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1.
N Engl J Med ; 390(18): 1663-1676, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38657265

RESUMEN

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). METHODS: We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent ß-thalassemia and a ß0/ß0, ß0/ß0-like, or non-ß0/ß0-like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed. RESULTS: A total of 52 patients with transfusion-dependent ß-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred. CONCLUSIONS: Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent ß-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.).


Asunto(s)
Hemoglobina Fetal , Edición Génica , Trasplante de Células Madre Hematopoyéticas , Talasemia beta , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Adulto Joven , Antígenos CD34 , Talasemia beta/terapia , Talasemia beta/genética , Transfusión Sanguínea , Busulfano/uso terapéutico , Sistemas CRISPR-Cas , Hemoglobina Fetal/biosíntesis , Hemoglobina Fetal/genética , Edición Génica/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas , Proteínas Represoras/genética , Acondicionamiento Pretrasplante , Trasplante Autólogo , Agonistas Mieloablativos/uso terapéutico , América del Norte , Europa (Continente)
2.
Blood ; 143(25): 2654-2665, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38493482

RESUMEN

ABSTRACT: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.


Asunto(s)
Anemia de Células Falciformes , Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped , Trasplante Haploidéntico , Humanos , Trasplante de Médula Ósea/métodos , Trasplante de Médula Ósea/efectos adversos , Masculino , Femenino , Niño , Adolescente , Adulto , Anemia de Células Falciformes/terapia , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante Haploidéntico/métodos , Preescolar , Adulto Joven , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Persona de Mediana Edad , Tiotepa/administración & dosificación , Tiotepa/uso terapéutico
3.
Br J Haematol ; 204(1): e1-e5, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37795523

RESUMEN

How important is choice of conditioning regimen in allogeneic haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD)? We compared HSCT outcomes by conditioning regimen in paediatric patients with SCD from the EBMT registry. In 2010-2020, 251 patients aged <18 years underwent a first matched sibling donor (MSD) HSCT with conditioning based on busulfan-fludarabine (bu-flu; n = 89) or treosulfan-fludarabine (treo-flu; n = 162). In the bu-flu and treo-flu groups, 51.7% and 99.4% of patients, respectively, received thiotepa. Median follow-up was 2.7 years. Two-year overall survival (OS) was 98.7% (95% confidence interval [CI]: 90.9-99.8) with bu-flu and 99.3% (95% CI: 95.2-99.9) with treo-flu (p = 0.63). Grade III-IV acute graft-versus-host disease (GVHD) at 100 days was 2.4% (95% CI: 0.4-7.5) and 0.6% (0.1%-3.2%) for bu-flu and treo-flu respectively (p = 0.25). The 2-year incidence of extensive chronic GVHD was 1.5% (95% CI: 0.1-7.3) with bu-flu and 8.0% (95% CI: 4.1-13.3) with treo-flu (p = 0.057). These multinational data confirm the excellent curative capacity of MSD HSCT with myeloablative conditioning. Both conditioning regimens yielded excellent OS, low rates of acute and chronic GVHD, and low rates of graft failure.


Asunto(s)
Anemia de Células Falciformes , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Niño , Busulfano/uso terapéutico , Hermanos , Vidarabina/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Acondicionamiento Pretrasplante , Anemia de Células Falciformes/terapia , Estudios Retrospectivos
4.
N Engl J Med ; 384(3): 252-260, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33283989

RESUMEN

Transfusion-dependent ß-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).


Asunto(s)
Anemia de Células Falciformes/terapia , Sistemas CRISPR-Cas , Hemoglobina Fetal/biosíntesis , Edición Génica/métodos , Terapia Genética , Proteínas Represoras/genética , Talasemia beta/terapia , Adulto , Anemia de Células Falciformes/genética , Femenino , Hemoglobina Fetal/genética , Humanos , Proteínas Represoras/metabolismo , Adulto Joven , Talasemia beta/genética
5.
Am J Hematol ; 99(8): 1523-1531, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38733340

RESUMEN

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.


