RESUMO
Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1-26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0-5.4) in nonresponders (P = 0.002). Grade 2-3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4+ CD127+ PD-1+ T cells might serve as a predictor of treatment response.ClinicalTrials.gov identifier NCT04541277.
Assuntos
Inibidores de Checkpoint Imunológico , Leucemia Mieloide Aguda , Humanos , Decitabina , Inibidores de Checkpoint Imunológico/uso terapêutico , Citarabina/uso terapêutico , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is one of the leading causes of early mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the efficacy, safety, prognostic factors, and optimal therapeutic protocol for SR-aGVHD patients treated with basiliximab in a real-world setting. Nine hundred and forty SR-aGVHD patients were recruited from 36 hospitals in China, and 3683 doses of basiliximab were administered. Basiliximab was used as monotherapy (n = 642) or in combination with other second-line treatments (n = 298). The cumulative incidence of overall response rate (ORR) at day 28 after basiliximab treatment was 79.4% (95% confidence interval [CI] 76.5%-82.3%). The probabilities of nonrelapse mortality and overall survival at 3 years after basiliximab treatment were 26.8% (95% CI 24.0%-29.6%) and 64.3% (95% CI 61.2%-67.4%), respectively. A 1:1 propensity score matching was performed to compare the efficacy and safety between the monotherapy and combined therapy groups. Combined therapy did not increase the ORR; conversely, it increased the infection rates compared with monotherapy. The multivariate analysis showed that combined therapy, grade III-IV aGVHD, and high-risk refined Minnesota aGVHD risk score before basiliximab treatment were independently associated with the therapeutic response. Hence, we created a prognostic scoring system that could predict the risk of having a decreased likelihood of response after basiliximab treatment. Machine learning was used to develop a protocol that maximized the efficacy of basiliximab while maintaining acceptable levels of infection risk. Thus, real-world data suggest that basiliximab is safe and effective for treating SR-aGVHD.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Aguda , Basiliximab/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estudos Retrospectivos , Esteroides/uso terapêuticoRESUMO
EP300-ZNF384 fusion is a rare recurrent cytogenetic abnormality associated with B cell acute lymphoblastic leukemia (B-ALL), which was rarely studied in Chinese patient cohort. Here, we used a customized RNA fusion gene panel to investigate gene fusions in 56 selected acute leukemia patients without conventional genetic abnormalities. Two EP300-ZNF384 fusion forms were detected in ten cases, which were in-frame fusions of EP300 exon 6 fused with exon 3 or 2 of ZNF384. The fusions led to the lack of most functional domains of EP300. We firstly reported EP300-ZNF384 fusion in a mixed-phenotype acute leukemia (MPAL) patient whose CD33 and CD13 were negative. The rest nine B-ALL patients with EP300-ZNF384 fusion expressed CD33 and/or CD13. Fifty-six percent of B-ALL patients (5/9) with EP300-ZNF384 fusion were positive with CD10. After the diagnosis of EP300-ZNF384 fusion, 70% of the patients achieved remission after chemotherapy. Our observations indicated that EP300-ZNF384 fusion consists of a distinct subgroup of B-ALL with a characteristic immunophenotype. These patients are sensitive to current chemotherapy regimen and have an excellent outcome.
