patients (12.90 months) (p = 0.003). Multivariate analyses revealed that the leading risk factors for post-relapse deaths were shorter intervals between HSCT and relapse (> 12 months vs ≤ 12 months, HR = 0.30, p < 0.001) and BMR (HR = 0.41, p = 0.002). In conclusion, EMR patients have better survival than BMR patients. ALL patients with allo-HSCT from MSDs, a history of EMD, and the T cell type were significantly associated with EMR.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
12.
Ann Hematol ; 99(10): 2393-2404, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32803312

RESUMO

The prognostic impacts of BCR-ABL1 fusion gene mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remain unknown. Using data from a nationwide Japanese registry, we have evaluated the prognostic impact of BCR-ABL1 mutations prior to the first allogeneic hematopoietic cell transplantation (HCT). The cohort included 289 patients with a median of 48 years of age (range: 16-70). Point mutations were detected in 110 patients. Of these, 90 (82%) harbored T315I mutations, while 20 had other mutations. With a median follow-up period of 29 months (range: 1-125), outcomes after 2 years were worse with mutations than without (overall survival [OS]: 34% vs 68%, p < 0.001; relapse rate [RR]: 48% vs 18%, p < 0.001), particularly with the presence of the T315I mutation (OS: 29% vs 68%, p < 0.001; RR: 54% vs 18%, p < 0.001). OS was significantly worse in the T315I group even among the cohort with hematological (p < 0.001) or molecular complete remission (p = 0.025) as compared to the no mutation group. Multivariate analysis determined the prognostic impact of the T315I mutation (OS: hazard ratio [HR] = 2.19, 95% confidence interval [CI]: 1.5-3.3, p < 0.001; RR: HR = 2.51, 95% CI: 1.5-4.2, p < 0.001). This study is the first to report on the prognostic significance of BCR-ABL1 mutations in Ph + ALL.


Assuntos
Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas , Mutação de Sentido Incorreto , Cromossomo Filadélfia , Mutação Puntual , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Idoso , Aloenxertos , Antineoplásicos/uso terapêutico , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
13.
Am J Hematol ; 95(12): 1466-1472, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32777149

RESUMO

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase four study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74 years), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received more than two lines of therapy. The median number of nelarabine cycles was two (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs 22%, log-rank P < .001). The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Nalbufina/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia de Salvação , Adolescente , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nalbufina/efeitos adversos , Recidiva , Taxa de Sobrevida
14.
PLoS One ; 15(7): e0235955, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663229

RESUMO

OBJECTIVES: At any point in time, a person's lifetime health is the number of healthy life years they are expected to experience during their lifetime. In this article we propose an equity-relevant health metric, Health Adjusted Age at Death (HAAD), that facilitates comparison of lifetime health for individuals at the onset of different medical conditions, and allows for the assessment of which patient groups are worse off. A method for estimating HAAD is presented, and we use this method to rank four conditions in six countries according to several criteria of "worse off" as a proof of concept. METHODS: For individuals with specific conditions HAAD consists of two components: past health (before disease onset) and future expected health (after disease onset). Four conditions (acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), schizophrenia, and epilepsy) are analysed in six countries (Ethiopia, Haiti, China, Mexico, United States and Japan). Data from 2017 for all countries and for all diseases were obtained from the Global Burden of Disease Study database. In order to assess who are the worse off, we focus on four measures: the proportion of affected individuals who are expected to have HAAD<20 (T20), the 25th and 75th percentiles of HAAD for affected individuals (Q1 and Q3, respectively), and the average HAAD (aHAAD) across all affected individuals. RESULTS: Even in settings where aHAAD is similar for two conditions, other measures may vary. One example is AML (aHAAD = 59.3, T20 = 2.0%, Q3-Q1 = 14.8) and ALL (58.4, T20 = 4.6%, Q3-Q1 = 21.8) in the US. Many illnesses, such as epilepsy, are associated with more lifetime health in high-income settings (Q1 in Japan = 59.2) than in low-income settings (Q1 in Ethiopia = 26.3). CONCLUSION: Using HAAD we may estimate the distribution of lifetime health of all individuals in a population, and this distribution can be incorporated as an equity consideration in setting priorities for health interventions.


