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Most reports of risk factors (RF) for developing transplant-associated thrombotic microangiopathy (TA-TMA) and death are derived from paediatric and young adult cohorts, with minimal data on differences in RF and outcomes by age. In this secondary CIBMTR analysis, we used a previously prepared dataset that included all first allogenic haematopoietic cell transplantation (HCT) recipients with malignant or non-malignant diseases between 2008 and 2016. The incidence of TA-TMA 6 months post HCT was similar in children and adults 2.1% and 2.0% respectively. Grade 2-4 acute graft-versus-host disease (aGVHD) was a significant adjusted RF for developing TA-TMA in both children and adults. In adults, additional adjusted RFs for TA-TMA included female sex and black race, and in children an unrelated donor. Compared to a calcineurin inhibitor and sirolimus, other forms of GVHD prophylaxis had an adjusted decreased risk of developing TA-TMA in adults. Adjusted RF for death in those with TA-TMA (n = 652) included age ≥18 years old, early onset of TA-TMA diagnosis (<100 days post HCT), grade 3-4 aGVHD and a performance score of <90 prior to HCT. In this cohort, the incidence of TA-TMA was similar in children and adults, and TA-TMA timing was a newly identified RF for death.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Microangiopatias Trombóticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/etiologia , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/prevenção & controle , Feminino , Masculino , Criança , Adolescente , Adulto , Pré-Escolar , Pessoa de Meia-Idade , Fatores Etários , Adulto Jovem , Fatores de Risco , Fatores de Tempo , Lactente , IncidênciaRESUMO
Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022. Patients were universally screened for TA-TMA and intermediate and high-risk patients were immediately treated with eculizumab. Sub-distribution cox-proportional hazards models were used to identify sub-distribution hazard ratios (sHR) for multi-organ dysfunction (MOD) and non-relapse-related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA-TMA and 21/36 (58%) developed MOD, significantly more than those without TA-TMA, (p < .0001). Of those with TA-TMA, 18 (50%) had high-risk TA-TMA (HR-TA-TMA), 11 (31%) had intermediate-risk TA-TMA (IR-TA-TMA), and 8 (22%) had standard risk (SR-TA-TMA). Twenty-six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D-dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8-32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA-TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA-TMA patients (sHR 10.54, 95% CI 3.8-29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA-TMA patients included SOS (HR 2.89, 95% 1.07-7.80) and elevated D-dimer (HR 3.82, 95% CI 1.14-12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0-113.6 and OR 6.5, 95% CI 1.1-38.6 respectively). TA-TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D-dimer in TA-TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi-institutional clinical trials are needed to understand the impact of TA-TMA-targeted therapies.
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio , Transplante de Células-Tronco Hematopoéticas , Microangiopatias Trombóticas , Humanos , Criança , Prognóstico , Estudos Prospectivos , Estudos de Coortes , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estudos RetrospectivosRESUMO
We prospectively collected PROMIS©25 and PROMIS©29 surveys in the Sickle Cell Transplant Evaluation of Long Term and Late Effects Registry (STELLAR). Mobility and social participation T-scores were decreased; all other domains were within the norm.
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BACKGROUND: Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality. OBJECTIVE: The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders. METHODS: We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models. RESULTS: Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001). CONCLUSIONS: Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Bussulfano/uso terapêutico , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfo-Histiocitose Hemofagocítica/terapia , Melfalan/uso terapêutico , Tiotepa , Condicionamento Pré-Transplante/efeitos adversos , Vidarabina/uso terapêuticoRESUMO
Sickle cell disease (SCD) leads to significant morbidity and early mortality, and hematopoietic cell transplantation (HCT) is the only widely available cure, with impacts seen on SCD-related organ dysfunction. Outcomes are excellent following matched-related donor (MRD) HCT, leading to significantly expanded application of this treatment over the past decade. The majority of SCD patients lack an MRD, but outcomes following alternative donor HCT continue to improve on clinical trials. Within this framework, we aim to provide our perspective on how to apply research findings to clinical practice, for an individual patient. We also emphasize that the preparation of SCD recipients for HCT and supporting them through HCT have special nuances that require awareness and close attention. Through the use of clinical vignettes, we provide our perpsective on the complex decision-making process in HCT for SCD as well as recommendations for the evaluation and support of these patients through HCT.
Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas , Aloenxertos , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Criança , Feminino , Humanos , MasculinoRESUMO
The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.