Asunto(s)
Anemia de Células Falciformes , Azatioprina , Trasplante de Células Madre Hematopoyéticas , Hidroxiurea , Hermanos , Acondicionamiento Pretrasplante , Humanos , Adulto , Trasplante de Células Madre Hematopoyéticas/métodos , Femenino , Masculino , Acondicionamiento Pretrasplante/métodos , Estudios Prospectivos , Hidroxiurea/uso terapéutico , Hidroxiurea/administración & dosificación , Persona de Mediana Edad , Anemia de Células Falciformes/terapia , Azatioprina/uso terapéutico , Azatioprina/administración & dosificación , Adulto Joven , Quimera por Trasplante , Alemtuzumab/uso terapéutico , Alemtuzumab/administración & dosificación , Rechazo de Injerto/prevención & control , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/etiología
6.
Ann Hematol ; 101(3): 655-665, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34999929

RESUMEN

Significant advances in supportive care for patients with transfusion-dependent thalassemia major (TDT) have improved patients' life expectancy. However, transfusion-associated iron overload remains a significant barrier to long-term survival with good quality of life. Today, allogeneic hematopoietic stem cell transplantation (HSCT) is the current curative standard of care. Alongside selection of the best available donor, an optimized conditioning regimen is crucial to maximize outcomes for patients with TDT undergoing HSCT. The aim of this retrospective analysis was to investigate the role of busulfan-fludarabine-based and treosulfan-fludarabine-based conditioning in TDT patients undergoing HSCT. We included 772 patients registered in the European Society for Blood and Marrow Transplantation (EBMT) database who underwent first HSCT between 2010 and 2018. Four hundred ten patients received busulfan-fludarabine-based conditioning (median age 8.6 years) and 362 patients received treosulfan-fludarabine-based conditioning (median age 5.7 years). Patient outcomes were retrospectively compared by conditioning regimen. Two-year overall survival was 92.7% (95% confidence interval: 89.3-95.1%) after busulfan-fludarabine-based conditioning and 94.7% (95% confidence interval: 91.7-96.6%) after treosulfan-fludarabine-based conditioning. There was a very low incidence of second HSCT overall. The main causes of death were infections, graft-versus-host disease, and rejection. In conclusion, use of busulfan or treosulfan as the backbone of myeloablative conditioning for patients with TDT undergoing HSCT resulted in comparably high cure rates. Long-term follow-up studies are warranted to address the important issues of organ toxicities and gonadal function.


Asunto(s)
Busulfano/análogos & derivados , Busulfano/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos/uso terapéutico , Vidarabina/análogos & derivados , Talasemia beta/terapia , Adolescente , Antineoplásicos/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Inmunosupresores/uso terapéutico , Lactante , Masculino , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Vidarabina/uso terapéutico
7.
Biol Blood Marrow Transplant ; 26(3): 480-485, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31733299

RESUMEN

There have been sporadic reports of the development of delayed disease recurrence after bone marrow transplantation for severe aplastic anemia despite sustained majority or full donor chimerism. This is termed "donor-type aplasia" (DTA). We describe the management and outcome of 11 pediatric patients from 8 institutions in Europe, the United States, and the Middle East who developed DTA at a mean of 35 months post-transplant. These patients were initially transplanted at a mean age of 10.0 years (range, 5.8 to 16.0 years), 9 from matched sibling donors and 2 from matched unrelated donors. Attempts to treat DTA with varying combinations of additional immunosuppression (including intravenous immunoglobulin, donor lymphocyte infusions, stem cell boosts, and other therapies) failed. Ten patients have received a conditioned second transplant, 9 from the same donor and 1 from a new matched unrelated donor. Aplasia has resolved in the remaining patient in response to ongoing eltrombopag therapy. All patients were alive at a mean of 92 months (range, 26 to 195) after a second transplant; 6 are in complete remission, but 4 suffered from second/recurrent DTA at 16 to 129 months after retransplant and required further transplant therapy.


