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Background: Nontyphoidal salmonella (NTS) are responsible for food-borne gastroenteritis and bacteremia, in immunosuppressed individuals. Antibiotic resistance in NTS is on the rise. This study reports the prevalence and antimicrobial susceptibility of nontyphoidal salmonella in clinical samples. Study Design. This is a hospital record-based cross-sectional, retrospective study. Methods: In our study, inpatient samples such as blood (n = 13546), urine (n = 11,333), pus (n = 1,010), and stool (n = 926) samples were cultured to isolate etiological agents in the microbiology department from January 2017 to June 2019. Relevant details such as duration of fever, platelet count, hemoglobin, WBC count, immune status, and mode of treatment were noted from the medical records. Data were analyzed, and continuous variables were expressed as mean and categorical variables as percentages. Results: A total of 24 NTS serovars were isolated, which included ten isolates from blood, five each from urine and pus, and four from stool samples. Of the NTS, five were Salmonella enterica subsp. enterica, three were S.enterica serovar Typhimurium, one was S.enterica subsp. diarizonae, and 15 S.enterica serovars could not be serologically differentiated. All were susceptible to ampicillin, chloramphenicol, and cefuroxime. However, 16.6% of NTS was resistant to ceftriaxone, 4% to cotrimoxazole, 58% to ciprofloxacin, and 75% to nalidixic acid. Conclusions: A low prevalence of NTS responsible for invasive infections is seen in this part of the country. Few isolates were resistant to more than one antibiotic. A higher rate of resistance to ceftriaxone is the cause of concern. Awareness of the distribution of NTS serogroups is of epidemiological and public health significance.
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Youth prefer to be involved in treatment decisions, yet youth participation is minimally present in decisions like stem cell transplant (SCT) that require frequent medications and social isolation to be successful in curing cancer and chronic illness. The purpose of our study is to identify the barriers and facilitators to youth decision-making involvement in the youth-parent interaction when referred for treatment with SCT. We report qualitative findings from our theory-driven mixed-methods study. We thematically analyzed our field notes of youth and parent observations and audio-recordings during SCT consultations and semi-structured interviews. Data were collected from 10 youth, 8 to 16 (median 12) years of age, and their parents (n = 20). Three themes emerged: (a) Reluctant unless motivated, (b) Uncertain but capable, and (c) Limited unless supported. Our findings emphasize the critical role parents may take in facilitating youth involvement in decisions.
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Background: Due to the risk of cerebral vascular injury, children and adolescents with high-risk sickle cell disease (SCD) experience neurocognitive decline over time. Haploidentical stem cell transplantation (HISCT) from human leukocyte antigen-matched sibling donors may slow or stop progression of neurocognitive changes. Objectives: The study is to determine if HISCT can ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression, determine which specific areas of neurocognitive functioning are particularly vulnerable to SCD, and determine if there are age-related differences in neurocognitive functioning over time. Methods: We performed neurocognitive and neuroimaging in SCD recipients following HISCT. Children and adolescents with high-risk SCD who received parental HISCT utilizing CD34+ enrichment and mononuclear cell (T-cell) addback following myeloimmunoablative conditioning received cognitive evaluations and neuroimaging at three time points: pre-transplant, 1 and 2 years post-transplant. Results: Nineteen participants (13.1 ± 1.2 years [3.3-20.0]) received HISCT. At 2 years post-transplant, neuroimaging and cognitive function were stable. Regarding age-related differences pre-transplantation, older children (≥13 years) had already experienced significant decreases in language functioning (p < 0.023), verbal intelligence quotient (p < 0.05), non-verbal intelligence quotient (p < 0.006), and processing speed (p < 0.05), but normalized post-HISCT in all categories. Conclusion: Thus, HISCT has the potential to ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression. Further studies are required to determine if neurocognitive performance remains stable beyond 2 years post-HISCT.Clinical trial registration: The study was conducted under an investigator IND (14359) (MSC) and registered at clinicaltrials.gov (NCT01461837).
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Acetatos , Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Quinazolinas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/etiologia , Criança , Masculino , Feminino , Pré-Escolar , Acetatos/uso terapêutico , Quinazolinas/uso terapêutico , Adolescente , Citomegalovirus , Antivirais/uso terapêutico , Lactente , Aloenxertos , Transplante HomólogoRESUMO
Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (aGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of aGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, nâ¯=â¯69, abatacept cohort, nâ¯=â¯73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 aGVHD, only aGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 aGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified aGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between aGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant aGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).
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Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.