Assuntos
Proteína p300 Associada a E1A , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras , RNA Neoplásico , Análise de Sequência de RNA , Transativadores , Adulto , Estudos de Coortes , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Feminino , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transativadores/genética , Transativadores/metabolismoRESUMO
In allogeneic hematopoietic stem cell transplantation recipients, cytomegalovirus (CMV) infection can cause overt CMV-associated disease, which is a main cause of transplantation-associated mortality. CMV infection correlates closely with donor's type. We therefore examined whether risk factors of CMV reactivation and clinical endpoints in patients with hematologic malignancies after allogeneic peripheral blood stem cell transplantation (PBSCT) differed between using matched-sibling donors (MSD-SCT) and haploidentical donors (HID-SCT). In this retrospective cohort study, we enrolled in 200 consecutive patients received an unmanipulated G-CSF-mobilized allogeneic PBSCT. Ninety (45%) patients received MSD-SCT and 110 (55%) received HID-SCT. Quantitative PCR was used for monitoring of CMV reactivation after transplantation. One-year cumulative incidence of CMV DNAemia was 55.0%, ranging from 23.5% in MSD-SCT group to 81.0% in HID-SCT group (p < 0.001). Although univariate analyses showed that non-myeloid malignancies, disease in complete remission status at transplantation, pretreatment with antithymocyte globulin, HLA-haploidentical donors, male donors, previous Epstein-Barr virus DNAemia, and absolute lymphocyte count on day 30 < 0.6 × 109/L were respectively associated with CMV reactivation after transplantation in total cohort of recipients (all p < 0.05), haploidentical donors were found to be the only independent predictor in multivariate analyses (Hazard ratio = 6.4, p < 0.001). Furthermore, univariate analyses revealed that non-myeloid malignancies and previous Epstein-Barr virus DNAemia were respectively associated with CMV reactivation in MSD-SCT recipients, and female was associated with CMV reactivation in HID-SCT recipients (all p < 0.05). In HID-SCT recipients, but not MSD-SCT recipients, previous CMV DNAemia was associated with a lower cumulative incidence of acute graft-versus-host disease (49.2% vs. 72.6%, p < 0.001). CMV DNAemia did not play a role in the relapse rate, but it was strongly associated with an increased risk of non-relapse mortality either in total cohort of recipients (30.5% vs. 13.7%; p = 0.003) or in the HID-SCT subgroup (36.0% vs. 16.7%; p = 0.030). Relapse-free survival and overall survival in total cohort of recipients with CMV DNAemia were both inferior to those without CMV DNAemia (45.3% vs. 57.6% and 54.8% vs. 65.8%, respectively; both p < 0.05). However, in subgroup analysis according to donor's type, neither relapse-free survival nor overall survival was impacted by CMV status (both p > 0.05). This study addressed differences in incidence, risk factors, and associations with clinical outcomes of CMV reactivation after haploidentical versus matched-sibling PBSCT.
Assuntos
Infecções por Citomegalovirus/mortalidade , Citomegalovirus/fisiologia , Neoplasias Hematológicas , Transplante de Células-Tronco de Sangue Periférico , Irmãos , Ativação Viral , Adolescente , Adulto , Aloenxertos , Criança , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
Donor lymphocyte infusion (DLI) might be used prophylactically to reduce relapse after allogeneic hematopoietic stem cell transplantation for very high-risk leukemia/lymphoma without effective targeted therapy. To compare the safety and efficacy of prophylactic DLI for prevention of relapse after allogeneic peripheral blood stem cell transplantation from haploidentical donors (HID-SCT) and matched-sibling donors (MSD-SCT) in patients with very high-risk acute myeloid leukemia (AML), we performed a retrospective analysis in a cohort of 21 HID-SCT and 13 MSD-SCT recipients, displaying similar baseline characteristics except for donor's gender distribution. Grade 2-4 acute graft-versus-host disease (GVHD) at 100-day post-DLI was higher in HID-SCT group than that in MSD-SCT group (59.5% vs. 30.8%, p = 0.05). The grade 3-4 acute GVHD (17.5% vs. 7.7%), 1-year chronic GVHD (36.6% vs. 33.2%), and severe chronic GVHD (15.3% vs. 27.3%) were not statistically significant different between groups. One-year non-relapse mortality was higher in HID-SCT group than that in MSD-SCT group with marginal significance (27.9% vs. 0.0%, p = 0.061). One-year relapse rate was not statistically significant different between HID-SCT group and MSD-SCT group (21.6% vs. 36.5%, p = 0.543). For HID-SCT recipients, 1-year relapse rate was lower in patients receiving prophylactic DLI than that in a control cohort of eight patients with same very high-risk features but not receiving prophylactic DLI (62.5% vs. 28.3%, p = 0.037). No statistically significant difference was observed in 1-year overall survival (OS, 55.1% vs. 83.9%, p = 0.325) and relapse-free survival (RFS, 50.1% vs. 74.0%, p = 0.419) rates between HID-SCT group and MSD-SCT group. In multivariate analyses, non-remission status prior to transplant, poor-risk gene mutations, and donor's age ≥ 48 years predicted a higher risk of relapse after DLI. Non-remission status prior to transplant predicted inferior OS and RFS. Patient's age ≥ 40 years also predicted an inferior OS. In conclusion, prophylactic DLI was very safe and efficient for reducing relapse in patients with very high-risk AML receiving MSD-SCT. In the recipients of HID-SCT, the application of prophylactic DLI could reduce the risk of relapse, although with a higher incidence of DLI-associated acute GVHD than those of MSD-SCT.
Assuntos
Seleção do Doador , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos , Transplante de Células-Tronco de Sangue Periférico , Segurança , Irmãos , Doença Aguda , Adolescente , Adulto , Fatores Etários , Aloenxertos , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
Unmanipulated haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) has been an established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of treatment failure for patients with relapsed/refractory disease or with very high-risk gene mutations such as TP53, TET2, and DNMT3a. In this study, we aimed to establish the tolerance and efficacy of prophylactic donor lymphocyte infusion (DLI) with G-CSF-primed peripheral blood progenitors for prevention of relapse in these very high-risk patients after haplo-PBSCT. The prophylactic DLI was given at a median of 77 days after transplantation in 31 of 45 consecutive patients with very high-risk leukemia/lymphoma. The median dose of CD3+ cells for infusion was 1.8 × 107/kg. The 100-day incidences of acute graft-versus-host disease (GVHD) grades 2-4 and 3-4 after DLI were 55.3% and 10.2%. The 2-year incidences of chronic GVHD and severe chronic GVHD were 52.0% and 18.2%. The 2-year incidences of non-relapse mortality and relapse were 33.1% and 32.5%. The 2-year probabilities of overall survival and relapse-free survival were 40.1% and 31.9%. Poor-risk gene mutations (p = 0.029), disease in non-remission status prior to transplantation (p = 0.005), and donors older than 40 years of age (p = 0.043) were associated with relapse after DLI. In multivariate analysis, disease in non-remission status prior to transplantation was an independent risk factor of relapse (hazard ratio = 4.079; p = 0.035). These data showed the feasibility of the prophylactic DLI in the haplo-PBSCT setting and the anti-leukemic efficacy in very high-risk leukemia/lymphoma.
Assuntos
Doadores de Sangue , Doença Enxerto-Hospedeiro/prevenção & controle , Leucemia/prevenção & controle , Transfusão de Linfócitos , Linfoma/prevenção & controle , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Incidência , Leucemia/genética , Leucemia/mortalidade , Linfoma/genética , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/genética , Recidiva , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
In allogeneic hematopoietic stem cell transplantation recipients, reactivation of Epstein-Barr virus (EBV) can cause post-transplantation lymphoproliferative disorder (PTLD), which may rapidly progress to multiorgan failure and even death. Development of EBV PTLD correlates very closely with use of anti-thymocyte globulin (ATG) and type of transplant. To assess the incidences and clinical features of EBV DNAemia and PTLD in the setting of stem cell transplantation using unmanipulated G-CSF-primed allogeneic peripheral blood stem cells as graft, we performed a retrospective analysis of stem cell transplantation from HLA-matched sibling donors (MSD-SCT, n = 90) or HLA-haploidentical related donors (HID-SCT, n = 110) in patients with hematological malignancies. All of HID-SCT recipients and 27.8% of MSD-SCT recipients received an ATG-containing conditioning regimen. One-year cumulative incidence of EBV DNAemia was 44.1%, ranging from 4.8% in MSD-SCT recipients not using ATG to 20.0% in MSD-SCT recipients using ATG, and 73.7% in HID-SCT recipients. Risk factors for EBV reactivation included use of ATG (p = 0.008), male donor (p = 0.034), and cytomegalovirus DNAemia (p < 0.001). One-year incidence of EBV PTLD was 11.9%, ranging from 1.8% in recipients of MSD-SCT not using ATG to 4.4% in recipients of MSD-SCT using ATG, and 23.5% in recipients of HID-SCT. Risk factors for PTLD after HID-SCT included in fludarabine-containing conditioning regimen (p = 0.010), cytomegalovirus DNAemia (p = 0.036), and patient's age < 40-yr (p = 0.032). Two-year non-relapse mortality was higher for patients with EBV DNAemia than those without EBV DNAemia (35.8% vs. 15.3%, p = 0.002). One-year relapse-free survival and overall survival among patients with PTLD were 40.2% and 44.9%, respectively, as opposed to 63.4% and 68.4% among patients without PTLD (both p < 0.05). In multivariate analyses, EBV DNAemia predicted a lower risk of relapse (p = 0.025), while PTLD was a marginally significant predictor of relapse (p = 0.092). This study identified patients at risk of EBV reactivation and PTLD after unmanipulated allogeneic peripheral blood stem cell transplantation.
Assuntos
DNA Viral/sangue , Infecções por Vírus Epstein-Barr , Neoplasias Hematológicas , Herpesvirus Humano 4/metabolismo , Transtornos Linfoproliferativos , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Adolescente , Adulto , Aloenxertos , Criança , Intervalo Livre de Doença , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/terapia , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virologia , Humanos , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Irmãos , Taxa de SobrevidaRESUMO
The features of graft-versus-host disease (GVHD) were compared between patients who underwent myeloablative conditioning and received a peripheral blood stem cell transplant (PBSCT) from either a haploidentical donor (HID) or a matched sibling donor (MSD) during the same period of time. The HID group included more patients with advanced disease. Both groups received the same GVHD prophylaxis with the addition of antithymoglobulin (ATG) in HID group. Higher cumulative incidences (CI) of acute GVHD grade 2-4 (35·1% vs. 13·9%, P = 0·003), similar CI of grade 3-4 (14·5% vs. 9·8%, P = 0·595), less 3-year CI of extensive chronic GVHD (17·1% vs. 41·5%, P = 0·017) and less severe chronic GVHD (5·8% vs. 21·2%, P = 0·049) occurred in the HID group compared with the MSD group. There was no difference in the sites of the involved organs between these two groups. Higher 3-year CI of non-relapse mortality (24·0% vs. 10·2%, P = 0·014), relapse (39·0% vs. 22·6%, P = 0·032) and inferior disease-free survival (45·7% vs. 78·9%, P = 0·000) were recorded in the HID cohort compared with the MSD group. More HID patients had Karnofsky scores above 90 than those in MSD group (P = 0·016). In conclusion, ATG plays a key role in the unmanipulated HID PBSCT protocol, producing better quality of life in survivors.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/terapia , Histocompatibilidade , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Adolescente , Adulto , Soro Antilinfocitário/uso terapêutico , Criança , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Incidência , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/métodos , Qualidade de Vida , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Adulto JovemRESUMO
The best donor for a related donor for a human leukocyte antigen (HLA) haplotype-mismatched transplant for hematological neoplasms is controversial. We studied outcomes in 1210 consecutive transplant recipients treated on a uniform protocol. Younger donors and male donors were associated with less nonrelapse mortality (NRM; hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.01-0.39; P = .008 and HR = 0.65; 95% CI = 0.49-0.85; P = .002) and better survival (HR = 0.73; 95% CI = 0.54-0.97; P = .033 and HR = 0.73; 95% CI = 0.59-0.91; P = .005). Father donors were associated with less NRM (HR = 0.65; 95% CI = 0.45-0.95; P = .02), acute graft-versus-host disease (GVHD) (HR = 0.69; 95% CI = 0.55-0.86; P = .001), and better survival (HR = 0.66; 95% CI = 0.50-0.87; P = .003) compared with mother donors. Children donors were associated with less acute GVHD than sibling donors (HR = 0.57; 95% CI = 0.31-0.91; P = .01). Older sister donors were inferior to father donors with regard to NRM (HR = 1.87; 95% CI = 1.10-3.20; P = .02) and survival (HR = 1.59; 95% CI = 1.05-2.40; P = .03). Noninherited maternal antigen-mismatched sibling donors were associated with the lowest incidence of acute GVHD compared with parental donors and noninherited paternal antigen-mismatched sibling donors. Specific HLA disparities were not significantly correlated with transplant outcomes. Our data indicate which HLA haplotype-mismatched related donors are associated with the best transplant outcomes in persons with hematological neoplasms.
Assuntos
Antígenos HLA , Teste de Histocompatibilidade , Doadores Vivos , Imunologia de Transplantes , Adulto , Seleção do Doador , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Haplótipos , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pais , Irmãos , Transplante/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective post-consolidation therapy and curative option for adult patients with Philadelphia chromosome-negative (Ph-negative) acute lymphoblastic leukemia (ALL) in first complete remission (CR1). A human leukocyte antigen (HLA)-haploidentical related donor (haplo-RD) is one of the most important alternative sources for those without HLA-identical sibling donor (ISD). The present study aimed to evaluate the outcomes of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in adult Ph-negative ALL CR1 patients (n = 183). We produced an unmanipulated haplo-HSCT protocol including granulocyte colony stimulating factor (G-CSF) for all donors, intensive immune suppression, anti-thymocyte globulin, and combination of G-CSF-primed bone marrow harvest and G-CSF-mobilized peripheral blood stem cells harvest as the source of stem cell grafts. The median age for high-risk versus low-risk groups were 29 versus 23 years. Three-year incidences of relapse mortality and nonrelapse mortality for high-risk versus low-risk groups were 7.1% versus 11.1% (p = 0.498) and 18.0% versus 16.2% (p = 0.717), respectively. Three-year probabilities of disease-free survival and overall survival for high-risk versus low-risk groups were 67.6% versus 68.2% (p = 0.896) and 74.9% versus 72.7% (p = 0.981), respectively. Multivariate analysis showed that limited cGVHD and a lower pre-HSCT comorbidity burden were associated with better outcomes. In summary, comparable outcomes were observed among high- and low-risk Ph-negative ALL CR1 patients after haplo-HSCT. Haplo-RD could be considered for adults with Ph-negative ALL in CR1 as an important alternative source of donors in cases when no ISD is available.
Assuntos
Haplótipos , Transplante de Células-Tronco Hematopoéticas , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Recidiva , Fatores de Risco , Quimeras de Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
We aimed to improve the outcome of t(8;21) acute myeloid leukemia (AML) in the first complete remission (CR1) by applying risk-directed therapy based on minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels. Risk-directed therapy included recommending allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk patients and chemotherapy/autologous-HSCT (auto-HSCT) for low-risk patients. Among 116 eligible patients, MRD status after the second consolidation rather than induction or first consolidation could discriminate high-risk relapse patients (P = .001). Allo-HSCT could reduce relapse and improve survival compared with chemotherapy for high-risk patients (cumulative incidence of relapse [CIR]: 22.1% vs 78.9%, P < .0001; disease-free survival [DFS]: 61.7% vs 19.6%, P = .001), whereas chemotherapy/auto-HSCT achieved a low relapse rate (5.3%) and high DFS (94.7%) for low-risk patients. Multivariate analysis revealed that MRD status and treatment choice were independent prognostic factors for relapse, DFS, and OS. We concluded that MRD status after the second consolidation may be the best timing for treatment choice. MRD-directed risk stratification treatment may improve the outcome of t(8;21) AML in CR1. This trial was registered at http://www.chictr.org as #ChiCTR-OCH-12002406.
Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Translocação Genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Quimioterapia de Consolidação , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Prognóstico , Indução de Remissão , Medição de Risco , Análise de Sobrevida , Adulto JovemRESUMO
Delayed platelet engraftment (DPE) is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This phenomenon is also a predictor of increased treatment-related mortality and poor survival. Therefore, therapies that promote platelet engraftment to prevent DPE are needed. This prospective randomized controlled trial was designed to investigate whether recombinant human thrombopoietin (rhTPO), administered subcutaneously at a daily dose of 15,000 U from the first day after transplantation, promotes platelet engraftment after haploidentical HSCT. The cumulative incidence of platelet engraftment (platelet recovery to ≥20 × 10(9)/L without transfusion support for seven consecutive days) on day 60 post-transplantation was significantly higher in the rhTPO group (n = 60) than in the control group (n = 60) (91.7 ± 3.8 % vs. 74.5 ± 5.8 %, P = 0.041). Additionally, the number of platelet transfusions from day 14 to day 60 was significantly lower in the rhTPO group than in the control group (4 ± 5 vs. 7 ± 9 Units, P = 0.018). No severe adverse effects were observed, with a median follow-up duration of 256 days (range, 48-586 days). The incidences of acute graft-versus-host disease (GVHD), chronic GVHD, and cytomegalovirus viremia and the probabilities of overall survival and disease-free survival did not differ between the two groups. A multivariate analysis of all patients revealed that regardless of assignment to the rhTPO group or the control group (hazard ratio (HR) = 1.514; 95 % CI (1.024-2.238); P = 0.038), the number of total infused CD34(+) cells (HR = 1.304; 95 % CI (1.148-1.482); P < 0.001) and slower neutrophil engraftment (HR = 2.777; 95 % CI (1.841-4.189); P < 0.001) were associated with platelet engraftment. In conclusion, rhTPO promotes platelet engraftment and safely reduces the requirement for platelet transfusion in patients after unmanipulated haploidentical HSCT. This trial was registered with the Chinese Clinical Trial Registry ( www.chictr.org ) as ChiCTR-TRC-11001774. http://www.chictr.org/cn/proj/show.aspx?proj=2132 .
