RESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA) associated bone marrow failure (BMF)/aplastic anemia (AA) and hematological malignancy. We performed a retrospective multicenter study on 813 FA children undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years (interquartile range, 3.4-4.0). Median age at transplant was 8.8 years (6.5-18.1). Overall survival (OS), event-free survival (EFS) and GvHD-free, relapse-free survival (GRFS) at 5 years were 83% (80-86%), 78% (75-81%) and 70% (67-74%) respectively. OS was comparable between matched family donor (MFD, n=441, 88%) and matched unrelated donor (MUD, n=162, 86%) and was superior to that of mismatched family or unrelated donor (MMFD/MMUD, n=144, 72%) and haploidentical donor (HID) (n=66, 70%, p<0.001). In multivariable analysis, a transplant indication of acute myeloid leukaemia/myelodysplastic syndrome compared to AA/BMF, use of MMFD/MMUD and HID compared to MFD, Fludarabine-Cyclophosphamide (FluCy) + other conditioning compared to FluCy independently predicted inferior OS, while alemtuzumab compared to ATG was associated with better OS. Age ï³ 10 years was associated with worse EFS and GRFS. Cumulative incidences (CIN) of primary and secondary graft failure were 2% (1-3%) and 3% (2-4%) respectively. CIN of grade II-IV acute GvHD, grade III-IV acute GvHD and chronic GvHD were 23% (20-26%), 12% (10-15%) and 8% (6-10%) respectively. The 5-year CIN of secondary malignancy was 2% (1-3%). These data suggest that HSCT should be offered to Fanconi Anemia patients with AA/BMF at a younger age in the presence of a well-matched donor.
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ABSTRACT: HLA-mismatched transplants with either in vitro depletion of CD3+ T-cell receptor (TCR)αß/CD19 (TCRαß) cells or in vivo T-cell depletion using posttransplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEIs). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEIs undergoing their first transplant between 2010 and 2019 from an HLA-mismatched donor using TCRαß (n = 167) or PTCY (n = 139). The median age for hematopoietic stem cell transplantation (HSCT) was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84) after TCRαß and 66% (57-74) after PTCY (P = .013). Pre-HSCT morbidity score (hazard ratio [HR], 2.27; 1.07-4.80, P = .032) and non-busulfan/treosulfan conditioning (HR, 3.12; 1.98-4.92, P < .001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50%-66%) after TCRαß and 57% (48%-66%) after PTCY (P = .804). The cumulative incidence of severe acute graft-versus-host disease (GvHD) was higher after PTCY (15%, 9%-21%) than TCRαß (6%, 2%-9%, P = .007), with no difference in chronic GvHD (PTCY, 11%, 6%-17%; TCRαß, 7%, 3%-11%, P = .173). The 3-year GvHD-free EFS was 53% (44%-61%) after TCRαß and 41% (32%-50%) after PTCY (P = .080). PTCY had significantly higher rates of veno-occlusive disease (14.4% vs TCRαß 4.9%, P = .009), acute kidney injury (12.7% vs 4.6%, P = .032), and pulmonary complications (38.2% vs 24.1%, P = .017). Adenoviremia (18.3% vs PTCY 8.0%, P = .015), primary graft failure (10% vs 5%, P = .048), and second HSCT (17.4% vs 7.9%, P = .023) were significantly higher in TCRαß. In conclusion, this study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes.
Assuntos
Antígenos CD19 , Ciclofosfamida , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos de Linfócitos T alfa-beta , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Criança , Pré-Escolar , Feminino , Masculino , Lactente , Adolescente , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Adulto Jovem , Depleção Linfocítica , Condicionamento Pré-Transplante/métodos , Antígenos HLA/imunologia , Adulto , Resultado do Tratamento , Recém-NascidoRESUMO
Data comparing hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) or peripheral blood stem cell (PBSC) grafts in children after alemtuzumab-based conditioning are lacking. We investigated whether in vivo T cell depletion using alemtuzumab could reduce the risk of severe acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) after HSCT with matched unrelated donor (MUD) BM or PBSCs. This retrospective multicenter study included 397 children (BM group, n = 202; PBSC group, n = 195) who underwent first MUD HSCT at 9 pediatric centers in the United Kingdom between 2015 and 2019. The median age at transplantation was 7.0 years (range, .1 to 19.3 years), and the median duration of follow-up was 3.1 years (range, .3 to 7.5 years). The 3-year overall survival was 81% for the entire cohort (BM group, 80%; PBSC group, 81%). The incidence of grade II-IV aGVHD was significantly higher in the PBSC group (31%) compared to the BM group (31% versus 19%; P = .003), with no difference in the incidence of grade III-IV aGVHD (BM, 7%; PBSC, 12%; P = .17). CD3+ T cell dose >5 × 108/kg and the use of PBSCs were independent predictors of grade II-IV aGVHD. When considering CD3+ T cell dose and GVHD prophylaxis, PBSC transplantation with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) and a CD3+ T cell dose ≤5 × 108/kg had a comparable grade II-IV aGVHD to BM transplantation plus a CNI (20% versus 18%; P = .52). PBSC transplantation was associated with a lower incidence of cGVHD compared to BM transplantation (6% versus 11%; P = .03). Within the limits of this study, we identified a potential strategy to reduce the risk of severe GVHD in pediatric PBSC recipients that includes a combination of in vivo T cell depletion using alemtuzumab and dual GVHD prophylaxis (with a CNI and MMF) and limiting the CD3+ T cell dose to ≤5 × 108/kg.
Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Células-Tronco de Sangue Periférico , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Adulto Jovem , Alemtuzumab/uso terapêutico , Medula Óssea , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T , Doadores não RelacionadosRESUMO
A significant complication of HSCT is graft failure, although few studies focus on this problem in patients with inborn errors of immunity (IE). We explored outcome of second HSCT for IEI by a retrospective, single-centre study between 2002 and 2022. Four hundred ninety-three patients underwent allogeneic HSCT for severe combined immunodeficiency (SCID; n = 113, 22.9%) or non-SCID IEI (n = 380, 77.1%). Thirty patients (6.0%) required second HSCT. Unconditioned infusion or no serotherapy at first HSCT was more common in patients who required second transplant. Median interval between first and second HSCT was 0.97 years (range: 0.19-8.60 years); a different donor was selected for second HSCT in 24/30 (80.0%) patients. Conditioning regimens for second HSCT were predominately treosulfan-based (with thiotepa: n = 18, 60.0%; without, n = 6, 20.0%). Patients received grafts from peripheral blood stem cell (n = 25, 83.3%) or bone marrow (n = 5, 16.7%) with median stem cell dose 9.5 × 106 CD34 + cells/kilogram (range: 1.4-32.3). Median follow-up was 1.92 years (0.22-16.0). Overall survival was 80.8% and event-free survival was 64.7%. Four patients died, two of early-transplant related complications, and two of late sepsis post-second HSCT. Three patients required third HSCT; all are alive with 100% donor chimerism. Cumulative incidence of acute graft-versus-host disease was 28.4%, (all grade I-II). Viral reactivation was seen in 13/30 (43.3%) patients, including HHV6 (n = 6), CMV (n = 4), and adenovirus (n = 2). At latest follow-up, 25/26 surviving patients have donor chimerism ≥ 90% and 16/25 (64.0%) have discontinued immunoglobulin replacement. Second HSCT offers IEI patients with graft failure curative treatment with good overall survival and immunological recovery.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Humanos , Estudos Retrospectivos , Adenoviridae , Quimerismo , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
A minority of children experience significant graft dysfunction after undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for inborn errors of immunity (IEI). The optimal approach to salvage HSCT in this scenario is unclear with respect to conditioning regimen and stem cell source. This single-center retrospective case series reports the outcomes of salvage CD3+TCRαß/CD19-depleted mismatched family or unrelated donor stem cell transplantation (TCRαß-SCT) between 2013 and 2022 for graft dysfunction in 12 children with IEI. Outcomes of interest were overall survival (OS), event-free survival (EFS), graft-versus-host disease (GVHD)-free and event-free survival (GEFS), toxicities, GVHD, viremia and long-term graft function. In this retrospective audit of patients who underwent second CD3+TCRαß/CD19-depleted mismatched donor HSCT using treosulfan-based reduced-toxicity myeloablative conditioning, the median age at first HSCT was 8.76 months (range, 2.5 months to 6 years), and that at second TCRαß-SCT was 3.6 years (range, 1.2 to 11 years). The median interval between first and second HSCTs was 1.7 years (range, 3 months to 9 years). The primary diagnoses were severe combined immunodeficiency (SCID) (n = 5) and non-SCID IEI (n = 7). Indications for second HSCT were primary aplasia (n = 1), secondary autologous reconstitution (n = 6), refractory acute GVHD (aGVHD) (n = 3), and secondary leukemia (n = 1). Donors were either haploidentical parental donors (n = 10) or mismatched unrelated donors (n = 2). All patients received TCRαß/CD19-depleted peripheral blood stem cell (PBSC) grafts with a median CD34+ cell dose of 9.3 × 106/kg (range, 2.8 to 32.3 × 106/kg) and a median TCRαß+ cell dose of 4 × 104/kg (range, 1.3 to 19.2 × 104/kg). All patients engrafted, with a median time neutrophil and platelet recovery of 15 days (range, 12 to 24 days) and 12 days (range, 9 to 19 days). One patient developed secondary aplasia, and 1 had secondary autologous reconstitution; both underwent a successful third HSCT. Four (33%) had grade II aGVHD, and none had grade III-IV aGVHD. No patients had chronic GVHD (cGVHD), but 1 patient developed extensive cutaneous cGVHD after their third HSCT using PBSCs and antithymocyte globulin. Nine (75%) had at least 1episode of blood viremia with human herpesvirus 6 (n = 6; 50%), adenovirus (n = 6; 50%), Epstein-Barr virus (n = 3; 25%), or cytomegalovirus (n = 3; 25%). The median duration of follow-up was 2.3 years (range, .5 to 10 years), and the 2-year OS, EFS, and GEFS were 100% (95% confidence interval [CI], 0 to 100%), 73% (95% CI, 37% to 90%), and 73% (95% CI, 37% to 90%), respectively. TCRαß-SCT from mismatched family or unrelated donors, using a chemotherapy-only conditioning regimen, is a safe alternative donor salvage transplantation strategy for second HSCT in patients without a suitably matched donor.
Assuntos
Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Lactente , Receptores de Antígenos de Linfócitos T alfa-beta , Doadores não Relacionados , Estudos Retrospectivos , Viremia , Herpesvirus Humano 4 , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodosRESUMO
Patients with inborn errors of immunity (IEI) have been transplanted for more than 50 years. Many long-term survivors have ongoing medical issues showing the need for further improvements in how hematopoietic stem cell transplantation (HSCT) is performed if patients in the future are to have a normal quality of life. Precise genetic diagnosis enables early treatment before recurrent infection, autoimmunity and organ impairment occur. Newborn screening for severe combined immunodeficiency (SCID) is established in many countries. For newly described disorders the decision to transplant is not straight-forward. Specific biologic therapies are effective for some diseases and can be used as a bridge to HSCT to improve outcome. Developments in reduced toxicity conditioning and methods of T-cell depletion for mismatched donors have made transplant an option for all eligible patients. Further refinements in conditioning plus precise graft composition and additional cellular therapy are emerging as techniques to personalize the approach to HSCT for each patient.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Recém-Nascido , Humanos , Qualidade de Vida , Condicionamento Pré-Transplante/métodos , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Imunodeficiência Combinada Severa/diagnóstico , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante HomólogoRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.
Assuntos
Bronquiectasia , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Bronquiectasia/etiologia , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Adulto JovemRESUMO
Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαß/CD19-depleted haploidentical family donor transplant (TCRαß-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαß-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8-16.6). Donors were TCRαß-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52-99%) for TCRαß-HaploSCT, 80% (41-98%) for MFD, 87% (36-98%) for MUD, and 89% (43-98%) for CB (p = 0.89). Cumulative incidence of grade II-IV acute graft-versus-host disease was 11% (2-79%) after TCRαß-HaploSCT, 0 after MFD, 29% (7-100%) after MUD, and 11% (2-79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0-100%) versus unconditioned transplant (median 3%, 0-9%) (p < 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p < 0.001). TCRαß-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Alemtuzumab , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Estudos Retrospectivos , Imunodeficiência Combinada Severa/cirurgia , Condicionamento Pré-Transplante , Doadores não RelacionadosRESUMO
Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC-busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC-treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8-99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8-25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7-100.0%) and 79% (55-91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.
Assuntos
Adenosina Desaminase , Agamaglobulinemia , Terapia de Reposição de Enzimas , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Adenosina Desaminase/genética , Agamaglobulinemia/cirurgia , Alemtuzumab/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Terapia Genética/métodos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estudos Retrospectivos , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/cirurgia , Condicionamento Pré-TransplanteRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Síndrome de Wiskott-Aldrich , Bussulfano/uso terapêutico , Pré-Escolar , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Síndrome de Wiskott-Aldrich/terapiaRESUMO
Hematopoietic cell transplantation (HCT) has become standard-of-care for an increasing number of inborn errors of immunity (IEI). This report is the first to compare transplant outcomes according to T-cell-replete (ie, T-replete) HLA-matched grafts using alemtuzumab (n = 117) and T-cell-depleted (ie, T-depleted) HLA-mismatched grafts using T-cell receptor-αß (TCRαß)/CD19 depletion (n = 47) in children with IEI who underwent first HCT between 2014 and 2019. All patients received treosulfan-based conditioning except patients with DNA repair disorders. For T-replete grafts, the stem cell source was marrow in 25 (21%) patients, peripheral blood stem cell (PBSC) in 85 (73%), and cord blood in 7 (6%). TCRαß/CD19 depletion was performed on PBSCs from 45 haploidentical parental donors and 2 mismatched unrelated donors. The 3-year overall survival (OS) and event-free survival for the entire cohort were 85% (77%-90%) and 79% (69%-86%), respectively. Analysis according to age at transplant revealed a comparable 3-year OS between T-replete grafts (88%; 76%-94%) and T-depleted grafts (87%; 64%-96%) in younger patients (aged <5 years at HCT). For older patients (aged >5 years), the OS was significantly lower in T-depleted grafts (55%; 23%-78%) compared with T-replete grafts (87%; 68%-95%) (P = .03). Grade III to IV acute graft-versus-host disease was observed in 8% of T-replete marrow, 7% of T-replete PBSC, 14% of T-replete cord blood, and 2% of T-depleted PBSC (P = .73). Higher incidence of viremia (P < .001) and delayed CD3 reconstitution (P = .003) were observed after T-depleted graft HCT. These data indicate that mismatched donor transplant after TCRαß/CD19 depletion represents an excellent alternative for younger children with IEI in need of an allograft.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Antígenos CD19 , Criança , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta , Transplante Homólogo/efeitos adversos , Doadores não RelacionadosRESUMO
AIM: This study aims to evaluate the utility of genetic testing of patients diagnosed with periodic fever syndromes and to assess the validity of existing scoring criteria. METHODS: This study retrospectively reviewed the clinical history of patients diagnosed with periodic fever syndromes at Queensland Children's Hospital between November 2014 and June 2018. RESULTS: Forty-three patients were diagnosed with periodic fever syndromes. Diagnoses in the cohort included periodic fever, adenitis, pharyngitis and aphthous stomatitis (10), tumour necrosis factor receptor-associated periodic syndrome (9), cryopyrin-associated periodic syndrome (6), mevalonate kinase deficiency (4) while 14 remained unspecified. No presenting symptoms were uniquely associated with any particular diagnosis. Genetic testing of between 1 and 26 genes was performed in 26 (60%) patients. Two (7.7%) patients had pathogenic variants identified. Variants of uncertain significance which were insufficient to confirm a monogenic disorder were identified in a further 7 (27%) patients. The Eurofever classification criteria correlated with clinical diagnosis for patients diagnosed with cryopyrin-associated periodic syndrome (P = 0.046) and tumour necrosis factor receptor-associated periodic syndrome (P = 0.025) but not for patients diagnosed with mevalonate kinase deficiency (P = 0.47); however, the Eurofever classification criteria were often positive for more than one diagnosis in these patients. CONCLUSION: The European classification criteria can form a potentially useful tool to guide diagnosis; however, clinical judgement remains essential, because the score is often positive for multiple diagnoses. The diagnostic yield of genetic testing in this cohort was low and genetic testing may be more useful to confirm a strong clinical suspicion than to clarify a diagnosis for patients with less clear symptoms.
Assuntos
Febre Familiar do Mediterrâneo , Linfadenite , Deficiência de Mevalonato Quinase , Faringite , Estomatite Aftosa , Criança , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Humanos , Linfadenite/diagnóstico , Linfadenite/genética , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genética , Estudos Retrospectivos , Estomatite Aftosa/diagnóstico , Estomatite Aftosa/genéticaRESUMO
Predisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαß/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36-330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor.
Assuntos
Doenças Genéticas Inatas/terapia , Transplante de Células-Tronco Hematopoéticas , Infecções por Mycobacterium/terapia , Adolescente , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Feminino , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Doença Enxerto-Hospedeiro , Humanos , Lactente , Masculino , Infecções por Mycobacterium/genéticaRESUMO
Blinatumomab, a single-chain, bispecific, T-cell-engaging antibody targeting CD19, is effective in B-precursor acute lymphoblastic leukemia (BCP-ALL), even in the context of chemotherapy-related partial T-cell immunodeficiency. We report 2 patients with BCP-ALL and congenital T-cell immunodeficiency, who obtained an excellent response to blinatumomab. The first, a 6-year-old girl with Schimke immuno-osseous dysplasia (SIOD) and combined immunodeficiency disorder (CID) obtained a minimum residual disease-negative (MRD-) remission of high hyperdiploid BCP-ALL with blinatumomab. At last follow-up, the remission had been sustained for 14 months from diagnosis. The second was a 9-year-old boy with Omenn syndrome and CID who received a mismatched bone marrow transplant from his mother at the age of 4 months and was diagnosed with t(3;11)+ (KMT2A-LARS2) BCP-ALL 9 years after his transplant. He received a 4-drug induction followed by blinatumomab for persistent MRD as a chemotherapy-sparing bridge to transplant and achieved an MRD- remission. T-lymphopenia, whether congenital or acquired, does not compromise the efficacy of blinatumomab.
Assuntos
Aminoacil-tRNA Sintetases , Anticorpos Biespecíficos , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anticorpos Biespecíficos/uso terapêutico , Criança , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Linfócitos TRESUMO
PURPOSE: Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory. METHOD: This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018. RESULTS: The indications of HCT were severe combined immunodeficiency (SCID, n = 158, 27%) and non-SCID PID (n = 438, 73%). The median age at HCT was 2.3 years (range, 0.04 to 18.3 years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3 years (0.08 to 14.7 years). The CIN of post-HCT AD was 3% (2-5%) at 1 year post-HCT, 7% (5-11%) at 5 years post-HCT, and 11% (7-17%) at 8 years post-HCT. The median onset of post-HCT AD was 2.2 years (0.12 to 9.6 years). Autoimmune thyroid disorder (n = 19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n = 7, 22%) and rheumatological manifestations (n = 5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p = 0.01) and T cell-depleted graft (p < 0.001) were significant predictors of post-HCT AD. None of the T cell-depleted graft recipients developed post-HCT AD. Patients with a lower CD3+ count at 6 months post-HCT had a significant higher incidence of post-HCT AD compared to disease controls. Graft-versus-host disease, viral infection, and donor chimerism had no association with post-HCT AD. CONCLUSION: Post-HCT AD occurred in 11% at 8 years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.