Asunto(s)
Anemia Aplásica , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adolescente , Anemia Aplásica/terapia , Trasplante de Médula Ósea/efectos adversos , Niño , Preescolar , Quimerismo , Europa (Continente) , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recurrencia
8.
Br J Haematol ; 189(4): 635-639, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32330288

RESUMEN

With the developing COVID-19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self-isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life-saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID-19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID-19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID-19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.


Asunto(s)
Anemia/complicaciones , Anemia/terapia , Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/complicaciones , Neumonía Viral/prevención & control , Transfusión Sanguínea , Trasplante de Médula Ósea , COVID-19 , Infección Hospitalaria/prevención & control , Humanos , SARS-CoV-2
9.
Transpl Infect Dis ; 22(1): e13222, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31782875

RESUMEN

BACKGROUND: Haploidentical bone marrow transplant (haplo-BMT) offers near universal donor availability as a curative modality for individuals with severe sickle cell disease (SCD). However, the required intense immunodepletion is associated with increased infectious complications. A paucity of data exists on immune reconstitution following haplo-BMT for SCD. METHODS: A multi-institution learning collaborative was developed in the context of a phase II clinical trial of a non-myeloablative, related haplo-BMT with post-transplant cyclophosphamide for SCD. We report results from a cohort of 23 patients for whom immune reconstitution data up to one year were available. RESULTS: Median age was 14.8 years. Out of 23, 18 participants received pre-conditioning with azathioprine, hydroxyurea, and hypertransfusions. 70% (16/23) of participants had multiple indications for haplo-BMT. We observed excellent immune reconstitution of CD4, CD8, CD19, and CD56 cellular subsets by 6 months post transplant. Engraftment rate and event-free survival in this cohort were 100% and 96%, respectively. 70% (16/23) of patients had at least one viral reactivation or infection, including CMV 35% (8/23), HHV-6 22% (5/23), and polyoma virus 17% (4/23), with no cases of post-transplant lymphoproliferative disease. CONCLUSION: Further prospective studies are needed to better characterize immune reconstitution and the immunologic basis for increased viral reactivation following haplo-BMT with post-transplant cyclophosphamide for SCD.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Trasplante de Médula Ósea/efectos adversos , Ciclofosfamida/administración & dosificación , Reconstitución Inmune , Inmunosupresores/administración & dosificación , Activación Viral , Adolescente , Adulto , Niño , Ensayos Clínicos Fase II como Asunto , Supervivencia sin Enfermedad , Enfermedad Injerto contra Huésped , Humanos , Estudios Prospectivos , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Haploidéntico/efectos adversos , Adulto Joven
10.
Biol Blood Marrow Transplant ; 25(6): 1197-1209, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30500440

RESUMEN

Curative therapy for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor has been frustratingly elusive. In with the goal of improving engraftment while minimizing transplantation-related morbidity, a multi-institutional learning collaborative was developed in the context of a Phase II clinical trial of nonmyeloablative, related HLA-haploidentical (haplo) bone marrow transplantation (BMT) with post-transplantation cyclophosphamide. All eligible participants had hemoglobin SS, and 89% (16 of 18) had an identifiable donor. The median patient age was 20.9 years (IQR, 12.1 to 26.0 years), and the most common indication for transplantation was overt stroke (in 69%; 11 of 16). In the first 3 patients, the conditioning regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. Primary graft rejection occurred in 2 of the 3 patients (67%), which triggered the study-stopping rule. To reduce graft rejection risk, thiotepa was added to the conditioning regimen, and then 15 patients (including 2 with previous graft rejection) underwent haplo-BMT with this thiotepa-augmented conditioning regimen. At a median follow-up of 13.3 months (interquartile range [IQR], 3.8 to 23.1 months), 93% (14 of 15) had >95% stable donor engraftment at 6 months, with 100% overall survival. The median time to neutrophil engraftment (>500) was 22 days (IQR, 19 to 27 days), and that for platelet engraftment (>50 x 109/L) was 28 days (IQR, 27 days to not reached). Two patients had grade III-IV acute GVHD, 1 patient had mild chronic GVHD, and 86% of patients (6 of 7) were off immunosuppression therapy by 1-year post-transplantation. Our data suggest that haplo-BMT with post-transplantation cyclophosphamide and thiotepa improves donor engraftment without significantly increasing morbidity or mortality and could dramatically expand curative options for individuals with SCD.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Médula Ósea/métodos , Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Tiotepa/uso terapéutico , Adolescente , Adulto , Antineoplásicos Alquilantes/farmacología , Niño , Ciclofosfamida/farmacología , Femenino , Humanos , Inmunosupresores/farmacología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tiotepa/farmacología , Donantes de Tejidos , Adulto Joven
11.
Br J Haematol ; 186(2): 321-326, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30980390

