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1.
Artigo em Inglês | MEDLINE | ID: mdl-31537901

RESUMO

The impact of AGVHD on healthcare utilization and cost is not well described. In this retrospective single center cohort study of 240 pediatric patients, we analyzed cost, healthcare utilization and patient outcomes for the first year post-alloHCT. Costs were estimated from charges recorded in the Pediatric Health Information System database and the hospital's accounting system. The overall incidence of grade I-IV aGVHD was 40.4%. The incidence of grade I, grade II, and grade III-IV aGVHD was 6.6%, 16.2%, and 17.5%, respectively. The overall incidence of steroid refractory (SR)-aGVHD was 10.8%. The median number of days of hospitalization in the first year post-alloHCT was significantly higher for patients with aGVHD vs. no aGVHD: 113 days (range: 35-354 days) vs. 63 days (range: 25-298 days), p < 0.001. Patients with SR-aGVHD had increased hospitalization compared with the patients with steroid responsive aGVHD (152.8 ± 66.6days vs. 111.3 ± 59.3 days, p = 0.004), with associated increased alloHCT cost of ~$200,000. On multivariable analysis of risk factor for alloHCT cost, aGVHD, was associated with significantly higher cost ($141,094 [SE = 31247], p < 0.001). In summary, aGVHD and SR-aGVHD is associated with prolonged hospitalization and higher cost and inferior survival among children. Better aGVHD prevention strategies are desperately needed. Despite significant advances, lack of effective salvage regimens for SR-aGVHD remains a major concern.

2.
Curr Opin Hematol ; 26(6): 448-452, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483336

RESUMO

PURPOSE OF REVIEW: Sickle cell disease (SCD) is a common monogenic disorder that is characterized by an A to T substitution in the ß-globin gene that leads to the production of hemoglobin S (HbS). Polymerization of HbS leads to significant morbidity including vaso-occlusion, pain, hemolytic anemia, and end organ damage. Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment; however, suitable donors are not always readily available. This study reviews the current status of allo-HCT and autologous cellular therapies for SCD. RECENT FINDINGS: Alternative sources of allogeneic stem cells from unmatched donors such as cord blood and haploidentical donors are gaining traction. Early experience has shown that better conditioning regimens and graft-versus-host disease prophylaxis are needed before these donor sources can gain widespread use. Clinical trials are underway to determine the feasibility and efficacy of autologous transplantation with gene modified hematopoietic stem cells. Gene therapy strategies include HbS gene correction, gene addition, and hemoglobin F induction. Preliminary results are very encouraging. SUMMARY: Matched sibling allo-HCT for patients with SCD results in more than 90% overall survival and more than 80% event-free survival. Because only 25-30% of patients have a matched sibling donor, alternative donor options such as matched unrelated donors, related haploidentical donors and unrelated umbilical cord blood donors are being considered. Clinical trials investigating various strategies for gene therapy followed by autologous transplantation are underway. One major challenge is obtaining sufficient hematopoietic stem cells for gene therapy. Studies are being conducted on the optimal mobilization regimen and collection strategy.

3.
Blood ; 134(3): 304-316, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31043425

RESUMO

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.

4.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30502538

RESUMO

Literature on the impact of cytomegalovirus (CMV)-related hospitalization in allogeneic hematopoietic cell transplant (alloHCT) pediatric patients is limited. The aim of this study was to determine utilization and outcomes of CMV-related hospitalization in alloHCT patients using a single-center clinical database. This was a retrospective study of 240 children ages 3 months to 21 years old who were transplanted between 2005 and 2016. Impact of CMV-related length of stay (LOS) and total healthcare costs were quantified. Factors associated with prolonged CMV viremia (>25 days) were also examined. The median age of patients was 9.5 years old. In at risk CMV patients, the incidence of CMV viremia was 38% (59/155), the median time to onset was 33 days (range 0-292 days), and the median time to resolution was 25 days (range 3-148 days, n=53). CMV infection was associated with an increase in LOS of 23.3 days (p=0.004) and added hospital costs of US$45,443 (p=0.162) compared to patients without CMV infection. In multivariable analysis, alemtuzumab (p=0.027) was associated with CMV viremia >25 days. In conclusion, CMV viremia is associated with prolonged LOS and higher hospital care costs and indicates a need for improved and cost-effective CMV prevention strategies. Further study into patient outcomes and costs in alloHCT pediatric populations is needed.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30127464

