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2.
Lancet Haematol ; 11(5): e368-e382, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38697731

RESUMO

Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.


Assuntos
Anemia de Diamond-Blackfan , Consenso , Humanos , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/terapia , Anemia de Diamond-Blackfan/genética , Gerenciamento Clínico , Transplante de Células-Tronco Hematopoéticas
3.
Am J Hematol ; 99(8): 1523-1531, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38733340

RESUMO

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.


Assuntos
Anemia Falciforme , Azatioprina , Transplante de Células-Tronco Hematopoéticas , Hidroxiureia , Irmãos , Condicionamento Pré-Transplante , Humanos , Adulto , Transplante de Células-Tronco Hematopoéticas/métodos , Feminino , Masculino , Condicionamento Pré-Transplante/métodos , Estudos Prospectivos , Hidroxiureia/uso terapêutico , