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1.
Cancer ; 126(3): 593-601, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31661160

RESUMO

BACKGROUND: Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification. METHODS: To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL. RESULTS: The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21). CONCLUSIONS: The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics.

2.
Br J Haematol ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674662

RESUMO

The relevance of donor-specific human leukocyte antigen (HLA) antibodies in HLA-mismatched haematopoietic cell transplant (HCT) is known, but the importance of HLA antibodies in HLA-matched HCT is unclear. We hypothesized that HLA antibodies detected before HCT would cause platelet transfusion refractoriness during HCT and investigated this in a multi-centre study. Pre-HCT samples from 45 paediatric patients with sickle cell disease (SCD) undergoing HLA-matched HCT were tested for HLA class I antibodies. The number of platelet transfusions received before day +45 was compared between those with and without antibodies. Thirteen of 45 (29%) patients had a positive HLA class I antibody screen, and these patients received significantly more platelet transfusions than patients without antibodies (median 19 vs. 7·5, P = 0·028). This platelet transfusion association remained significant when controlling for conditioning regimen. Among alloimmunized patients, there was no association between the panel-reactive antibody and the number of platelet transfusions. Patients with HLA class I antibodies also had a higher incidence of acute graft-versus-host disease (GVHD): 6/13 (46%) vs. 3/32 (9%), P = 0·011. Pre-HCT HLA class I alloimmunization is associated with increased platelet transfusion support and acute GVHD in paediatric HLA-matched HCT for SCD. Further studies are needed to investigate the pathobiology of this association.

3.
Blood ; 132(4): 362-368, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-29895667

RESUMO

Adolescents and young adults (AYAs) form a unique group of patients with newly diagnosed acute myeloid leukemia (AML). They differ in terms of disease biology, psychosocial challenges, survival, and in other important respects from children as well as from middle-aged and older adults. AYAs may be treated using pediatric protocols developed in trials composed primarily of younger patients, or using adult protocols developed in trials composed primarily of older patients. After reviewing the distinguishing characteristics of AYAs with AML, we compare and contrast the chemotherapy approaches and argue that neither the pediatric nor adult approaches may be ideally suited for AYAs and the development of AYA-specific approaches merits further consideration. We finish by putting forth ideas for future research to optimize chemotherapy treatment of AYAs with AML.


Assuntos
Tomada de Decisões , Leucemia Mieloide Aguda/terapia , Guias de Prática Clínica como Assunto/normas , Adolescente , Adulto , Gerenciamento Clínico , Humanos , Leucemia Mieloide Aguda/patologia , Fatores de Risco , Adulto Jovem
5.
Pediatr Dev Pathol ; 20(3): 224-231, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28521628

RESUMO

Objective We observed that pediatric patients with B lymphoblastic leukemia which expressed CD36 at diagnosis seemed to have worse outcome than patients whose blasts did not. Here, we describe the patient, disease characteristics, pathological, molecular, and genetic features and outcomes of patients with CD36+ B-LL compared to patients with CD36- B-LL. Methods We retrospectively reviewed all flow cytometry reports from September 2008 to December 2015 to identify patients diagnosed at our institution with CD36 expression on B lymphoblasts. CD36- control patients were chosen from our leukemia database and matched 2:1 to CD36+ patients for National Cancer Institute (NCI) risk group at diagnosis. We reviewed diagnostic marrow slides for cytoplasmic granules and abstracted clinical data from patient charts. To identify underlying genetic abnormalities, clinical FISH testing and RNA sequencing was performed on 5 of our CD36+ patients, and RNA-seq data from the NIH Therapeutically Applicable Research to Generate Effective Treatments (TARGET) ALL Expansion Phase 2 data set were examined. Results Twenty-five of 366 (6.83%) patients diagnosed at our institution in the study period had CD36+ blasts. With a median follow-up of 5.32 years, 5-year event-free survival (EFS) and overall survival (OS) were significantly worse for CD36+ patients compared to CD36- patients who were NCI Standard Risk at diagnosis (EFS: 60% ± 15.49 vs 95% ± 4.87, P = .016; OS: 90% ± 9.5 vs 100%, P = .019). NCI Standard Risk patients whose blasts were both CD36+ and had granules had the worst survival compared to CD36- patients without granules (EFS 25% ± 21.65 vs 95% ± 4.87, P = .0004). From our CD36+ patients and the TARGET database, we found 2 ABL2 mutations, 1 PDGFRB mutation, and 2 NRAS mutations. Conclusions For NCI Standard Risk patients, CD36 expression on B-lymphoblasts identifies patients with B-LL who have especially poor outcome. This may be due to underlying genetic abnormalities that may be amenable to targeted therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Antígenos CD36/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Adolescente , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
6.
Transfusion ; 56(9): 2267-73, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27385599

RESUMO

BACKGROUND: Alloimmunization to red blood cell (RBC) antigens after transfusion is well described in patients with sickle cell disease (SCD). We recently demonstrated that leukocyte-reduced RBC transfusions appeared to induce human leukocyte antigen (HLA) antibodies in some children with SCD; now, we hypothesize that residual platelets contained in transfused RBC products may lead to platelet glycoprotein antibody formation. STUDY DESIGN AND METHODS: A cross-sectional study was conducted among never pregnant pediatric patients with SCD who either had received many RBC transfusions or had never received any transfusions. Serum was tested for antibodies to platelet-specific glycoproteins using a commercial enzyme immunoassay. RESULTS: Platelet-specific glycoprotein antibodies were found in 12 of 90 patients (13%) in the transfused group versus 5 of 24 patients (21%) in the never transfused group (p = 0.35). The prevalence of antibodies as well as the median standardized optical density for these two groups was not significantly different for any of the studied platelet glycoprotein antigens. There was no association with the presence of platelet-specific glycoprotein antibodies with either RBC or HLA antibodies. CONCLUSIONS: Leukocyte-reduced RBC transfusions do not appear to induce platelet-specific glycoprotein antibodies. The positive platelet-specific glycoprotein antibody results from this study may represent platelet autoantibodies, platelet alloantibodies, or false-positive reactions. A better understanding of the immunobiology of patients with SCD at baseline and after blood product exposure may help improve future transfusion and transplantation.


Assuntos
Anemia Falciforme/sangue , Anticorpos/sangue , Anticorpos/imunologia , Transfusão de Eritrócitos/métodos , Glicoproteínas da Membrana de Plaquetas/imunologia , Autoanticorpos/imunologia , Plaquetas/imunologia , Estudos Transversais , Humanos , Isoanticorpos/imunologia
7.
Pediatr Blood Cancer ; 63(5): 908-13, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26757445

RESUMO

BACKGROUND: Splenic dysfunction is a significant complication of sickle cell disease (SCD). Hematopoietic stem cell transplant (HSCT) is a proven cure for SCD; however, its long-term effect on splenic function is not well characterized. PROCEDURE: We conducted a retrospective cohort study of pediatric patients who had HSCT for SCD at two transplant centers. (99m) Tc liver-spleen (LS) scans were blindly reviewed and classified as demonstrating absent, decreased, or normal splenic uptake. RESULTS: Considering all engrafted nonsplenectomized Hb SS and Sß(0) -thalassemia patients with LS scans available, at a median of 2.0 years post-HSCT (range 1.0-9.3 years) eight of 53 (15%) had normal, 40 of 53 (75%) decreased, and five of 53 (9%) absent splenic uptake. More patients had splenic uptake after HSCT: pre-HSCT 14/38 (37%) versus post-HSCT 34/38 (89%), P < 0.0001. Older age at HSCT was associated with worse splenic function post-HSCT (median age at HSCT for absent uptake 16.6 years vs. present uptake 8.0 years, P = 0.030). Extensive chronic GVHD was also more common in patients with absent splenic uptake compared to patients with present uptake (absent 40% vs. present 6%, P = 0.064). CONCLUSIONS: HSCT significantly improves splenic function for most pediatric patients with SCD, but older patient age at time of HSCT and extensive chronic GVHD appear to be risk factors for poor post-HSCT splenic function.


Assuntos
Anemia Falciforme , Transplante de Células-Tronco Hematopoéticas , Recuperação de Função Fisiológica , Baço , Adolescente , Fatores Etários , Aloenxertos , Anemia Falciforme/diagnóstico por imagem , Anemia Falciforme/fisiopatologia , Anemia Falciforme/terapia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Fígado/diagnóstico por imagem , Fígado/fisiopatologia , Masculino , Cintilografia , Estudos Retrospectivos , Baço/diagnóstico por imagem , Baço/fisiopatologia
8.
Am J Hematol ; 90(12): 1135-41, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26361243

RESUMO

Alloimmunization against red blood cell (RBC) antigens is a cause of morbidity and mortality in transfused patients with sickle cell disease (SCD). To investigate distinguishing characteristics of patients who develop RBC alloantibodies after transfusion (responders) versus those who do not (non-responders), a cross-sectional study of 90 children with SCD on chronic RBC transfusion therapy at a single institution was conducted in which 18 immune parameters (including T and B cell subsets) were tested via flow cytometry, and medical records were reviewed. RBC alloimmunization was present in 26/90 (29%) patients, with anti-E, K, and C among the most commonly detected alloantibodies despite prophylactic matching for these antigens at the study institution. In addition, RBC autoantibodies had been detected in 18/26 (69%) of alloimmunized versus 7/64 (11%) of non-alloimmunized patients (P < 0.0001). Alloimmunized patients were significantly older (median 13.0 years vs. 10.7 years, P = 0.010) and had more RBC unit exposures (median 148 U vs. 82 U, P = 0.020) than non-alloimmunized patients. Sex, age at initiation of chronic transfusion, splenectomy, stroke, and transfusion outside of the study institution were not significantly associated with RBC alloimmunization. Alloimmunized patients had a significantly increased percentage of CD4+ T memory cells compared to non-alloimmunized patients (57% vs. 49%, P = 0.0047), with no other significant differences in immune cell subsets or laboratory values detected between these groups. Additional research of RBC alloimmunization is needed to optimize transfusion therapy and to develop strategies to prevent alloimmunization.


Assuntos
Anemia Falciforme/sangue , Transfusão de Eritrócitos/métodos , Imunofenotipagem/métodos , Isoanticorpos/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Adulto Jovem
9.
Mini Rev Med Chem ; 16(3): 193-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26202191

RESUMO

Graft versus host disease (GVHD) remains a major life threatening complication and one of the primary barriers to successful allogeneic hematopoietic stem cell transplantation, limiting its application in nonmalignant conditions. Immunosuppression is used for prevention and treatment of GVHD, dampening the graft versus leukemia effect. Intestinal bacteria play a major role in inflammation and augmenting the GVHD cytokine response. Early studies in murine models showed that manipulating the presence of intestinal flora or counteracting its byproducts could limit GVHD. Thus multiple clinical trials targeting gut decontamination were conducted, with the aims of modulating inflammation and protecting against GVHD, with mixed results. More recent work has improved our understanding of the role of intestinal microbiota in the maintenance of innate immunity, mucosal integrity and limiting inflammation. This review offers a summary of this data, with a discussion of potential therapeutic interventions manipulating the intestinal microbiota.


Assuntos
Microbioma Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/microbiologia , Imunidade Inata , Doença Enxerto-Hospedeiro/patologia , Humanos
10.
Blood ; 125(25): 3835-50, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-25852054

RESUMO

Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8(+) effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31(+)/CD4(+) putative thymic emigrants. T-cell receptor ß (TCRß) deep sequencing revealed a striking contraction of CD8(+) Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Ativação Viral/imunologia , Adolescente , Adulto , Idoso , Criança , Feminino , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
11.
Br J Haematol ; 170(2): 247-56, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25891976

RESUMO

Blood transfusions can induce alloantibodies to antigens on red blood cells (RBCs), white blood cells and platelets, with these alloantibodies affecting transfusion and transplantation. While transfusion-related alloimmunization against RBC antigens and human leucocyte antigens (HLA) have been studied, transfusion-related alloimmunization to minor histocompatibility antigens (mHA), such as H-Y antigens, has not been clinically characterized. We conducted a cross-sectional study of 114 children with sickle cell disease (SCD) and tested for antibodies to 5 H-Y antigens and to HLA class I and class II. Few patients had H-Y antibodies, with no significant differences in the prevalence of any H-Y antibody observed among transfused females (7%), transfused males (6%) and never transfused females (4%). In contrast, HLA class I, but not HLA class II, antibodies were more prevalent among transfused than never transfused patients (class I: 33% vs. 13%, P = 0·046; class II: 7% vs. 8%, P = 0·67). Among transfused patients, RBC alloantibody history but not amount of transfusion exposure was associated with a high (>25%) HLA class I panel reactive antibody (Odds ratio 6·8, 95% confidence interval 2·1-22·3). These results are consistent with immunological responder and non-responder phenotypes, wherein a subset of patients with SCD may be at higher risk for transfusion-related alloimmunization.


Assuntos
Anemia Falciforme/imunologia , Anemia Falciforme/terapia , Transfusão de Eritrócitos , Antígeno H-Y/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Isoanticorpos/imunologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Transfusão de Eritrócitos/efeitos adversos , Feminino , Humanos , Imunofenotipagem , Isoanticorpos/sangue , Masculino , Razão de Chances , Adulto Jovem
12.
Br J Haematol ; 169(4): 574-83, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25753210

RESUMO

Sickle cell disease (SCD) is increasingly appreciated as an inflammatory condition associated with alterations in immune phenotype and function. In this cross-sectional study we performed a multiparameter analysis of 18 immune markers in 114 paediatric SCD patients divided by treatment group [those receiving hydroxycrabamide (HC, previously termed hydroxyurea), chronic transfusion (CT), or no disease-modifying therapy] and 29 age-matched African American healthy controls. We found global elevation of most immune cell counts in SCD patients receiving no disease-modifying therapy at steady state. Despite the decrease in percentage of haemoglobin S associated with CT therapy, the abnormal cellular immune phenotype persisted in patients on CT. In contrast, in both univariate and multivariate analysis, treatment with HC was associated with normalization of the vast majority of leucocyte populations. This study provides additional support for HC treatment in SCD, as it appears that HC decreases the abnormally elevated immune cell counts in patients with SCD.


Assuntos
Anemia Falciforme/imunologia , Anemia Falciforme/terapia , Antidrepanocíticos/administração & dosagem , Transfusão de Sangue , Hidroxiureia/administração & dosagem , Leucócitos/imunologia , Adolescente , Afro-Americanos , Anemia Falciforme/sangue , Criança , Seguimentos , Humanos , Contagem de Leucócitos
13.
Biol Blood Marrow Transplant ; 21(5): 900-5, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25617808

RESUMO

High-dose busulfan, cyclophosphamide, and antithymocyte globulin (BU-CY-ATG) is the most commonly used conditioning regimen in HLA-matched related hematopoietic cell transplantation for children with sickle cell disease. Disease-free survival with this regimen is now approximately 95%; however, it produces significant morbidity. We hypothesized we could create a less toxic regimen by adding fludarabine (FLU) to BU-CY-ATG and reduce the dosages of busulfan and cyclophosphamide. We conducted a multicenter dose de-escalation trial with the objective of decreasing the doses of busulfan and cyclophosphamide by 50% and 55%, respectively. Using day +28 donor-predominant chimerism as a surrogate endpoint for sustained engraftment, we completed the first 2 of 4 planned levels, enrolling 6 patients at each and reducing the total dose of cyclophosphamide from 200 mg/kg to 90 mg/kg. On the third level, which involved a reduction of i.v. busulfan from 12.8 mg/kg to 9.6 mg/kg, the first 2 patients had host-predominant T cell chimerism, which triggered trial-stopping rules. All 14 patients survive disease-free. No patients suffered severe regimen-related toxicity. Our results suggest BU-FLU-CY-ATG using lower dose CY could be a less toxic yet effective regimen. Further evaluation of this regimen in a full-scale clinical trial is warranted.


Assuntos
Anemia Falciforme/terapia , Soro Antilinfocitário/administração & dosagem , Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adolescente , Aloenxertos , Criança , Pré-Escolar , Humanos , Vidarabina/administração & dosagem
14.
Biol Blood Marrow Transplant ; 20(7): 1056-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24641826

RESUMO

Impairment of gut mucosal immunity by the transplant process could facilitate translocation of commensal bacteria and thereby augment the graft-versus-host response. To begin to assess the influence of gut mucosal immunity on the development of acute graft-versus-host disease (GVHD), we conducted a prospective study in 24 pediatric allogeneic hematopoietic cell transplant recipients, assessing 4 fecal markers of mucosal immunity: calprotectin, soluble CD8 (sCD8), soluble intracellular adhesion molecule 1, and ß-defensin-2. Stool samples were collected prospectively on transplant days 0, +5, +10, and +15 and analyzed by ELISA. Lower levels on day +5 (calprotectin and ß-defensin-2) and day +10 (calprotectin, ß-defensin-2, and sCD8) were associated with subsequent acute GVHD. The most striking difference was with calprotectin on day +10. Patients with levels below 424 mg/kg had an incidence of 77.8%, whereas those with levels above this threshold had a cumulative incidence of 0% (P = .002). Relative defects in gut mucosal immunity may be important in the pathogenesis of acute GVHD.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Aguda , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Imunidade nas Mucosas , Lactente , Masculino , Transplante Homólogo , Adulto Jovem
15.
Pediatr Blood Cancer ; 61(6): 1126-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24391118

RESUMO

We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy-eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL.


Assuntos
Síndrome de Down/complicações , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Adolescente , Adulto , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Criança , Pré-Escolar , Terapia Combinada , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Predisposição Genética para Doença , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Lactente , Estimativa de Kaplan-Meier , Doadores Vivos , Agonistas Mieloablativos/efeitos adversos , Agonistas Mieloablativos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recidiva , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Irradiação Corporal Total/efeitos adversos
16.
Blood ; 123(10): 1615-20, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24435046

RESUMO

The safety and efficacy of reduced-intensity conditioning (RIC) regimens for the treatment of pediatric acute myeloid leukemia is unknown. We compared the outcome of allogeneic hematopoietic cell transplantation in children with acute myeloid leukemia using RIC regimens with those receiving myeloablative-conditioning (MAC) regimens. A total of 180 patients were evaluated (39 with RIC and 141 with MAC regimens). Results of univariate and multivariate analysis showed no significant differences in the rates of acute and chronic graft-versus-host disease, leukemia-free, and overall survival between treatment groups. The 5-year probabilities of overall survival with RIC and MAC regimens were 45% and 48%, respectively (P = .99). Moreover, relapse rates were not higher with RIC compared with MAC regimens (39% vs 39%; P = .95), and recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%; P = .73). After carefully controlled analyses, we found that in this relatively modest study population, the data supported a role for RIC regimens for acute myeloid leukemia in children undergoing allogeneic hematopoietic cell transplantation. The data also provided justification for designing a carefully controlled randomized clinical trial that examines the efficacy of regimen intensity in this population.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Adolescente , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento
17.
Pediatr Blood Cancer ; 61(2): 269-75, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23955900

RESUMO

BACKGROUND: We sought to better define the role of hematopoietic cell transplantation (HCT) in first remission (CR1) for high-risk pediatric acute myeloid leukemia (AML). PROCEDURES: Outcomes were compared among patients aged less than 21 years with cytogenetically defined poor-risk AML treated with chemotherapy, matched related (MRD), or unrelated donor (URD) transplantation in CR1. Poor-risk cytogenetics was defined as monosomy 7/del7q, monosomy 5/del 5q, abnormalities of 3q, t(6;9)(p23;q34), or complex karyotype. Included are patients treated on Children's Oncology Group trials or reported to the Center for International Blood and Marrow Transplant Research from 1989 to 2006. RESULTS: Of the 233 patients, 123 received chemotherapy, 55 received MRD HCT, and 55 received URD HCT. The 5-year overall survival from the time of consolidation chemotherapy or transplant conditioning was similar: chemotherapy (43% ± 9%), MRD (46% ± 14%), or URD (50% ± 14%), P = 0.99. Similarly, multivariate analysis demonstrated no significant differences in survival [(reference group = chemotherapy); MRD HR 1.08, P = 0.76; URD HR 1.13, P = 0.67] despite lower relapse risk with URD HCT (HR = 0.43, P = 0.01). CONCLUSIONS: Our findings do not provide support for the preferential use of HCT over chemotherapy alone for children with cytogenetically defined poor-risk AML in CR1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Seleção do Doador , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Terapia Combinada , Análise Citogenética , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Doadores Vivos , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Transplante Autólogo , Doadores não Relacionados , Adulto Jovem
18.
Biol Blood Marrow Transplant ; 19(11): 1638-49, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24047754

RESUMO

We performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4(+) T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4(+) Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P < .01). The ABA patients demonstrated a low rate of aGVHD, despite robust immune reconstitution, with 2 of 10 patients diagnosed with grade II-IV aGVHD before day +100, no deaths from infection, no day +100 TRM, and with 7 of 10 evaluable patients surviving (median follow-up, 16 months). These results suggest that costimulation blockade with abatacept can significantly affect CD4(+) T cell proliferation and activation post-transplantation, and may be an important adjunct to standard immunoprophylaxis for aGVHD in patients undergoing unrelated-donor HCT.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Linfócitos T/imunologia , Condicionamento Pré-Transplante/métodos , Abatacepte , Doença Aguda , Adolescente , Adulto , Idoso , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
19.
Biol Blood Marrow Transplant ; 19(6): 893-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23467128

RESUMO

Data on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Medula Óssea , Síndrome de Down/terapia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Adolescente , Criança , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/imunologia , Síndrome de Down/mortalidade , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Recidiva , Indução de Remissão , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
20.
J Pediatr Hematol Oncol ; 35(4): e149-52, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23274384

RESUMO

In murine allogeneic hematopoietic cell transplantation models, inhibiting bacterial translocation stemming from conditioning-induced damage to the gut mucosa abrogates inflammatory stimulation of donor T cells, preventing acute graft-versus-host disease (AGVHD). We conducted a phase I trial to begin testing the hypothesis that rifaximin, a broadly acting oral antibiotic, would reduce systemic inflammation and T-cell activation. We administered rifaximin to 20 adolescents and younger adults (day -10 through day +30) receiving intensive conditioning. We measured the plasma level of interleukin-6, as a marker of conditioning-induced inflammation, and the levels of soluble tumor necrosis factor receptor-1 and soluble interleukin-2 receptor, as surrogate markers of AGVHD. We formed a historical control group (n=24), from a previous study of biomarkers in AGVHD. The increase in the treatment group's mean interleukin-6 level from baseline to day 0 was 73% less than that in the control group (P=0.006). The increase from baseline to day 15 in the treatment group's mean soluble tumor necrosis factor-1 and soluble interleukin-2 receptor levels was similar to the control group. Incidences of grade 2 to 4 AGVHD also did not differ. This suggests that rifaximin may abrogate bacterial translocation and resultant inflammation, but in alternative donor transplants this does not prevent downstream activation of donor T cells.


Assuntos
Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/prevenção & controle , Inflamação/sangue , Inflamação/prevenção & controle , Leucemia/cirurgia , Rifamicinas/uso terapêutico , Linfócitos T/efeitos dos fármacos , Doença Aguda , Adolescente , Adulto , Anti-Infecciosos/uso terapêutico , Biomarcadores/sangue , Transplante de Medula Óssea , Estudos de Casos e Controles , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Inflamação/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Leucemia/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Masculino , Receptores de Interleucina-2/sangue , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Rifaximina , Linfócitos T/imunologia , Linfócitos T/transplante , Condicionamento Pré-Transplante , Adulto Jovem
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