RESUMO

The costs associated with allogeneic hematopoietic cell transplantation (alloHCT) are high. Differences in costs and healthcare utilization among potential donor sources for alloHCT are not well characterized in pediatric recipients of alloHCT. One potential reason for these high costs could be the donor source of hematopoietic cells. In this retrospective study, inpatient costs, outpatient costs, and markers of healthcare utilization associated with unrelated donor alloHCT for malignant and non-malignant disease were analyzed for 131 pediatric patients during the first year post-transplant, for whom the donor sources were 38% umbilical cord blood (UCB), 14% unmanipulated peripheral blood stem cell (PBSC), 26% bone marrow (BM), and 22% PBSC with CD-34 selection. The median cost per day survived (through day +365) was lowest for patients receiving PBSC with CD-34 selection $926 (322-5316) as compared to UCB $1918 (491-107,93), unmanipulated PBSC $1516 (630-27,516), and BM $1205 (506-11,181) (p = 0.010). For non-malignant alloHCT, UCB had the highest costs per day survived $1530 (491-793) and PBSC with CD-34 selection had the lowest at $482 (322-3092) (p < 0.001). In a multivariable model for costs per day survived, high-risk disease (p = 0.009) and graft failure (p < 0.001) were significantly associated with higher cost and alloHCT between 2010 and 2015 as compared to 2005 and 2009 (p = 0.017) was significantly associated with lower cost per day survived. This study illustrates important differences in cost and healthcare utilization among the different donor sources used for unrelated alloHCT.

7.
Biol Blood Marrow Transplant ; 24(10): 2040-2046, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29933069

RESUMO

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.

8.
Biol Blood Marrow Transplant ; 24(7): 1313-1321, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29653206

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) can halt organ damage and eliminate symptoms in hemoglobin disorders, including sickle cell disease (SCD) and thalassemia major. Managing the residual manifestations of pre-HCT disease complications and the long-term effects of HCT requires systematic monitoring, follow-up and intervention when indicated. Late complications vary with age and disease status at HCT and with transplant variables such as preparative regimen, donor source and compatibility, and immune reconstitution. An international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium in May 2016 entitled "Late Effects Screening and Recommendations Following HCT for Immune Deficiency and Nonmalignant Hematologic Disorders" focused on follow-up after HCT for hemoglobinopathy. An earlier publication from experts who participated in this session described the pathophysiology and spectrum of complications that HCT recipients experience after HCT for SCD and thalassemia major. This companion publication summarizes the consensus reached by this group of experts about long-term follow-up guidelines after HCT for hemoglobinopathy. In addition, these guidelines might also be included in studies of novel curative therapies such as autologous HCT after hematopoietic progenitor stem cell gene modification.

9.
Biol Blood Marrow Transplant ; 24(2): 324-329, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29074373

RESUMO

To ensure optimal clinical outcomes for patients while retaining adequate protection for donors, the National Marrow Donor Program developed guidelines specifying that up to 20 mL/kg of bone marrow can be harvested from donors. These guidelines, originally developed for unrelated adult donors, are followed in children as well. We studied the impact of granulocyte colony-stimulating factor (G-CSF) priming on the cellular composition of harvested bone marrow, sought to develop an algorithm to optimize bone marrow harvest volume from pediatric matched sibling donors, and studied the impact of CD34+ cell dose on clinical outcomes. We analyzed data from 92 bone marrow harvests and clinical outcomes for 69 sibling recipient-donor duos, The mean age of recipients was 9.85 ± 5.90 years, and that of donors was 11.85 ± 6.36 years. G-CSF priming was not associated with higher yield of CD34+ cells/µL. The median CD34+ cell count obtained from donors was 700 cells/µL (range, 400-1700 cells/µL) in donors age <6 years, 360 cells/µL (range, 100-1100 cells/µL) in donors age 6 to 12 years, and 300 cells/µL (range, 80-800 cells/µL) in donors age >12 years (P < .001). The number of CD34+ cells infused had no impact on traditional clinical outcomes; however, it was significantly related to graft-versus-host disease/relapse/rejection-free survival. Our investigation revealed that ultimately, a CD34+ cell count of approximately 3 to 5 × 106/kg was a threshold beyond which increasing CD34+ cell dose did not impact outcome. In this study, we addressed the broad question of whether harvesting up to 20 mL/kg of bone marrow from a child donor is truly necessary for optimal outcomes in every pediatric case.

10.
Am J Ophthalmol ; 183: 91-98, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28860042

RESUMO

PURPOSE: Based on standard screening techniques, sickle retinopathy reportedly occurs in 10% of adolescents with sickle cell disease (SCD). We performed a prospective, observational clinical study to determine if ultra-widefield fluorescein angiography (UWFA), spectral-domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCT-A) detect more-frequent retinopathy in adolescents with SCD. DESIGN: Cross-sectional study. METHODS: Setting: Institutional. SUBJECTS: Sixteen adolescents with SCD, aged 10-19 years (mean age 14.9 years), and 5 age-equivalent controls (mean age 17.4 years). OBSERVATION PROCEDURES: Examinations including acuity, standard slit-lamp biomicroscopy, UWFA, SD-OCT, and OCT-A were performed. MAIN OUTCOME MEASURES: Sickle retinopathy defined by biomicroscopic changes, Goldberg stages I-V, Penman scale, flow void on OCT-A, or macular thinning on SD-OCT. RESULTS: While 22 of 32 SCD eyes (68.8%) had retinopathy on biomicroscopy, by UWFA 4 of 24 (16.7%) SCD eyes had peripheral arterial occlusion (Goldberg I), and 20 of 24 eyes (83.3%) had peripheral arteriovenous anastomoses (Goldberg II) in addition. No patients had Goldberg stages III-V. By SD-OCT and OCT-A, thinning of the macula and flow voids in both the superficial and deep retinal capillary plexus were found in 6 of 30 (20%) eyes. CONCLUSIONS: All 24 eyes with adequate UWFA studies demonstrated sickle retinopathy. SD-OCT and OCT-A, which have not been previously reported in the adolescent population, detected abnormal macular thinning and flow abnormalities undetected by biomicroscopy. These findings suggest that pediatric sickle retinopathy may be more prevalent than previously suspected. If these findings are confirmed with larger cross-sectional and prospective analyses, these approaches may enhance early screening for sickle retinopathy.


Assuntos
Anemia Falciforme/complicações , Angiofluoresceinografia/métodos , Macula Lutea/patologia , Retina/patologia , Doenças Retinianas/diagnóstico , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Adolescente , Criança , Estudos Transversais , Feminino , Seguimentos , Fundo de Olho , Humanos , Masculino , Estudos Prospectivos , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Doenças Retinianas/etiologia , Vasos Retinianos/fisiopatologia , Adulto Jovem
11.
Pediatr Transplant ; 21(7)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28845921

RESUMO

HPC infusions have been associated with a variety of adverse events related to either patient or HPC product-related factors. Studies documenting infusion-related AEs in children are limited. We reviewed HPC infusion records in 354 children. Infusion-related adverse events were classified as follows: grade 0-absent, grade I-mild, grade II-moderate, grade III-severe, grade IV-life-threatening, and grade V-death. The percentage of patients with grade 0, I, and II-IV AEs was as follows: 0 = 67%, I = 23.4%, and II-V = 9.6% (one patient had fatal anaphylactic reaction to dimethyl sulfoxide). The incidence of grade II-IV hypertension was 7.1%. There was a higher incidence of AEs with infusion of allogeneic bone marrow versus allogeneic PBSCs (47.4% vs 25.3%, P = .001). Cryopreserved products had a lower incidence of infusion-associated AEs compared with fresh HPC products (24% vs 39.4%, P = .003). Allogeneic HPC infusion volume (>100 mL) was a significant risk factor for infusion-associated AEs (P < .001). Patients >10 years who received autologous HPC infusions had higher risk of AEs when compared to patients <10 years (P = .01). Our study demonstrated that despite a high incidence of infusion-associated hypertension, HPC infusion is relatively safe in children. Investigating strategies to optimize management of hypertension in the setting of HPC infusion is warranted.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adolescente , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Lactente , Infusões Intravenosas , Masculino , Neoplasias/terapia , Melhoria de Qualidade , Estudos Retrospectivos , Fatores de Risco
12.
J Pediatr Hematol Oncol ; 39(8): 618-625, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28737601

RESUMO

Sickle retinopathy reflects disease-related vascular injury of the eye, which can potentially result in visual loss from vitreous hemorrhage or retinal detachment. Here we review sickle retinopathy among children with sickle cell disease, describe the epidemiology, pediatric risk factors, pathophysiology, ocular findings, and treatment. Newer, more sensitive ophthalmological imaging modalities are available for retinal imaging, including ultra-widefield fluorescein angiography, spectral-domain optical coherence tomography, and optical coherence tomography angiography. Optical coherence tomography angiography provides a noninvasive view of retinal vascular layers that could previously not be imaged and can be quantified for comparative or prospective analyses. Ultra-widefield fluorescein angiography provides a more comprehensive view of the peripheral retina than traditional imaging techniques. Screening for retinopathy by standard fundoscopic imaging modalities detects a prevalence of approximately 10%. In contrast, these more sensitive methods allow for more sensitive examination that includes the retina perimeter where sickle retinopathy is often first detectable. Use of these new imaging modalities may detect a higher prevalence of early sickle pathology among children than has previously been reported. Earlier detection may help in better understanding the pathogenesis of sickle retinopathy and guide future screening and treatment paradigms.