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Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced-intensity conditioning with melphalan, fludarabine, and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary end point was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow-up of 20 months, the 1-year OS for transplanted patients was 80.4% (90% confidence interval [CI], 68.6%-88.2%). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI, 52.9%-77.3%). Two patients experienced primary graft failure, and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion [DLI]). At 1 year, the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI, 25.2%-54.6%), and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI, 45.4 %-74.9%). The day 100 incidence of grade II to IV acute GVHD was 17.4% (95% CI, 8.1%-29.7%), and 1-year incidence of chronic GVHD was 26.7% (95% CI, 14.6%-40.4%). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).
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Transplante de Células-Tronco Hematopoéticas/métodos , Linfo-Histiocitose Hemofagocítica/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Alemtuzumab/uso terapêutico , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Masculino , Melfalan/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto JovemRESUMO
The leukodystrophies are a heterogeneous group of inherited diseases characterized by progressive demyelination of the central nervous system leading to devastating neurologic symptoms and premature death. Hematopoietic stem cell transplantation (HSCT) has been successfully used to treat certain leukodystrophies, including adrenoleukodystrophy, globoid leukodystrophy (Krabbe disease), and metachromatic leukodystrophy, over the past 30 years. To date, these complex patients have primarily been transplanted at a limited number of pediatric centers. As the number of cases identified through pregnancy and newborn screening is increasing, additional centers will be required to treat these children. Hunter's Hope created the Leukodystrophy Care Network in part to create and standardize high-quality clinical practice guidelines to guide the care of affected patients. In this report the clinical guidelines for the care of pediatric patients with leukodystrophies undergoing treatment with HSCT are presented. The initial transplant evaluation, determination of patient eligibility, donor selection, conditioning, supportive care, and post-transplant follow-up are discussed. Throughout these guidelines the need for early detection and treatment and the role of the partnership between families and multidisciplinary providers are emphasized.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucodistrofia de Células Globoides/terapia , Leucodistrofia Metacromática/terapia , Aloenxertos , Humanos , Recém-Nascido , Guias de Prática Clínica como AssuntoRESUMO
INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking. METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016. RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2 years following allogeneic HCT. CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.
Assuntos
Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/mortalidade , Transplante de Células-Tronco Hematopoéticas , Doenças Inflamatórias Intestinais/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , Lactente , Contagem de Leucócitos , Masculino , Neutrófilos , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Quimeras de Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/µL, CD8 < 50 cells/µL, CD45RA < 10%, or a restricted Vß T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Reconstituição Imune , Imunodeficiência Combinada Severa/terapia , Pré-Escolar , Feminino , Genótipo , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Reconstituição Imune/genética , Lactente , Recém-Nascido , Infecções/etiologia , Masculino , Triagem Neonatal , Estudos Prospectivos , Fatores de Risco , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/mortalidade , Análise de Sobrevida , Doadores de TecidosRESUMO
Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a potent immunosuppressant that is increasingly used in prevention and treatment of graft-vs-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) patients. However, data regarding its adverse effects in HSCT patients remain limited. We describe an 18-year-old HSCT patient with a history of invasive fungal infection, who developed pericardial effusion with cardiac tamponade and interstitial pneumonitis while receiving sirolimus for GVHD prophylaxis. Our case illustrates potentially life-threatening complications of sirolimus use in allogeneic HSCT patients.
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Tamponamento Cardíaco/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/complicações , Derrame Pericárdico/complicações , Complicações Pós-Operatórias/diagnóstico , Sirolimo/efeitos adversos , Adolescente , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Micoses/complicações , Recidiva , IrmãosAssuntos
Vírus BK , Cistite , Transplante de Células-Tronco Hematopoéticas , Infecções por Polyomavirus , Humanos , Fator 7 de Crescimento de Fibroblastos , Hemorragia/terapia , Hemorragia/complicações , Cistite/tratamento farmacológico , Cistite/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Polyomavirus/complicaçõesRESUMO
Hematopoietic cell transplantation (HCT) is the only cure for sickle cell disease (SCD), but engraftment remains challenging in patients lacking matched donors. Infusion of mesenchymal stromal cells (MSCs) at the time of HCT may promote hematopoiesis and ameliorate graft-versus-host disease. Experimental murine models suggest MSC major histocompatibility complex compatibility with recipient impacts their in vivo function, suggesting autologous MSCs could be superior to third-party MSCs for promoting HCT engraftment. Here we tested whether bone marrow (BM)-derived MSCs from SCD subjects have comparable functionality compared with MSCs from healthy volunteers. SCD MSC doubling time and surface marker phenotype did not differ significantly from non-SCD. Third-party and autologous (SCD) T cell proliferation was suppressed in a dose-dependent manner by all MSCs. SCD MSCs comparably expressed indoleamine-2,3-dioxygenase, which based on transwell and blocking experiments appeared to be the dominant immunomodulatory pathway. The expression of key genes involved in hematopoietic stem cell (HSC)-MSC interactions was minimally altered between SCD and non-SCD MSCs. Expression was, however, altered by IFN-γ stimulation, particularly CXCL14, CXCL26, CX3CL1, CKITL, and JAG1, indicating the potential to augment MSC expression by cytokine stimulation. These data demonstrate the feasibility of expanding BM-derived MSCs from SCD patients that phenotypically and functionally do not differ per International Society of Cell Therapy essential criteria from non-SCD MSCs, supporting initial evaluation (primarily for safety) of autologous MSCs to enhance haploidentical HSC engraftment in SCD.
Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Adolescente , Adulto , Anemia Falciforme/patologia , Comunicação Celular/genética , Técnicas de Cultura de Células , Proliferação de Células , Criança , Pré-Escolar , Feminino , Voluntários Saudáveis , Humanos , Imunofenotipagem , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Masculino , Transplante Autólogo/métodos , Adulto JovemRESUMO
Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory T cells, which drive alloimmunization, are relatively resistant to commonly used conditioning agents. Alefacept, a recombinant leukocyte function antigen-3/IgG1 fusion protein, targets CD2 and selectively depletes memory versus naive T cells. Three multiply transfused pediatric patients with NMD received a short course of high-dose i.v. alefacept (.25 mg/kg/dose on days -40 and -9 and .5 mg/kg/dose on days -33, -26, -19, and -12) before undergoing unrelated allogeneic transplant in the setting of reduced-intensity pretransplant conditioning and calcineurin inhibitor-based post-transplant graft-versus-host disease (GVHD) prophylaxis. Alefacept infusions were well tolerated in all patients. Peripheral blood flow cytometry was performed at baseline and during and after alefacept treatment. As expected, after the 5 weekly alefacept doses, each patient demonstrated selective loss of CD2(hi)/CCR7(-)/CD45RA(-) effector memory (Tem) and CD2(hi)/CCR7(+)/CD45RA(-) central memory (Tcm) CD4(+) and CD8(+) T cells with relative preservation of the CD2(lo) Tem and Tcm subpopulations. In addition, depletion of CD2(+) natural killer (NK) cells also occurred. Neutrophil recovery was rapid, and all 3 patients had 100% sorted (CD3/CD33) peripheral blood donor chimerism by day +100. Immune reconstitution (by absolute neutrophil, monocyte, and lymphocyte counts) was comparable with a cohort of historical control patients. All 3 patients developed GVHD but are all now off immune suppression and >2 years post-transplant with stable full-donor engraftment. These results suggest that alefacept at higher dosing can deplete both memory T cells and NK cells and that incorporating CD2-targeted depletion into a reduced-intensity transplant regimen is feasible and safe in heavily transfused patients.
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Transplante de Medula Óssea , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Depleção Linfocítica/métodos , Proteínas Recombinantes de Fusão/uso terapêutico , Condicionamento Pré-Transplante , Alefacept , Anemia Aplástica/terapia , Transfusão de Componentes Sanguíneos/estatística & dados numéricos , Antígenos CD2/imunologia , Criança , Disceratose Congênita/terapia , Anemia de Fanconi/terapia , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Estudo Historicamente Controlado , Humanos , Memória Imunológica , Imunofenotipagem , Lactente , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Projetos Piloto , Proteínas Recombinantes de Fusão/provisão & distribuição , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Doadores não RelacionadosRESUMO
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells known to modulate the immune system and to promote hematopoiesis. These dual effects make MSCs attractive for use as cellular therapy in hematopoietic cell transplantation (HCT). MSCs can be used peri-HCT or pre-engraftment to modulate immune reconstitution, promoting hematopoietic stem cell (HSC) engraftment and/or preventing graft-versus-host disease (GVHD). Pre-clinical studies have demonstrated that MSCs can potentiate HSC engraftment and prevent GVHD in a variety of animal models. Clinical trials have been small and largely non-randomized but have established safety and early evidence of efficacy, supporting the need for larger randomized trials.