Assuntos
Epilepsia/mortalidade , Nível de Saúde , Leucemia Mieloide Aguda/mortalidade , Mortalidade/tendências , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Anos de Vida Ajustados por Qualidade de Vida , Esquizofrenia/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Esquizofrenia/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
15.
Medicine (Baltimore) ; 99(29): e21015, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702842

RESUMO

BACKGROUND: Down syndrome (DS) also known as Trisomy 21, is a chromosomal disorder affecting approximately 1 in 732newborns annually in the United States. Children with DS are more likely to develop acute lymphoblastic leukemia (ALL). For the management of pediatric ALL, different treatment protocols have been set up since years. However, ALL children with coexisting DS have shown to have increased therapy-related toxicities compared to those without DS. Therefore, in this study, we aimed to systematically analyze the treatment outcomes in acute ALL children with versus without coexisting DS. METHODS: Electronic databases including the Web of Science, EMBASE, Cochrane Central, MEDLINE, http://www.ClinicalTrials.gov, and Google scholar were searched for publications reporting treatment related outcomes in ALL children with versus without co-existing DS. Several treatment protocols were used accordingly. This study had a long-term follow-up time period ranging from 5 to 10 years. The RevMan 5.3 software was used to carry out this analysis. Odds ratios (OR) with 95% confidence intervals (CI) were used to represent the results post analysis. RESULTS: A total number of 31,476 children with ALL enrolled between the years 1981 and 2011 were included. Among the total number of children with ALL, 1303 had coexisting DS. Our results showed that event-free survival was similar in ALL children with versus without DS (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 0.51-3.50; P = .55). Overall mortality (OR: 1.63, 95% CI: 0.86-3.10; P = .13) and participants who achieved clinical remission (OR: 1.04, 95% CI: 0.12-9.29; P = .97) were also similarly manifested. However, treatment-related mortality (OR: 4.29, 95% CI: 2.90-6.36; P = .00001) and induction failure (OR: 2.77, 95% CI: 1.08-7.07; P = .03) were significantly higher in the DS group. Also, total (OR: 1.38, 95% CI: 1.02-1.88; P = .04) and bone marrow relapses (OR: 1.29, 95% CI: 1.00-1.67; P = .05) were significantly higher in ALL children with DS. Nevertheless, central nervous system relapse (OR: 1.15, 95% CI: 0.60-2.20; P = .67), testicular relapse (OR: 0.84, 95% CI: 0.38-1.85; P = .87), and other relapses (OR: 1.12, 95% CI: 0.27-4.62; P = .88) were not significantly different when these outcomes were separately analyzed. CONCLUSION: Based on this analysis of the treatment outcomes in ALL children with versus without DS, event-free survival, overall mortality, and patients who achieved clinical remission were similar during this long-term follow-up time period. However, due to the significantly higher treatment-related mortality, induction failure, and certain relapses in ALL children with DS, new guidelines might have to focus on reconsidering or modifying treatment regimens for ALL children with DS.


Assuntos
Síndrome de Down/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Indução de Remissão , Falha de Tratamento
16.
Ann Hematol ; 99(8): 1833-1843, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32577842

RESUMO

Monosomal karyotype (MK) is associated with poor prognosis in patients with myeloid neoplasms; however, its prognostic significance in Philadelphia chromosome-negative (Ph-negative) acute lymphoblastic leukemia (ALL) remains unclear. Data of 323 patients with Ph-negative ALL treated at Peking University People's Hospital were retrospectively analyzed. MK was identified in 49 (14.8%) patients. The patients with MK had lower hemoglobin levels (P = 0.026), lower platelet count (P = 0.032), higher percentages of blasts in the peripheral blood at diagnosis (P = 0.008), and higher percentages of high-risk karyotypes (P < 0.001) compared with those without MK. The complete remission (CR) rate and the minimal residual disease negativity rate were not significantly different between patients with and without MK. In the multivariate analysis, MK was identified as an independent factor associated with higher cumulative incidence of relapse (CIR) (hazard ratio (HR), 2.07; 95% confidence interval (CI), 1.02, 4.21; P = 0.043), shorter disease-free survival (DFS) (HR, 2.80; 95% CI, 1.20, 6.54; P = 0.017) and shorter overall survival (OS) (HR, 5.75; 95% CI, 2.07, 16.03; P = 0.001) in the chemotherapy cohort; however, MK had no impact on outcomes in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) cohort. Mantel-Byar analysis showed that allo-HSCT was associated with lower CIR (P < 0.001), longer DFS (P < 0.001), and longer OS (P < 0.001) in CR patients with MK. In conclusion, our study showed that MK was an independent predictor of poor outcomes in patients with Ph-negative ALL receiving chemotherapy but not allo-HSCT, and allo-HSCT could improve the outcomes of patients with MK.


Assuntos
Antineoplásicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Idoso , Aloenxertos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos
18.
Medicine (Baltimore) ; 99(21): e20009, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481267

RESUMO

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies of the hematologic system in children. Typically, ALL children with various genetic changes show different incidences, development, and prognoses. This study aimed to analyze the incidence of molecular genetic subtype among ALL children based on their clinical information, and to further investigate the relationship of genetic varieties with the prognostic factors.From 2010 to 2016, a total of 888 ALL children with TEL-AML1 fusion gene, hyperdiploidy, hypodiloidy, IL3-IGH rearranged, E2A PBX1 fusion gene, BCR-ABL1 fusion gene, or mixed lineage leukemia (MML) rearranged were selected and analyzed through the Surveillance, Epidemiology, and End Results database.Our results suggested that, ALL children who lived in the Northern Plains were more likely to experience genetic varieties. In addition, the TEL-AML1 fusion gene, hyperdiploidy, and hypodiloidy were more likely to be detected in ALL children aged 1 to 9 years, while MLL rearrangement was probably detected among ALL children aged <1 year. On the other hand, the 5-year overall survival varied depending on different regions (East: 42.21%; Alaska: 0.001%; Northern Plains: 1.8%; Pacific Coast: 16.3%; and Southwest: 8%), races (African American: 44.5%; white: 18.2%; and Other: 16.3%), and genetic features (TEL-AML1: 10.1%; hyperdiploidy: 19.4%; hypodiloidy: 64.7%; IL3-IGH: 0.01%; E2A PBX1: 14.2%; BCR-ABL1: 15.2%; MLL rearranged: 12.3%).In conclusion, our study found that genetic varieties among ALL children were closely related to their prognoses, and the detection rate of genetic molecules was associated with the age, race, and living area of children.


Assuntos
Variação Genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core , Feminino , Humanos , Lactente , Masculino , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Programa de SEER , Estados Unidos/epidemiologia
19.
Leukemia ; 34(10): 2766-2775, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393841

RESUMO

The ideal stem cell graft source remains unknown in haploidentical haematopietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide (PTCy). This study compared outcomes of bone marrow (BM) versus peripheral blood (PB) stem cell graft for haplo-HCT in acute lymphoblastic leukemia (ALL). A total of 314 patients with ALL (BM-157; PB-157) were included in this study. The cumulative incidence of engraftment at day 30 was higher in the PB group compared with BM (93% vs. 88%, p < 0.01). The incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were not significantly different between the study cohorts. In the multivariate analysis, there were tendencies toward a higher incidence of grade II-IV acute GVHD (hazard ratio (HR) = 1.52, p = 0.07), chronic GVHD (HR = 1.58, p = 0.05), and nonrelapse mortality (NRM) (HR = 1.66, p = 0.06) in patients receiving PB versus BM graft, respectively. The use of PB grafts was associated with lower leukemia-free survival (LFS) (HR = 1.43, p = 0.05), overall survival (OS) (HR = 1.59, p = 0.02), and GVHD-free, relapse-free survival (GRFS) (HR = 1.42, p = 0.03) compared with BM grafts. There was no difference in relapse incidence (HR = 1.23, p = 0.41) between the study groups. In conclusion, use of BM graft results in better survival after haplo-HCT with PTCy in patients with ALL, compared with PB stem cell graft.


Assuntos
Transplante de Medula Óssea , Mobilização de Células-Tronco Hematopoéticas , Depleção Linfocítica , Transplante de Células-Tronco de Sangue Periférico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante Haploidêntico , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Causas de Morte , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Transplante de Células-Tronco de Sangue Periférico/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Modelos de Riscos Proporcionais , Linfócitos T , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento
20.
Am J Cardiol ; 127: 163-168, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32444028

RESUMO

Anthracycline-induced cardiotoxicity can lead to clinical and subclinical heart failure. Decrease of global longitudinal strain is a predictor for heart failure. Early detection of subclinical cardiotoxicity is crucial for timely intervention and prevention of further progression. Cardiac function of 41 survivors of childhood acute lymphoblastic leukemia (ALL) was assessed. Values of cardiac troponin T, N-terminal-pro-brain natriuretic peptide, conventional and myocardial 2D strain echocardiography were measured before (T = 0), during (T = 1, cumulative dose of 120 mg/m2), shortly after (T = 2) and long after anthracycline treatment (T = 3, ≥5 years after anthracycline exposure). Cardiac function of survivors at the latest follow up was compared with 70 healthy age-matched controls. None of the survivors showed clinical signs of cardiac failure at T = 3. Strain values decreased during anthracycline treatment and an ongoing reduction was seen at the latest follow-up (T = 3) with preserved cardiac function (normal ejection fraction and shortening fraction). At T = 1, a relative reduction in longitudinal strain (≥10% compared with baseline) was observed in 38% of the survivors, which increased to 54% at T=3. ALL survivors showed significantly lower conventional and myocardial 2D strain values, especially strain rate, compared with healthy age-matched controls. At T = 3, we did not find any abnormal cardiac troponin T levels. Six percent of the survivors showed abnormal N-terminal-pro-brain natriuretic peptide levels. This prospective study showed an ongoing reduction of 2D myocardial strain and strain rate, with preserved left ventricular ejection fraction (≤10% decrease compared with baseline) in asymptomatic ALL survivors at late follow-up.


Assuntos
Antraciclinas/uso terapêutico , Ecocardiografia/métodos , Eletrocardiografia , Cardiopatias/fisiopatologia , Contração Miocárdica/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Cardiopatias/diagnóstico , Cardiopatias/etiologia , Humanos , Masculino , Países Baixos/epidemiologia , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo
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