RESUMEN

Diamond-Blackfan anaemia (DBA) is a rare bone marrow failure syndrome characterised by anaemia, congenital anomalies and cancer predisposition. Although infections are the second leading cause of mortality in non-transplanted patients, immune function is largely unexplored. We identified quantitative deficits in serum immunoglobulins and/or circulating T, natural killer and B lymphocytes in 59 of 107 unselected patients (55·1%) attending our centre over a 7-year period. Immune abnormalities were independent of ribosomal protein genotype and arose in both steroid-treated and steroid-untreated patients. In summary, these data highlight the high prevalence and spectrum of infections and immune defects in DBA.


Asunto(s)
Anemia de Diamond-Blackfan , Genotipo , Inmunidad Celular , Inmunidad Humoral , Adolescente , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/inmunología , Anemia de Diamond-Blackfan/mortalidad , Anemia de Diamond-Blackfan/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/inmunología , Reino Unido/epidemiología
12.
Blood ; 129(11): 1548-1556, 2017 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-27965196

RESUMEN

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


Asunto(s)
Anemia de Células Falciformes/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/mortalidad , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Supervivencia de Injerto , Antígenos HLA , Trasplante de Células Madre Hematopoyéticas/mortalidad , Histocompatibilidad , Humanos , Lactante , Masculino , Hermanos , Encuestas y Cuestionarios , Tasa de Supervivencia , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento
13.
Biol Blood Marrow Transplant ; 24(7): 1313-1321, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29653206

RESUMEN

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


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Hemoglobinopatías/terapia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Guías como Asunto , Hemoglobinopatías/patología , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Adulto Joven
14.
Biol Blood Marrow Transplant ; 23(5): 726-735, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28115275

RESUMEN

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled "Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease" held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group.


Asunto(s)
Anemia Aplásica/terapia , Enfermedades de la Médula Ósea/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Hemoglobinuria Paroxística/terapia , Efectos Adversos a Largo Plazo , Anemia Aplásica/complicaciones , Anemia de Diamond-Blackfan/complicaciones , Anemia de Diamond-Blackfan/terapia , Investigación Biomédica/métodos , Investigación Biomédica/tendencias , Enfermedades de la Médula Ósea/complicaciones , Trastornos de Fallo de la Médula Ósea , Niño , Disqueratosis Congénita/complicaciones , Disqueratosis Congénita/terapia , Anemia de Fanconi/complicaciones , Anemia de Fanconi/terapia , Predicción , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemoglobinuria Paroxística/complicaciones , Humanos , Guías de Práctica Clínica como Asunto/normas
15.
Biol Blood Marrow Transplant ; 23(4): 552-561, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28065838

RESUMEN

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


Asunto(s)
Anemia de Células Falciformes/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Talasemia/terapia , Niño , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Factores de Riesgo , Factores de Tiempo , Donantes de Tejidos/provisión & distribución , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo
16.
Biol Blood Marrow Transplant ; 23(9): 1422-1428, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28533057

RESUMEN

Patients with inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia (FA), dyskeratosis congenita (DC), or Diamond Blackfan anemia (DBA), can have hematologic manifestations cured through hematopoietic cell transplantation (HCT). Subsequent late effects seen in these patients arise from a combination of the underlying disease, the pre-HCT therapy, and the HCT process. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium on late effects screening and recommendations following allogeneic hematopoietic cell transplantation for immune deficiency and nonmalignant hematologic diseases held in Minneapolis, Minnesota in May 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. This multidisciplinary group of experts in rare diseases and transplantation late effects has already published on the state of the science in this area, along with discussion of an agenda for future research. This companion article outlines consensus disease-specific long-term follow-up screening guidelines for patients with IMBFS.