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Hematopoese , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Imunomodulação , Células-Tronco Mesenquimais/metabolismo , Animais , Ensaios Clínicos como Assunto , Sobrevivência de Enxerto , Hematopoese/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Humanos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Modelos AnimaisRESUMO
Rapamycin (RAPA) inhibits the mechanistic target of rapamycin (mTOR), a crucial immune system regulator. Dendritic cells (DC) generated in RAPA (RAPA-DC) enrich for CD4(+) forkhead box p3 (FoxP3(+)) regulatory T cells and induce T cell apoptosis by an unknown mechanism. RAPA-DC also promote experimental allograft survival, yet paradoxically secrete increased IL-12, crucial for the generation of IFN-γ(+) CD4(+) T cells. However, IFN-γ is pro-apoptotic and IL-12-driven IFN-γ inhibits experimental graft-versus-host disease (GVHD). We hypothesized that IL-12(hi) RAPA-DC would facilitate IFN-γ-mediated apoptosis of alloreactive T cells and, unlike control (CTR)-DC, would reduce lethal GVHD. Following LPS stimulation, RAPA-DC exhibited decreased MHCII and co-stimulatory molecules and contained a significant population of CD86(lo) IL-12(hi) cells. Consistent with our hypothesis, both unstimulated and LPS-stimulated RAPA-DC enhanced alloreactive CD4(+) T cell apoptosis in culture. Augmented T cell apoptosis was ablated by IFN-γ neutralization or using T cells lacking the IFN-γ receptor, and it was associated with increased expression of Fas and cleaved caspase 8. DC production or responses to IFN-γ were not important to increased apoptotic functions of RAPA-DC. LPS-stimulated IL-12p40(-/-) RAPA-DC induced lower levels of T cell apoptosis in culture, which was further decreased with addition of anti-IFN-γ. Finally, whereas CTR-DC accelerated mortality from GVHD, LPS-treated RAPA-DC significantly prolonged host survival. In conclusion, increased apoptosis of allogeneic CD4(+) T cells induced by LPS-stimulated IL-12(hi) RAPA-DC is mediated in vitro through IFN-γ and in part by increased IL-12 expression. Enhanced production of IL-12, the predominant inducer of IFN-γ by immune cells, is a probable mechanism underlying the capacity of LPS-treated RAPA-DC to reduce GVHD.
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Antibióticos Antineoplásicos/uso terapêutico , Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Interleucina-12/imunologia , Sirolimo/uso terapêutico , Animais , Antibióticos Antineoplásicos/imunologia , Diferenciação Celular , Proliferação de Células , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Sirolimo/imunologiaRESUMO
Hematopoietic stem cell transplantation is the only curative treatment for many malignant hematologic diseases, with an often critical graft-versus-leukemia effect. Despite peritransplant prophylaxis, GVHD remains a significant cause of posthematopoietic stem cell transplantation morbidity and mortality. Traditional therapies have targeted T cells, yet immunostimulatory dendritic cells (DCs) are critical in the pathogenesis of GVHD. Furthermore, DCs also have tolerogenic properties. Monitoring of DC characteristics may be predictive of outcome, and therapies that target DCs are innovative and promising. DCs may be targeted in vivo or tolerogenic (tol) DCs may be generated in vitro and given in the peritransplant period. Other cellular therapies, notably regulatory T cells (T(reg)) and mesenchymal stem cells, mediate important effects through DCs and show promise for the prevention and treatment of GVHD in early human studies. Therapies are likely to be more effective if they have synergistic effects or target both DCs and T cells in vivo, such as tolDCs or T(reg). Given the effectiveness of tolDCs in experimental models of GVHD and their safety in early human studies for type 1 diabetes, it is crucial that tolDCs be investigated in the prevention and treatment of human GVHD while ensuring conservation of graft-versus-leukemia effects.