Assuntos
Plaquetas/fisiologia , Haploidia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Trombopoetina/administração & dosagem , Adolescente , Adulto , Feminino , Seguimentos , Neoplasias Hematológicas/diagnóstico , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Adulto JovemRESUMO
To compare the impacts of low-dose methotrexate (MTX) with cyclosporine (CSA) on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after haploidentical modified donor lymphocyte infusion (DLI). Fifty-five consecutive patients who had relapsed acute leukemia after haploidentical hematopoietic stem cell transplantation (HSCT) and received modified DLI were retrospectively studied. Forty-one patients received CSA and 14 received low-dose MTX after DLI to prevent DLI-associated GVHD. The incidence of acute GVHD and grade 2-4 acute GVHD in MTX group showed a trend toward being higher than in CSA group (61.0% vs. 37.3%, p = 0.198 and 61.0% vs. 35.5%, p = 0.155). However, no significant difference in the incidence of grade 3-4 acute GVHD between two groups (p = 0.982) was observed. Moreover, compared with CSA, patients treated with MTX had lower re-relapse rate (38.1% vs. 80.8%, p = 0.029), better disease-free survival (DFS) (51.9% vs. 15.6%, p = 0.06), and higher absolute lymphocyte counts at 30, 45, 60, and 90 d after modified DLI (p < 0.05). This study suggested that after haploidentical modified DLI, low-dose MTX is at least as effective as CSA in the prevention of DLI-associated GVHD and probably allowed stronger GVL effect than CSA. This phenomenon was probably due to a direct antitumor effect and a better reconstitution of lymphocytes after modified DLI induced by low-dose MTX.
Assuntos
Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Transfusão de Linfócitos/efeitos adversos , Metotrexato/uso terapêutico , Adolescente , Adulto , Criança , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
To evaluate the prognostic value of the expression of the mixed lineage leukemia (MLL) gene for predicting the relapse of patients with MLL-rearranged acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the levels of MLL transcripts in bone marrow (BM) specimens were monitored serially by real-time quantitative polymerase chain reaction (RQ-PCR) at predetermined time points in 40 patients with MLL-rearranged AL who were treated with allo-HSCT. These patients were followed for a median of 24.5 months (range, 8 to 60 months). A total of 236 BM samples were collected and analyzed. Of these, 230 were monitored concurrently for minimal residual disease (MRD) by flow cytometry (FCM) for leukemia-associated aberrant immune phenotypes and by RQ-PCR for the expression of the Wilms tumor (WT1) gene. The 3-year cumulative incidence of relapse in patients who experienced MLL-positive patients (MLL > .0000%) (n = 9) after HSCT was 93.5% (95% confidence interval [CI], 87% to 100%) compared with 12.5% (95% CI, 5.6% to 19.4%) for MLL-negative patients (n = 31) (P < .001). For these 2 patient groups, the 3-year overall survival (OS) was 12.5% (95% CI, .8% to 24.2%) and 77.8% (95% CI, 68.4% to 87.2%) (P < .001), respectively, and the 3-year leukemia-free survival (LFS) was 0% and 72.2% (95% CI, 61.1% to 83.3%), respectively (P < .001). MLL positivity was associated with a higher rate of relapse (hazard ratio [HR], 18.643; 95% CI, 3.449 to 57.025; P = .001), lower LFS (HR, 7.267; 95% CI, 2.038 to 25.916; P = .002), and lower OS (HR, 8.259; 95% CI, 2.109 to 32.336; P = .002), as determined by Cox multivariate analysis. The expression of the MLL gene had a higher specificity and sensitivity than WT1 or MRD monitored by FCM for predicting the relapse of the patients with MLL + AL. Our results suggest that monitoring the expression of the MLL gene may help to identify patients with MLL + AL who are at high risk of relapse after allo-HSCT and may provide a guide for suitable intervention.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Aguda Bifenotípica/terapia , Proteína de Leucina Linfoide-Mieloide/biossíntese , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Leucemia Aguda Bifenotípica/genética , Leucemia Aguda Bifenotípica/metabolismo , Leucemia Aguda Bifenotípica/patologia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Fatores de Risco , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Adulto JovemRESUMO
We examined the incidence, risk factors, treatment, and clinical outcomes of extramedullary relapse (EMR) in 961 acute leukemia patients undergoing HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) between 2002 and 2013. Multiple control subjects were selected at random from the same cohort and matched to EMR cases for diagnosis, disease status at HSCT, age at the time of the HSCT, and year of HSCT. Forty patients exhibited EMR, with a median time to EMR of 207 days. The cumulative incidence of EMR was 4.0% at 3 years, and the incidence was higher in acute lymphoblastic leukemia patients compared with acute myeloid leukemia patients (5.6% versus 2.4%). In the multivariate analysis, non-complete remission (CR) status at HSCT (hazard ratio [HR] = 4.6; P = .018) and non-chronic graft-versus-host disease after HSCT (HR = 3.2; P < .001) were the independent risk factors for EMR after haplo-HSCT. Twenty-seven patients received combination treatments, and the proportion of patients who achieved CR was higher than those who received single treatment. Multifocal involvement at EMR (HR = 2.7; P = .024) and non-CR after EMR treatments (HR = 4.6; P < .001) were the independent risk factors for poor survival rates among EMR patients. We found that graft-versus-leukemia effect may help to prevent EMR after haplo-HSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Efeito Enxerto vs Leucemia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Taxa de SobrevidaRESUMO
We wanted to compare the efficacy of haploidentical hematopoietic stem cell transplantation (HSCT) with chemotherapy alone in adults with standard-risk acute lymphoblastic leukemia (ALL) in first complete remission (CR1). One hundred thirty-eight consecutive adult patients with standard-risk ALL in CR1 were retrospectively investigated. Of these patients, 59 received chemotherapy alone (group A) and 79 received unmanipulated haploidentical HSCT (group B). Cumulative incidence of relapse at 5 years in group A was significantly higher than that in group B (66.3% versus 29.9%, P < .0001). Overall and disease-free survival in group A were significantly inferior to group B (P < .0001). Moreover, multivariate analyses demonstrated that central nervous system leukemia (P = .002), T cell immunophenotype (P = .044), expression of E2A-PBX1 (P = .007), and positive minimal residual disease after the first cycle of consolidation (P = .004) were correlated with relapse. Patients with 1 of 4 risk factors were assigned to the high-risk group. Otherwise, patients without risk factors were assigned to the low-risk group. In the high-risk group, HSCT had lower relapse rates and superior DFS compared with chemotherapy (P < .05), but in the low-risk group, there were no differences between HSCT and chemotherapy (P > .05). This study is the first to demonstrate that compared with chemotherapy alone, haploidentical HSCT is a better postremission therapy in adults with standard-risk ALL in CR1. Moreover, based on the 4 risk factors, the establishment of risk stratification could identify the subgroup of patients with a higher risk of relapse in adults with standard-risk ALL in CR1. Furthermore, risk stratification-directed postremission therapies using haploidentical HSCT or chemotherapy alone not only reduce relapse rate but also avoid unnecessary treatment-related mortality and improve survival.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sobrevida , Condicionamento Pré-Transplante/mortalidade , Adulto JovemRESUMO
We studied the impact of risk stratification-directed interventions for minimal residual disease (MRD) on relapse and disease-free survival (DFS) prospectively in 814 subjects with standard-risk acute leukemia receiving allotransplantation in first or second complete remission. A total of 709 subjects were MRD(-) after transplantation (Group A); 105 subjects were MRD(+), 49 received low-dose IL-2 (Group B), and 56 received modified donor lymphocyte infusion (DLI) with or without low-dose IL-2 (Group C). Posttransplantation immune suppression for GVHD was also modified based on MRD state. The cumulative risk of relapse was significantly less and DFS was significantly better in subjects in Group C than in subjects in Group B (P = .001 and P = .002, respectively), but was not different from subjects in Group A (P = .269 and P = .688, respectively). Multivariate analyses confirmed that MRD state and modified DLI were significantly correlated with relapse (P = .000, odds ratio [OR] = 0.255 and P = .000, OR = 0.269) and DFS (P = .001, OR = 0.511 and P = .006, OR = 0.436, respectively). These data suggest that risk stratification-directed interventions with modified DLI in patients with standard-risk acute leukemia who are MRD(+) after transplantation may improve transplantation outcomes.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia/terapia , Transfusão de Linfócitos , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Recidiva , Indução de Remissão , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
We report the results of a prospective, patient self-selected study evaluating whether haploidentical related donor stem cell transplantation (HRD-HSCT) is superior to chemotherapy alone as postremission treatment for patients with intermediate- or high-risk acute myeloid leukemia (AML) in first complete remission (CR1). Among totally 419 newly diagnosed AML patients, 132 patients with intermediate- and high-risk cytogenetics achieved CR1 and received chemotherapy alone (n = 74) or HSCT (n = 58) as postremission treatment. The cumulative incidence of relapse at 4 years was 37.5% ± 4.5%. Overall survival (OS) and disease-free survival (DFS) at 4 years were 64.5% ± 5.1% and 55.6% ± 5.0%, respectively. The cumulative incident of relapse for the HRD-HSCT group was significantly lower than that for the chemotherapy-alone group (12.0% ± 4.6% vs 57.8% ± 6.2%, respectively; P < .0001). HRD-HSCT resulted in superior survival compared with chemotherapy alone (4-year DFS, 73.1% ± 7.1% vs 44.2% ± 6.2%, respectively; P < .0001; 4-year OS, 77.5% ± 7.1% vs 54.7% ± 6.3%, respectively; P = .001). Multivariate analysis revealed postremission treatment (HRD-HSCT vs chemotherapy) and high WBC counts at diagnosis as independent risk factors affecting relapse, DFS, and OS. Our results suggest that HRD-HSCT is superior to chemotherapy alone as postremission treatment for AML.
Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/cirurgia , Adolescente , Adulto , Análise Citogenética , Intervalo Livre de Doença , Feminino , Antígenos HLA/imunologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/prevenção & controle , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Late-onset hemorrhagic cystitis (LOHC) is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is primarily associated with viral infection. We prospectively quantified cytomegalovirus (CMV), BK virus (BKV), and adenovirus in urine and plasma using Q-RT-PCR in 50 consecutive patients to define the relationship between virus and LOHC. Of the 50 patients, 21 developed LOHC at a median of 29 days (range 4-64 days), with a cumulative incidence of 42% (±7.1%). The cumulative incidence of LOHC on day 100 in patients with and without CMV viremia (prior to or at the onset of LOHC) were 56.3% (±8.9%) and 16.7% (±9.1%) (P = 0.018), respectively, and it was 59.3% (±9.8%) and 21.7% (±8.8%) in patients with and without CMV viruria (prior to or at the onset of LOHC) (P = 0.021), respectively. The cumulative incidence of LOHC was also higher in patients with a plasma BKV load increased ≥3 log10 or with a urine BKV load increased ≥4 log10 than those without the increase (P < 0.001). Only one patient with LOHC was tested positive for ADV. Both the univariate and multivariate analyses showed that CMV viremia (HR = 3.461, 95% CI: 1.005-11.922, P = 0.049) and a plasma BKV load that was increased ≥3 log10 (HR = 10.705, 95%CI: 2.469-46.420, P = 0.002) were independent risk factors for the development of LOHC. We conclude that both CMV viremia and an increase of plasma BKV are independent risk factors for LOHC. And the role of CMV viremia was firstly demonstrated.
Assuntos
Cistite/etiologia , Cistite/patologia , Infecções por Citomegalovirus/complicações , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemorragia/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Cistite/epidemiologia , Infecções por Citomegalovirus/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo , Transplante Homólogo , Adulto JovemRESUMO
The purpose of this study is to define the role for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in mixed-lineage-leukemia (MLL)-rearranged acute leukemia, which is now poorly understood. A prospective, multi-center cohort study to determine whether allo-HSCT could decrease relapse rates and improve long-term survival of MLL+ leukemia patients was performed. Fifty-six consecutive patients diagnosed with MLL-rearranged acute leukemia undergoing allo-HSCT from two transplant centers in China were enrolled between October 2007 and October 2012. The trial was registered at www.chictr.org as # ChiCTR-ONC-12002739. The incidences of grades II to IV acute graft versus host disease (aGVHD) and of grades III and IV aGVHD were 28.8% (CI, 16.87-40.8%), and 14.2% (CI, 5.4-23.0%), respectively. The cumulative incidences for chronic GVHD (cGVHD) at 2 years after HSCT were 35.2% (CI, 21.2-49.2%). Up to April 30, 2013, 12 patients had relapsed and 11 died from relapse, and 37 patients were still alive without disease recurrence. The relapse and NRM rates at 3 years were 25.3% (CI, 12.7-37.9%) and 18.0% (CI, 2.6-33.4%), respectively. The probalities of overall survival and leukemia free survival were 61.8% (CI, 46.0-77.6%) and 56.3% (CI, 38.1-74.5%) at 3 years, respectively. Patients transplanted during their hematological first complete remission (CR1) had a lower relapse rate (17.9% vs. 48.1%, P = 0.03) compared with patients transplanted beyond CR1. The median overall survival for the 29 patients not receiving allo-HSCT during the study period was 145 days from diagnosis. This study showed that allo-HSCT could be a valuable treatment choice for MLL+ acute leukemia.