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Doença Enxerto-Hospedeiro , Humanos , Doença Enxerto-Hospedeiro/mortalidade , Masculino , Feminino , Doença Crônica , Adulto , Pessoa de Meia-Idade , Intervalo Livre de Doença , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Taxa de Sobrevida , IdosoAssuntos
COVID-19 , Hipertireoidismo , Transplante de Fígado , Humanos , SARS-CoV-2 , Hipertireoidismo/etiologiaRESUMO
Sickle cell disease is a debilitating hemoglobinopathy with high morbidity and mortality. Hematopoietic stem cell transplantation (HCT) is curative, but the presence of mixed donor/recipient chimerism post-HCT raises concerns about disease control long-term. Mixed donor/recipient chimerism is reported in significant numbers even after aggressive HCT conditioning regimens. Post-HCT, adequacy of donor erythropoiesis is crucial for disease control. This review explores the relationship between mixed donor/recipient chimerism and outcomes post-HCT. Serial chimerism analysis in lineage specific manner in erythroid or myeloid cells post-HCT predicts for disease control and HCT success. Adequate and stable donor-derived erythropoiesis is essential for reversing SCD manifestations. Myeloid lineage chimerism mirrors erythropoiesis is commercially available, and a reliable indicator of adequacy. Using this tool, the minimum threshold of donor chimerism is required to prevent SCD-related complications and maintain sickle hemoglobin less than 50% is approximately 20-25% even when a donor has Hb S trait. Curative interventions should, at a minimum, meet this goal long-term. Achieving a balance between successful engraftment while minimizing toxicity is important in patients vulnerable because of age or preexisting morbidity and is the objective of recent clinical trials. As HCT and gene therapies evolve, efficient long-term follow-up that includes durability assessment of mixed donor/recipient chimerism will be crucial.
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Anemia Falciforme , Transplante de Células-Tronco Hematopoéticas , Humanos , Quimerismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Anemia Falciforme/terapia , Anemia Falciforme/etiologia , Transplante de Células-Tronco , Doadores de Tecidos , Condicionamento Pré-Transplante , Quimeras de TransplanteRESUMO
Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children's Oncology Group cellular therapy-based trials advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T-cell depletion is used, and the depth of remission as measured by next-generation sequencing-based minimal residual disease assessment pretransplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Criança , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Doadores não RelacionadosRESUMO
In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 µg/mL. However, a higher Ctrough_1 (≥39 µg/mL, attained in â¼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 µg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 µg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.
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Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Abatacepte/efeitos adversos , Infecções por Vírus Epstein-Barr/etiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4RESUMO
Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 µg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 µg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 µg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.
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Anticorpos Monoclonais Humanizados , Transplante de Células-Tronco Hematopoéticas , Humanos , Alemtuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Melfalan/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doadores de Tecidos , Quimiocina CXCL9RESUMO
Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
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Antineoplásicos , Histona-Lisina N-Metiltransferase , Leucemia Mieloide Aguda , Nucleofosmina , Proteínas Proto-Oncogênicas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Histona-Lisina N-Metiltransferase/química , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Neoplasia Residual/tratamento farmacológico , Nucleofosmina/genética , Prognóstico , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Indução de RemissãoAssuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Humanos , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/prevenção & controle , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Polidesoxirribonucleotídeos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (-19.4 mL/100 g/min) and OEF (-8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, -0.9 mL/100 g/min; P = .024; OEF, -3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.
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Anemia Falciforme , Transplante de Células-Tronco Hematopoéticas , Acidente Vascular Cerebral , Humanos , Criança , Anemia Falciforme/terapia , Acidente Vascular Cerebral/prevenção & controle , Hemodinâmica , Oxigênio , Circulação CerebrovascularRESUMO
BACKGROUND: Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes. OBJECTIVE: We hypothesized that CD4+ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients. METHODS: We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT. RESULTS: Compared to post-HCT SCID patients with normal CD4+ T-cell counts, those with poor T-cell reconstitution showed lower frequency of naive CD45RA+/CCR7+ T cells, recent thymic emigrants, and TCR excision circles. They also had a restricted TCR repertoire, increased expression of inhibitory receptors (PD-1, 2B4, CD160, BTLA, CTLA-4), and increased activation markers (HLA-DR, perforin) on their total and naive CD8+ T cells, suggesting T-cell exhaustion and aberrant activation, respectively. The exhaustion score of CD8+ T cells was inversely correlated with CD4+ T-cell count, recent thymic emigrants, TCR excision circles, and TCR diversity. Exhaustion scores were higher among recipients of unconditioned HCT, especially when further in time from HCT. Patients with fewer CD4+ T cells showed a transcriptional signature of exhaustion. CONCLUSIONS: Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.