Assuntos
Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Transplante de Células-Tronco Hematopoéticas , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Animais , Células Dendríticas/patologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Linfócitos T Reguladores/patologia , Transplante HomólogoRESUMO
Consensus diagnostic and risk stratification of transplantation-associated thrombotic microangiopathy (TA-TMA) was recently achieved from international transplantation groups. Although the proposed diagnostic criteria have been applied to multiple pediatric cohorts, there are scant data applying the novel risk stratification approach in children with TA-TMA. In this retrospective cohort study, all children undergoing an allogeneic HCT or autologous HCT for neuroblastoma were prospectively screened for TA-TMA, diagnosed, and risk-stratified using the Jodele criteria from August 2019 to October 2023. Our institutional practice during the study period was treat all Jodele intermediate-risk (IR) and high-risk (HR) patients with eculizumab. Harmonization risk stratification criteria were applied retrospectively. All survival analyses were calculated from the day of TA-TMA diagnosis. To identify which specific harmonization high-risk features were the most important predictors for nonrelapse mortality (NRM), full and reduced logistical regression models were tested. The lowest Bayes information criterion and optimal Mallows CP statistic were used to identify the best subset. The analysis was performed with SAS 9.4 (SAS Institute, Cary, NC). Fifty-two children were diagnosed with TA-TMA during the study period, at a median of 37.5 days post-HCT (range, 3 to 735 days). Using Jodele risk stratification, 11 (21%) were SR, 21 (40%) were IR, and 20 (39%) were HR. Forty (77%) were treated with eculizumab. There were no statistically significant differences in NRM among Jodele risk groups, although overall survival (OS) differed significantly. Using the harmonized stratification, 49 children (94%) were stratified as HR and 3 as standard risk (SR), there were no statistically significant differences in NRM or OS between groups. Eight children (15.4%) were classified as SR using Jodele risk stratification but restratified as HR using the harmonization criteria. One child (12.5%) died in the setting of severe GVHD, and the remaining 7 were alive at the last follow-up. In a best subset model, lactate dehydrogenase (LDH) level >2 times the upper limit of normal (ULN) (odds ratio [OR], 6.52, 95% confidence interval [CI], .96 to 44.3; P = .05), grade II-IV acute graft-versus-host disease (GVHD) at the time of TA-TMA diagnosis (OR, 15.4; 95% CI, 2.14 to 110.68; P = .01), and organ dysfunction at the time of TA-TMA (OR, 21.5; 95% CI, 2.96 to 156.37; P = .002) were significantly associated with NRM; elevated sC5b-9, urine protein/creatinine ratio, and viral infections were not significantly associated with NRM. Using these best-fit criteria, 14 patients were classified as SR and 38 were classified as HR, NRM was significantly higher, and OS was significantly lower. In this cohort of children with TA-TMA, retrospective application of the harmonization criteria resulted in more patients stratified as HR compared to use of the previously described Jodele criteria. The intention of the harmonization criteria was to identify those at greatest risk of poor outcomes; while all harmonization SR patients survived, this risk stratification was very sensitive. Previous criticisms of harmonization risk stratification include limited access to sC5b-9 testing. These data suggest that organ dysfuncion, acute GVHD, and LDH >2 times ULN are the most important predictors of NRM in this cohort, allowing risk stratification even in the absence of available sC5b-9 testing. Additional studies are needed to validate these findings.
RESUMO
Conditioning regimens for hematopoietic cell transplant (HCT) in patients with sickle cell disease (SCD) place patients at risk for reproductive health issues. The purpose of this study was to assess reproductive health and reports of fertility counseling in patients with SCD who received a transplant. This was a secondary analysis of gonadal hormone production, future infertility risk assessment, and parent-proxy/patient reports of fertility counseling in SCD transplant recipients who are currently pubertal and were enrolled in the Atlanta sites of the Sickle Cell Transplant Evaluation of Long-term and Late Effects Registry (STELLAR) between May 2017 and October 2023. Clinical information was abstracted from medical records and reproductive health survey data from the STELLAR database. Descriptive statistics were reported as median (interquartile range [IQR]) or percentages. There were 20 females and 12 males in the study population. Females were median (IQR) 19.6 (9.4) years old and males 20.8 (11.4) years old at the time of the study. Transplants most commonly occurred in the decade 2010 to 2019 at 10.7 (4.8) years old for females and 11.1 (4.1) years old for males. Most participants received bone marrow stem cells (95.0% females, 100.0% males) from matched sibling donors (90.0% females, 100.0% males). Participants received one of seven HCT conditioning regimens with cyclophosphamide equivalent doses ranging from 3388 to 9706 mg/m2. The majority of females (90.0%) had diminished ovarian reserve with low anti-Mullerian hormone levels, and 61.1% had premature ovarian insufficiency with two follicle-stimulating hormone levels (FSH) ≥40 mIU/mL post-HCT. All males had normal testosterone levels, but 63.6% had elevated FSH levels suggestive of impaired spermatogenesis post-HCT. Parent proxies (for patients <18 years old) and patients ≥18 years old completed surveys 9.0 years (5.2) and 7.9 years (9.3) since HCT in females and males respectively. Twenty-five percent of parent proxies and 45% of patients reported that they had not been informed by a healthcare provider of the risk of infertility post-transplant. There are high rates of gonadal dysfunction post-HCT, but many parent proxies and patients do not recall being told of the risk for future infertility. More effective methods of education are warranted to ensure SCD patients and their families clearly understand the risk for reproductive health issues post-HCT.