Asunto(s)
Anemia Aplásica/diagnóstico , Anemia de Diamond-Blackfan/diagnóstico , Enfermedades de la Médula Ósea/diagnóstico , Disqueratosis Congénita/diagnóstico , Anemia de Fanconi/diagnóstico , Trasplante de Células Madre Hematopoyéticas , Hemoglobinuria Paroxística/diagnóstico , Anemia Aplásica/inmunología , Anemia Aplásica/patología , Anemia Aplásica/terapia , Anemia de Diamond-Blackfan/inmunología , Anemia de Diamond-Blackfan/mortalidad , Anemia de Diamond-Blackfan/terapia , Enfermedades de la Médula Ósea/inmunología , Enfermedades de la Médula Ósea/patología , Enfermedades de la Médula Ósea/terapia , Trastornos de Fallo de la Médula Ósea , Niño , Consenso , Conferencias de Consenso como Asunto , Disqueratosis Congénita/inmunología , Disqueratosis Congénita/mortalidad , Disqueratosis Congénita/terapia , Anemia de Fanconi/inmunología , Anemia de Fanconi/mortalidad , Anemia de Fanconi/terapia , Hemoglobinuria Paroxística/inmunología , Hemoglobinuria Paroxística/patología , Hemoglobinuria Paroxística/terapia , Humanos , Cooperación Internacional , Análisis de Supervivencia , Trasplante Homólogo
17.
Blood ; 125(16): 2553-7, 2015 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-25755292

RESUMEN

Diamond-Blackfan anemia (DBA) is a disorder characterized by a selective defect in erythropoiesis. Delineation of the precise defect is hampered by a lack of markers that define cells giving rise to erythroid burst- and erythroid colony-forming unit (BFU-E and CFU-E) colonies, the clonogenic assays that quantify early and late erythroid progenitor (EEP and LEP) potential, respectively. By combining flow cytometry, cell-sorting, and single-cell clonogenic assays, we identified Lin(-)CD34(+)CD38(+)CD45RA(-)CD123(-)CD71(+)CD41a(-)CD105(-)CD36(-) bone marrow cells as EEP giving rise to BFU-E, and Lin(-)CD34(+/-)CD38(+)CD45RA(-)CD123(-)CD71(+)CD41a(-)CD105(+)CD36(+) cells as LEP giving rise to CFU-E, in a hierarchical fashion. We then applied these definitions to DBA and identified that, compared with controls, frequency, and clonogenicity of DBA, EEP and LEP are significantly decreased in transfusion-dependent but restored in corticosteroid-responsive patients. Thus, both quantitative and qualitative defects in erythroid progenitor (EP) contribute to defective erythropoiesis in DBA. Prospective isolation of defined EPs will facilitate more incisive study of normal and aberrant erythropoiesis.


Asunto(s)
Anemia de Diamond-Blackfan/sangre , Células de la Médula Ósea/metabolismo , Células Precursoras Eritroides/metabolismo , Eritropoyesis , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/metabolismo , Antígenos CD/metabolismo , Antígenos CD36/genética , Antígenos CD36/metabolismo , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Endoglina , Citometría de Flujo , Factor de Transcripción GATA1/genética , Factor de Transcripción GATA2/genética , Expresión Génica , Humanos , Inmunofenotipificación , Estudios Prospectivos , Receptores de Superficie Celular/metabolismo
18.
Blood ; 126(2): 176-84, 2015 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-26024875

RESUMEN

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution.


Asunto(s)
Disqueratosis Congénita/genética , Epigénesis Genética , Telomerasa/genética , Alelos , Secuencia de Bases , Células Cultivadas , Estudios de Cohortes , Familia , Humanos , Patrón de Herencia , Datos de Secuencia Molecular , Mutación , Linaje , ARN/genética
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