RESUMEN
This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty-two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first- or second-generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1-guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second-year post-transplant. All patients engrafted. The 1-year transplant-related mortality was 3% (confidence interval [CI]: 0%-6%). After a median follow-up of 6.3 years, 5-year overall survival and event-free survival are 97% (CI: 93%-100%) and 91% (CI: 79%-100%) respectively. The current 5-year leukaemia-free survival with BCR::ABL1 <0.01% is 97% (CI: 88%-100%) and the current TKI- and DLI-free survival is 95% (CI: 85%-100%). The incidence of chronic graft-versus-host disease (GvHD) was 32%, being severe in four patients (13%). At last follow-up, 31 patients are GvHD-free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP-CML with an excellent disease-free and TKI-free survival.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva , Acondicionamiento Pretrasplante , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Niño , Acondicionamiento Pretrasplante/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Femenino , Preescolar , Estudios Prospectivos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Resultado del Tratamiento , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
We report 5 children with bone marrow failure (BMF) after primary varicella zoster virus (VZV) infection or VZV vaccination, highlighting the highly variable course. Two patients were treated with intravenous immunoglobulins; one had a slow hematologic recovery, and the other was rescued by allogeneic hematopoietic stem cell transplantation (HSCT). Of the 2 patients treated with immunosuppressive therapy with antithymocyte globulin and cyclosporine, one had a complete response, and the other was transplanted for nonresponse. One patient underwent a primary allograft. All patients are alive. This study demonstrated that VZV-associated BMF is a life-threatening disorder that often requires HSCT.
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Trasplante de Células Madre Hematopoyéticas , Infección por el Virus de la Varicela-Zóster , Humanos , Masculino , Femenino , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Preescolar , Herpesvirus Humano 3 , Trastornos de Fallo de la Médula Ósea/etiología , Vacunación/efectos adversos , Enfermedades de la Médula Ósea/etiología , Vacuna contra la Varicela/efectos adversos , Adolescente , Inmunoglobulinas Intravenosas/uso terapéutico , LactanteRESUMEN
We performed a retrospective analysis on 124 patients with transfusion-dependent thalassemia who were registered in the German pediatric registry for stem cell transplantation. All patients underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 2011 and 2020 and belonged mainly to Pesaro risk class 1-2. Four-year overall (OS) and thalassemia-free survival (TFS) were 94.5% ± 2.9% and 88.0% ± 3.4% after treosulfan-fludarabine-thiotepa- and 96.9% ± 3.1% (P = 0.763) and 96.9% ± 3.1% (P = 0.155) after busulfan-fludarabine-based conditioning. Mixed chimerism below 75% occurred predominantly in treosulfan-based regimens (27.5% versus 6.2%). OS and TFS did not differ significantly between matched sibling, other matched family and matched unrelated donor (UD) HSCTs (OS: 100.0%, 100.0%, 96.3% ± 3.6%; TFS: 96.5% ± 2.4%, 90.0% ± 9.5%, 88.9% ± 6.0%). However, mismatched UD-HSCTs performed less favorable (OS: 84.7% ± 7.3% (P = 0.029); TFS: 79.9% ± 7.4% (P = 0.082)). We generated a scoring system reflecting the risk to develop mixed chimerism in our cohort. The main risk-reducing factors were a high CD3+ cell count (≥6 × 107/kg) in the graft, busulfan-conditioning, pre-conditioning therapy and low-targeted ciclosporin A trough levels. Acute GvHD grade III-IV in treosulfan-based concepts predominantly occurred in patients with UD and reduced GvHD prophylaxis but not in the context of high CD3+ cell doses. Taken together, this information might be used to develop more risk-adapted HSCT regimens for thalassemia patients.