Assuntos
Anemia Falciforme/complicações , Doenças Retinianas/diagnóstico , Doenças Retinianas/etiologia , Anemia Falciforme/epidemiologia , Diagnóstico por Imagem/métodos , Técnicas de Diagnóstico Oftalmológico , Humanos , Encaminhamento e Consulta , Doenças Retinianas/epidemiologia , Doenças Retinianas/terapia , Fatores de Risco
13.
Biol Blood Marrow Transplant ; 23(10): 1695-1700, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28627425

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) is curative in patients with ß-thalassemia major. However, most reports on HCT outcomes lack long-term follow-up data with the exception of single-center reports. An international multicenter retrospective data collection and analysis was conducted in 176 ß-thalassemia patients who were 1 year or beyond after first HCT to evaluate follow-up methods and outcomes at 7 centers. Median age at HCT was 5.5 years (range, .6 to 18.5), and median follow-up was 7 years (range, 1 to 20). HCT was predominantly from HLA-matched related donors (91%) with bone marrow as stem cell source (91%) and myeloablative conditioning regimens (88%). Late mortality or persistent chronic graft-versus-host disease (GVHD) was rare (<2%). Graft rejection was reported in 23% (24% of these occurred beyond 1 year) post-HCT. Of 119 patients with donor chimerism results available for ≥4 years post-HCT, 50% had >95%, 22% had 50% to 95%, 7% had 20% to 50% and 25 (21%) had <20% donor chimerism. Organ dysfunction was identified in 10% pre-HCT and in 20% post-HCT even without complete clinical details on all patients. Hypogonadism and elevated creatinine for age were most commonly reported and significantly higher in recipients ≥ 7 years at the time of HCT (P = .007) and in those with pre-existing morbidity before HCT (P = .02). Outcomes were unaffected by pre-HCT ferritin or GVHD. Mean z scores for height and weight were low at baseline and remained low post-HCT (79%), confirming that growth impairment from disease lacked recovery post-HCT during this follow-up period. HCT for ß-thalassemia has a high rate of cure and low mortality, especially in the young and from HLA-matched related donors. Half of the number of recipients live with mixed chimerism that requires continued follow-up because of a risk of late graft rejection (14%). Organ function after HCT when <7 years of age was generally preserved. Hypogonadism, renal dysfunction, and growth impairment that failed to correct were late complications identified most frequently in older transplant recipients. Systematic follow-up of individual organs such as lung and heart were inadequate but important. These data support the development of simple measures of uniformly tracking long-term HCT outcomes and organ functions in children and adolescents who undergo HCT for thalassemia, allowing for systematic identification and implementation of standardized surveillance strategies and interventions.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Talassemia beta/terapia , Adolescente , Criança , Pré-Escolar , Seguimentos , Humanos , Lactente , Estudos Longitudinais , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
14.
Biol Blood Marrow Transplant ; 23(4): 670-676, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28089760

RESUMO

Progressive neurovasculopathy in children with sickle cell disease (SCD) results in decreased cognitive function and quality of life (QoL). Hematopoietic cell transplantation (HCT) is believed to halt progression of neurovasculopathy. Quantitative analysis of T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) for white matter hyperintensity (WMH) burden provides a meaningful estimate of small vessel cerebrovascular disease. We asked if quantitative analysis of WMH could complement standardized clinical assessment of MRI/magnetic resonance angiography (MRA) for assessing SCD central nervous system vasculopathy before and after HCT. Retrospective longitudinal clinical examination of scheduled annual MRI/MRA and quantitative analysis of WMH were performed before and 1 to 7 years after HCT at scheduled annual intervals, along with QoL measurements, in children who had engrafted after HCT. Of 18 patients alive and persistently engrafted (median age, 9.1 years), pretransplantation MRI demonstrated that 9 and 5 had sickle-related stroke and/or small infarcts, respectively. Patients were divided into WMH severity tertiles based on pretransplantation WMH volumes. MRI and WMH were assessed 1 to 7 years after HCT. MRI/MRA and WMH volume were stable or slightly better in 17 of 18 patients. By parent- and self-report, post-HCT QoL improved for children in the lowest WMH tertile significantly more than in the other groups. Based on this single-institution retrospective sample, we report that WMH appears to quantitatively support MRI-based findings that HCT stabilizes long-term small and large vessel cerebrovascular changes and is associated with the degree of improved QoL. While confirmation in larger prospective studies and evaluation by neurocognitive testing are needed, these findings suggest that WMH is a useful biomarker of neurovasculopathy after transplantation for SCD.


Assuntos
Anemia Falciforme/patologia , Encéfalo/diagnóstico por imagem , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Anemia Falciforme/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/terapia , Criança , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Microcirculação , Estudos Retrospectivos , Adulto Jovem
15.
Biol Blood Marrow Transplant ; 23(4): 552-561, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28065838

RESUMO

Sustained donor engraftment after allogeneic hematopoietic cell transplantation (HCT) converts to healthy donor hemoglobin synthesis and halts disease symptoms in patients with sickle cell disease and thalassemia major. A disease-free survival probability that exceeds 90% has been reported when HCT using an HLA-matched sibling donor is performed in young patients with low-risk disease or treatment-related risk factors. Alternate donor HCT and HCT in adults is performed infrequently because of a higher risk profile. Transplant-specific risks include conditioning regimen-related toxicity, graft-versus-host disease, graft rejection with marrow aplasia or disease recurrence, and infections associated with immunosuppression and delayed immune reconstitution. The magnitude of risk depends on patient age, clinical status of the underlying disease (eg, organ injury from vasculopathy and iron overload), donor source, and intensity of the conditioning regimen. These risks are commonly monitored and reported in the short term. Documenting very late outcomes is important, but these data are rarely reported because of challenges imposed by patient drop-out and insufficient resources. This report summarizes long-term follow-up results after HCT for hemoglobin disorders, identifies gaps in knowledge, and discusses opportunities for future investigations. This consensus summary will be followed by a second article detailing comprehensive long-term follow-up recommendations to aid in maintaining health in these individuals and identifying late complication risks that could facilitate interventions to improve outcomes.


Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Talassemia/terapia , Criança , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Fatores de Risco , Fatores de Tempo , Doadores de Tecidos/provisão & distribução , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
16.
Biol Blood Marrow Transplant ; 23(4): 696-700, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28063963

RESUMO

The utility and optimal timing of routine bone marrow (BM) and cerebrospinal fluid (CSF) surveillance after allogeneic hematopoietic cell transplantation (alloHCT) in children with leukemia have not been previously studied. To examine the current practice concerning relapse surveillance in this population, we conducted a national survey of pediatric bone marrow transplant physicians. Sixty-two of 152 potential participants (41%) completed the survey. For acute lymphoblastic leukemia (ALL) patients, 41 physicians (66%) reported performing routine BM analysis in all such patients, 15 (24%) in some patients and 6 (10%) in no patients. Data were similar for acute myeloid leukemia (AML). Among those who do such screening in the ALL population, 11 physicians (24%) reported performing 1 BM analysis in the first year, 11 (24%) performed 2, 6 (13%) performed 3, 12 (27%) performed 4, and 5 (12%) performed 5 to 10. Data were similar for AML. The most common time point for screening in both diseases was day 100, followed closely by day 365. With respect to central nervous system (CNS) screening in ALL, 11 physicians (18%) screened all patients, 28 (45%) screened no patients, and 23 (37%) screened only patients with prior CNS disease. Use of intrathecal chemotherapy in these patients also varied, with 7 (12%) doing so in all patients, 17 (29%) only in previously CNS-positive patients, and 35 (59%) in no patients. To assess the utility of surveillance procedures, we performed a retrospective review of 108 childhood leukemia patients after alloHCT at our center. Forty-one relapses (38%) occurred with a median time to relapse of 171 days. Five (12%) occurred after day 365. Of the 36 relapses within the first year, 20 (56%) were identified by clinical suspicion, whereas 16 (44%) were identified by routine screening procedures. The percentages of patients in whom routine screening detected relapse at days 100, 180, 270, and 365, respectively, was 6.7%, 11.1%, 11.9%, and 0%. That is, by day 365, no patient (of 38) who had routine BM surveillance had evidence of relapse on analysis of the BM. Our survey confirms a lack of standardization regarding routine BM and CSF relapse surveillance after alloHCT in children with leukemia. We have demonstrated that while day 365 post-alloHCT is a very commonly utilized time point for routine screening, the yield of such screening at this time is very low, such that the performance of these procedures may not be justified at that time. Prospective collaboration among pediatric alloHCT centers may help to provide more robust evidence-based guidelines designed to maximize utility and minimize risk.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Exame de Medula Óssea , Sistema Nervoso Central/patologia , Criança , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Estudos Retrospectivos , Inquéritos e Questionários , Fatores de Tempo , Transplante Homólogo
17.
Blood ; 129(11): 1548-1556, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-27965196

RESUMO

Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.


Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Anemia Falciforme/epidemiologia , Anemia Falciforme/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas/mortalidade , Histocompatibilidade , Humanos , Lactente , Masculino , Irmãos , Inquéritos e Questionários , Taxa de Sobrevida , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento
18.
Blood ; 128(21): 2561-2567, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27625358

RESUMO

Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420.


Assuntos
Anemia Falciforme/mortalidade , Anemia Falciforme/terapia , Transplante de Medula Óssea , Doadores não Relacionados , Adolescente , Aloenxertos , Anemia Falciforme/fisiopatologia , Inibidores de Calcineurina/administração & dosagem , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Taxa de Sobrevida
19.
Am J Infect Control ; 44(12): 1650-1655, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27378008

RESUMO

INTRODUCTION: There are only few reports describing the influence of central line-associated bloodstream infection (CLABSI) prevention strategies on the incidence of bacterial bloodstream infections (BBSIs). METHODS: We performed a retrospective cohort study among pediatric recipients of allogeneic hematopoietic stem cell transplantation (allo-HCT) to assess potential changes in BBSI rates during 3 time periods: pre-CLABSI prevention era (era 1, 2004-2005), CLABSI prevention implementation era (era 2, 2006-2009), and maintenance of CLABSI prevention era (era 3, 2010-2012). BBSI from day 0-365 following allo-HCT were studied. The comparison of person-years incidence rates among different periods was carried out by Poisson regression analysis. RESULTS: The mean age of patients was 10.0 years. During the study period, 126 (65%) of 190 patients had at least a single BBSI. From day 0-30, day 31-100, day 101-180, and day 181-365, 20%, 28%, 30%, and 17% of patients, respectively, experienced BBSIs. The rate of Staphylococcus epidermidis and gram-negative pathogens significantly declined from 3.16-0.93 and 6.32-2.21 per 100 person-months during era 1 and era 3, respectively (P = .001). CONCLUSIONS: Patients undergoing allo-HCT during era 3 were associated with decreased risk of BBSI (P = .012). Maintenance of CLABSI protocols by nursing staff and appropriate education of other care providers is essential to lower incidence of BBSI in this high-risk population, and further strategies to decrease infection burden should be studied.


Assuntos
Bacteriemia/epidemiologia , Bacteriemia/prevenção & controle , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/prevenção & controle , Cateterismo Venoso Central/efeitos adversos , Controle de Infecções/métodos , Transplantados , Adolescente , Bactérias/classificação , Bactérias/isolamento & purificação , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas , Hospitais Pediátricos , Humanos , Incidência , Lactente , Masculino , Estudos Retrospectivos , Medição de Risco , Transplante Homólogo
20.
Br J Haematol ; 174(4): 515-25, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27255787

RESUMO

Sickle cell disease is an inherited disorder that affects over 5 million people worldwide. Current maintenance therapy has been successful in reducing complications and enhancing life expectancy; yet subclinical complications persist. To date, allogeneic haematopoietic stem cell transplant (HSCT) remains the only available curative therapy for sickle cell disease. With declining incidences of rejection and transplant- related mortality, disease-free survival after human leucocyte antigen-identical sibling transplant exceeds 90%. However, the majority of individuals with sickle cell disease do not have an human leucocyte antigen (HLA)-identical sibling; therefore, research is expanding to focus on new approaches to alternative donor transplant. Advances in supportive care and conditioning regimens have led to expansion of the pool of donors to unrelated donors and haploidentical donors. Challenges remain in improving the safety and efficacy of HSCT from alternate donors. Early results from gene therapy may provide another curative option in patients with sickle cell disease. These approaches show early promise, but larger, longitudinal studies are needed to better determine the optimal clinical circumstances for transplant in sickle cell disease.


Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Intervalo Livre de Doença , Terapia Genética , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Doadores não Relacionados
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