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Transplante de Células-Tronco Hematopoéticas , Linfopenia , Imunodeficiência Combinada Severa , Humanos , Linfócitos T CD8-Positivos , Exaustão das Células T , Receptores de Antígenos de Linfócitos TRESUMO
Hematopoietic cell transplantation (HCT) is an established cure for sickle cell disease (SCD) supported by long-term survival, but long-term organ function data are lacking. We sought to describe organ function and assess predictors for dysfunction in a retrospective cohort (n = 247) through the Sickle cell Transplant Advocacy and Research alliance. Patients with <1-year follow-up or graft rejection/second HCT were excluded. Organ function data were collected from last follow-up. Primary measures were organ function, comparing pre- and post-HCT. Bivariable and multivariable analyses were performed for predictors of dysfunction. Median age at HCT was 9.4 years; the majority had HbSS (88.2%) and severe clinical phenotype (65.4%). Most received matched related (76.9%) bone marrow (83.3%) with myeloablative conditioning (MAC; 57.1%). Acute and chronic graft-versus-host disease (GVHD) developed in 24.0% and 24.8%. Thirteen patients (5.3%) died ≥1 year after HCT, primarily from GVHD or infection. More post-HCT patients had low ejection or shortening fractions than pre-HCT (0.6% â 6.0%, P = .007 and 0% â 4.6%, P = .003). The proportion with lung disease remained stable. Eight patients (3.2%) had overt stroke; most had normal (28.3%) or stable (50.3%) brain magnetic resonance imaging. On multivariable analysis, cardiac dysfunction was associated with MAC (odds ratio [OR] = 2.71; 95% confidence interval [CI], 1.09-6.77; P = .033) and severe acute GVHD (OR = 2.41; 95% CI, 1.04-5.62; P = .041). Neurologic events were associated with central nervous system indication (OR = 2.88; 95% CI, 2.00-4.12; P < .001). Overall organ dysfunction was associated with age ≥16 years (OR = 2.26; 95% CI, 1.35-3.78; P = .002) and clinically severe disease (OR = 1.64; 95% CI, 1.02-2.63; P = .043). In conclusion, our results support consideration of HCT at younger age and use of less intense conditioning.
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Anemia Falciforme , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos Retrospectivos , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Anemia Falciforme/terapia , Anemia Falciforme/complicaçõesRESUMO
Introduction: We previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients. Methods: CD34 cells were enriched using the CliniMACS® system with a target dose of 10 x 106 CD34+ cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x105 CD3/kg in the final product. Pre-transplant HLA antibodies were characterized. Donor chimerism was monitored 1-24 months post-transplant. Comprehensive assessment of immune reconstitution included lymphocyte subsets, plasma cytokines, complement levels, anti-viral T-cell responses, activation markers, and cytokine production. Infections were monitored. Results: HLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 days, donor chimerism was 93-99% and natural killer cell levels were restored. By 60 days, CD19 B cells were normal. CD8 and CD4 T-cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T-cells were elevated at 100-365 days post-transplant while naïve cells remained below baseline. Tregs were elevated at 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were near baseline. At one year, cytokine levels were not significantly different from baseline. Discussion: These results suggest that haploidentical transplantation with CD34-enriched cells and peripheral blood mononuclear cell addback results in rapid engraftment, sustained donor chimerism and broad-based immune reconstitution.
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Anemia Falciforme , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Criança , Humanos , Transplante Haploidêntico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucócitos Mononucleares , Quimerismo , Anemia Falciforme/terapia , CitocinasRESUMO
Curative therapies for sickle cell disease include allogeneic hematopoietic stem cell transplantation (HSCT) and gene-modified autologous stem cell transplantation. HSCT has been used for 30 years with success measured by engraftment, symptom control, graft-vs-host disease (GVHD) risk, organ toxicity, and immune reconstitution. While human leukocyte antigen-matched sibling donor (MSD) transplants have excellent outcomes, alternate donor transplants (unrelated/haploidentical) are just beginning to overcome GVHD and engraftment hurdles to match MSD. Gene therapy, a newly developed treatment, is undergoing careful evaluation in many trials with varying approaches. The risk/benefit ratio to the patient in relation to outcomes, toxicities, and mortality risk drives eligibility for curative interventions. Consequently, eligibility criteria for MSD transplants can be less stringent, especially in the young. Posttransplant outcome analysis after the "cure" with respect to organ function recovery is essential. While established damage such as stroke is irreversible, transplant can help stabilize (pulmonary function), prevent further deterioration (stroke), improve (neurocognition), and protect unaffected organs. Tracking organ functions postintervention uniformly between clinical trials and for adequate duration is essential to answer safety and efficacy questions related to curative therapies. Age-appropriate application/outcome analyses of such therapies will be the ultimate goal in overcoming this disease.