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Busulfano/análogos & derivados , Trasplante de Células Madre Hematopoyéticas , Talasemia , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Niño , Talasemia/terapia , Preescolar , Estudios Retrospectivos , Adolescente , Acondicionamiento Pretrasplante/métodos , Complejo CD3 , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Terapia de Inmunosupresión/métodos , LactanteRESUMEN
Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This prospective, randomized, phase 2 trial compared safety and efficacy of busulfan with treosulfan based preparative regimens. Children with non-malignant diseases received fludarabine and either intravenous (IV) busulfan (4.8 to 3.2 mg/kg/day) or IV treosulfan (10, 12, or 14 g/m2/day). Thiotepa administration (2 × 5 mg/kg) was at the investigator's discretion. Primary endpoint was freedom from transplantation (treatment)-related mortality (freedom from TRM), defined as death between Days -7 and +100. Overall, 101 patients (busulfan 50, treosulfan 51) with at least 12 months follow-up were analyzed. Freedom from TRM was 90.0% (95% CI: 78.2%, 96.7%) after busulfan and 100.0% (95% CI: 93.0%, 100.0%) after treosulfan. Secondary outcomes (transplantation-related mortality [12.0% versus 3.9%]) and overall survival (88.0% versus 96.1%) favored treosulfan. Graft failure was more common after treosulfan (n = 11), than after busulfan (n = 2) while all patients were rescued by second procedures except one busulfan patient. CTCAE Grade III adverse events were similar in both groups. This study confirmed treosulfan to be an excellent alternative to busulfan and can be safely used for conditioning treatment in children with non-malignant disease.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Niño , Humanos , Busulfano/uso terapéutico , Estudios Prospectivos , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Vidarabina/uso terapéutico , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
ABSTRACT: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.
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Trasplante de Células Madre Hematopoyéticas , Linfohistiocitosis Hemofagocítica , Trastornos Linfoproliferativos , Recién Nacido , Humanos , Etopósido/uso terapéutico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/diagnóstico , Resultado del Tratamiento , Trasplante de Células Madre Hematopoyéticas/métodos , Trastornos Linfoproliferativos/etiologíaRESUMEN
Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).
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Deleción Cromosómica , Síndromes Mielodisplásicos , Humanos , Niño , Preescolar , Lactante , Remisión Espontánea , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Progresión de la Enfermedad , Factores de Transcripción/genética , Monosomía , Cromosomas Humanos Par 7/genética , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
Intravenously infused treosulfan was evaluated in adult and pediatric patients for conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. A population pharmacokinetic (PK) model was initially developed on 116 adult and pediatric PK profiles from historical trials, to support treosulfan dose recommendations for children in 2 prospective trials. The aim was to assess and update the initial population PK model by inclusion of additional 83 pediatric PK profiles from these 2 trials. The final population PK model was 2-compartmental with dosing in the central compartment, linear elimination, and inter-compartmental clearance. Inter-individual variability was included on clearance (CL), central volume (V1), peripheral volume (V2), and inter-compartmental clearance (Q). The final model described an effect of the body surface area (BSA) on CL, V1, V2, and Q. The final model resulted in a modified dose recommendation for children and advises treosulfan doses of 10 g/m2, 12 g/m2, and 14 g/m2 for BSAs of <0.4 m2, ≥0.4 to <0.9 m2, and ≥0.9 m2, respectively. This simplified BSA-dependent dose recommendation was developed for children, ensuring a well comparable treosulfan exposure as a dose of 14 g/m2 in adults - irrespective of their age and without applying individual therapeutic drug monitoring.
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Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Adulto , Humanos , Niño , Estudios Prospectivos , Acondicionamiento Pretrasplante/métodos , Busulfano/farmacocinética , Busulfano/uso terapéuticoRESUMEN
BACKGROUNDAdoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications.METHODSWe provide results of a personalized T cell manufacturing program evaluating donor, patient, T cell product, and outcome data. Patient-tailored clinical-grade EBV-specific cytotoxic T lymphocyte (EBV-CTL) products from stem cell donors (SCDs), related third-party donors (TPDs), or unrelated TPDs from the allogeneic T cell donor registry (alloCELL) at Hannover Medical School were manufactured by immunomagnetic selection using a CliniMACS Plus or Prodigy device and the EBV PepTivators EBNA-1 and Select. Consecutive manufacturing processes were evaluated, and patient outcome and side effects were retrieved by retrospective chart analysis.RESULTSForty clinical-grade EBV-CTL products from SCDs, related TPDs, or unrelated TPDs were generated for 37 patients with refractory EBV infections or EBV-associated malignancies with and without a history of transplantation, within 5 days (median) after donor identification. Thirty-four patients received 1-14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to a complete response in 20 of 29 patients who were evaluated for clinical response. No infusion-related toxicity was reported. EBV-specific T cells in patients' blood were detectable in 16 of 18 monitored patients (89%) after transfer, and their presence correlated with clinical response.CONCLUSIONPersonalized clinical-grade manufacture of EBV-CTL products via immunomagnetic selection from SCDs, related TPDs, or unrelated TPDs in a timely manner is feasible. Overall, EBV-CTLs were clinically effective and well tolerated. Our data suggest EBV-CTL transfer as a promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT, as well as patients with preexisting organ dysfunction.TRIAL REGISTRATIONNot applicable.FUNDINGThis study was funded in part by the German Research Foundation (DFG, 158989968/SFB 900), the Deutsche Kinderkrebsstiftung (DKS 2013.09), Wilhelm-Sander-Stiftung (reference 2015.097.1), Ellen-Schmidt-Program of Hannover Medical School, and German Federal Ministry of Education and Research (reference 01EO0802).
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Infecciones por Virus de Epstein-Barr , Inmunoterapia Adoptiva , Humanos , Herpesvirus Humano 4 , Inmunoterapia Adoptiva/métodos , Estudios Retrospectivos , Linfocitos T Citotóxicos , Donante no EmparentadoRESUMEN
Human adenovirus (HAdV) infection is a serious complication that can lead to significant morbidity and mortality, especially in immunocompromised pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Control and elimination of HAdV requires the presence of the respective antiviral T cells, and adoptive transfer of virus-specific T cells has become an important new treatment option for patients refractory to antiviral treatment. Although the adenoviral capsid protein hexon is known to be a major immunodominant T cell target across HAdV species, up to 30% of HAdV-seropositive donors show no T cell responses to the overlapping peptide pool spanning the entire protein. Our group recently verified the capsid protein penton as a second immunodominant target in HAdV infection. Here we aimed to investigate the prevalence of both penton-specific and hexon-specific HAdV T cells and their impact in virus control after HSCT. We analyzed the prevalence and characteristics of HAdV-specific T cells in 33 consecutive pediatric patients with HAdV reactivation following allogeneic HSCT and correlated them with viral load analysis. Our study demonstrates that penton is an important immunodominant target antigen of HAdV reactivation/ infection after HSCT in most patients. We demonstrate that in the majority of patients, both penton- and hexon-specific T cells appear at similar time intervals after transplantation. Despite the prevalence for either hexon-specific or penton-specific T cells in individual patients, we were unable to attribute the predominance to specific HLA types or HAdV serotypes. The occurrence of HAdV-specific T cells was closely linked to viral control, arguing for immune monitoring strategies to tailor antiviral treatment and adoptive T cell therapy.
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Infecciones por Adenovirus Humanos , Adenovirus Humanos , Trasplante de Células Madre Hematopoyéticas , Humanos , Niño , Proteínas de la Cápside , Linfocitos T , Adenoviridae , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones por Adenovirus Humanos/epidemiología , Infecciones por Adenovirus Humanos/etiología , AntiviralesRESUMEN
BACKGR OUND: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. METHODS: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. RESULTS: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. CONCLUSION: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.
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Linfopenia , Inmunodeficiencia Combinada Grave , Niño , Recién Nacido , Humanos , Tamizaje Neonatal/métodos , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/terapia , Estudios Prospectivos , Linfopenia/diagnóstico , ADN , Alemania/epidemiología , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
BACKGROUND: Characterization of clinical phenotypes in context with tumor and host genomic information can aid in the development of more effective and less toxic risk-adapted and targeted treatment strategies. To analyze the impact of therapy-related hyperbilirubinemia on treatment outcome and to identify contributing genetic risk factors of this well-recognized adverse effect we evaluated serum bilirubin levels in 1547 pediatric patients with acute lymphoblastic leukemia (ALL) and conducted a genome-wide association study (GWAS). PATIENTS AND METHODS: Patients were treated in multicenter trial AIEOP-BFM ALL 2000 for pediatric ALL. Bilirubin toxicity was graded 0 to 4 according to the Common Toxicity Criteria (CTC) of the National Cancer Institute. In the GWAS discovery cohort, including 650 of the 1547 individuals, genotype frequencies of 745,895 single nucleotide variants were compared between 435 patients with hyperbilirubinemia (CTC grades 1-4) during induction/consolidation treatment and 215 patients without it (grade 0). Replication analyses included 224 patients from the same trial. RESULTS: Compared to patients with no (grade 0) or moderate hyperbilirubinemia (grades 1-2) during induction/consolidation, patients with grades 3-4 had a poorer 5-year event free survival (76.6 ± 3% versus 87.7 ± 1% for grades 1-2, P = 0.003; 85.2 ± 2% for grade 0, P < 0.001) and a higher cumulative incidence of relapse (15.6 ± 3% versus 9.0 ± 1% for grades 1-2, P = 0.08; 11.1 ± 1% for grade 0, P = 0.007). GWAS identified a strong association of the rs6744284 variant T allele in the UGT1A gene cluster with risk of hyperbilirubinemia (allelic odds ratio (OR) = 2.1, P = 7 × 10- 8). TT-homozygotes had a 6.5-fold increased risk of hyperbilirubinemia (grades 1-4; 95% confidence interval (CI) = 2.9-14.6, P = 7 × 10- 6) and a 16.4-fold higher risk of grade 3-4 hyperbilirubinemia (95% CI 6.1-43.8, P = 2 × 10- 8). Replication analyses confirmed these associations with joint analysis yielding genome-wide significance (allelic OR = 2.1, P = 6 × 10- 11; 95% CI 1.7-2.7). Moreover, rs6744284 genotypes were strongly linked to the Gilbert's syndrome-associated UGT1A1*28/*37 allele (r2 = 0.70), providing functional support for study findings. Of clinical importance, the rs6744284 TT genotype counterbalanced the adverse prognostic impact of high hyperbilirubinemia on therapy outcome. CONCLUSIONS: Chemotherapy-related hyperbilirubinemia is a prognostic factor for treatment outcome in pediatric ALL and genetic variation in UGT1A aids in predicting the clinical impact of hyperbilirubinemia. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov ; #NCT00430118.
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Estudio de Asociación del Genoma Completo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Bilirrubina/uso terapéutico , Hiperbilirrubinemia/inducido químicamente , Hiperbilirrubinemia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Resultado del Tratamiento , NiñoRESUMEN
BACKGROUND: The diagnostic yield of next-generation sequencing (NGS) technologies in the diagnosis of monogenic inborn errors of immunity (IEI) remains limited, rarely exceeding 30%. Monoallelic pathogenic germline variants in cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) result in variable immunodeficiency and immune dysregulation. The genetic diagnosis of CTLA-4 insufficiency can affect follow-up procedures and may lead to consideration of treatment with CTLA-4-Ig. OBJECTIVES: The aim of the study was to identify the genetic cause of familial immunodeficiency and immune dysregulation in cases where single nucleotide variant analysis of short-read NGS data yielded no diagnostic result. METHODS: Analysis of copy number variants (CNVs) was applied on short-read NGS data. RESULTS: We identified a novel monoallelic deletion-insertion variant in CTLA-4 (c.445_568-544delinsTTTGCGATTG) resulting in familial autoimmunity. This is the second larger scale variant in CTLA-4, which despite consistently reduced expression of CTLA-4 displayed variable expressivity, ranging from typical juvenile idiopathic arthritis to common variable immunodeficiency-like immunodeficiency. CONCLUSIONS: Our report suggests the significance of integration of CNV analysis in routine evaluation of NGS, which may increase its diagnostic yield in IEI.
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Inmunodeficiencia Variable Común , Síndromes de Inmunodeficiencia , Humanos , Pruebas Genéticas/métodos , Antígeno CTLA-4/genética , Variaciones en el Número de Copia de ADN , Abatacept/genética , Síndromes de Inmunodeficiencia/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Inmunodeficiencia Variable Común/genéticaRESUMEN
Total body irradiation (TBI)-based conditioning is associated with superior leukemia-free survival in children with ALL undergoing HSCT. However, the risk for subsequent malignant neoplasms (SMN) remains a significant concern. We analyzed 705 pediatric patients enrolled in the prospective ALL-SCT-BFM-2003 trial and its subsequent registry. Patients >2 years received conditioning with TBI 12 Gy/etoposide (n = 558) and children ≤2 years of age or with contraindications for TBI received busulfan/cyclophosphamide/etoposide (n = 110). The 5- and 10-year cumulative incidence of SMN was 0.02 ± 0.01 and 0.13 ± 0.03, respectively. In total, 39 SMN (34 solid tumors, 5 MDS/AML) were diagnosed in 33 patients at a median of 5.8 years (1.7-13.4), exclusively in the TBI group. Of 33 affected patients, 21 (64%) are alive at a median follow-up of 5.1 years (0-9.9) after diagnosis of their first SMN. In univariate analysis, neither age at HSCT, donor type, acute GVHD, chronic GVHD, nor CMV constituted a significant risk factor for SMN. The only significant risk factor was TBI versus non-TBI based conditioning. This analysis confirms and quantifies the increased risk of SMN in children with ALL after conditioning with TBI. Future strategies to avoid TBI will need careful tailoring within prospective, controlled studies to prevent unfavorable outcomes.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Neoplasias , Humanos , Niño , Irradiación Corporal Total/efectos adversos , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/patología , Acondicionamiento Pretrasplante/efectos adversos , Incidencia , Estudios de Seguimiento , Trasplante Homólogo/efectos adversos , Etopósido , Estudios Prospectivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Busulfano , Ciclofosfamida , Neoplasias/complicacionesRESUMEN
Mucopolysaccharidosis type I (MPS I) is an autosomal-recessive metabolic disorder caused by an enzyme deficiency of lysosomal alpha-l-iduronidase (IDUA). Haematopoietic stem cell transplantation (HSCT) is the therapeutic option of choice in MPS I patients younger than 2.5 years, which has a positive impact on neurocognitive development. However, impaired growth remains a problem. In this monocentric study, 14 patients with MPS I (mean age 1.72 years, range 0.81-3.08) were monitored according to a standardised follow-up program after successful allogeneic HSCT. A detailed anthropometric program was carried out to identify growth patterns and to determine predictors of growth in these children. All patients are alive and in outpatient care (mean follow-up 8.1 years, range 0.1-16.0). Progressively lower standard deviation scores (SDS) were observed for body length (mean SDS -1.61; -4.58 - 3.29), weight (-0.56; -3.19 - 2.95), sitting height (-3.28; -7.37 - 0.26), leg length (-1.64; -3.88 - 1.49) and head circumference (0.91; -2.52 - 6.09). Already at the age of 24 months, significant disproportions were detected being associated with increasing deterioration in growth for age. Younger age at HSCT, lower counts for haemoglobin and platelets, lower potassium, higher donor-derived chimerism, higher counts for leukocytes and recruitment of a matched unrelated donor (MUD) positively correlated with body length (p ≤ 0.05). In conclusion, this study characterised predictors and aspects of growth patterns in children with MPS I after HSCT, underlining that early HSCT of MUD is essential for slowing body disproportion.
RESUMEN
We report two patients with DNA repair disorders (Artemis deficiency, Ataxia telangiectasia) with destructive skin granulomas, presumably triggered by live-attenuated rubella vaccinations. Both patients showed reduced naïve T cells. Rapid resolution of skin lesions was observed following hematopoietic stem cell transplantation. However, the patient with AT died due to complications of severe hepatic veno-occlusive disease 6 month after HSCT. Dried blood spots obtained after birth were available from this patient and showed absent T-cell receptor excision circles (TRECs). Therefore, newborn screening may help to prevent patients with moderate T-cell deficiency from receiving live-attenuated rubella vaccine potentially causing granulomas.
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Ataxia Telangiectasia , Trastornos por Deficiencias en la Reparación del ADN , Trasplante de Células Madre Hematopoyéticas , Síndromes de Inmunodeficiencia , Ataxia Telangiectasia/genética , Niño , Trastornos por Deficiencias en la Reparación del ADN/complicaciones , Granuloma/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Síndromes de Inmunodeficiencia/genética , Recién Nacido , Virus de la Rubéola/genéticaRESUMEN
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.
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Bronquiectasia , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Bronquiectasia/etiología , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante Homólogo , Adulto JovenRESUMEN
Viral infections and reactivations are major causes of morbidity and mortality after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) as well as in patients with immunodeficiencies. Latent herpesviruses (e.g., cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6), lytic viruses (e.g., adenovirus), and polyomaviruses (e.g., BK virus, JC virus) can cause severe complications. Antiviral drugs form the mainstay of treatment for viral infections and reactivations after transplantation, but they have side effects and cannot achieve complete viral clearance without prior reconstitution of functional antiviral T-cell immunity. The aim of this study was to establish normal ranges for virus-specific T-cell (VST) frequencies in healthy donors. Such data are needed for better interpretation of VST frequencies observed in immunocompromised patients. Therefore, we measured the frequencies of VSTs against 23 viral protein-derived peptide pools from 11 clinically relevant human viruses in blood from healthy donors (n = 151). Specifically, we determined the VST frequencies by interferon-gamma enzyme-linked immunospot assay and classified their distribution according to age and gender to allow for a more specific evaluation and prediction of antiviral immune responses. The reference values established here provide an invaluable tool for immune response evaluation, intensity of therapeutic drugs and treatment decision-making in immunosuppressed patients. This data should make an important contribution to improving the assessment of immune responses in immunocompromised patients.
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Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Virosis , Antivirales , Herpesvirus Humano 4 , Humanos , Huésped Inmunocomprometido , Valores de Referencia , Linfocitos T , Virosis/diagnósticoRESUMEN
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. OBJECTIVE: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. METHODS: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. RESULTS: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P < .001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P < .001). Genetic subgroups did not differ in 2-year OS (P = .1) and EFS (P = .073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5 × 10e3/µL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. CONCLUSION: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.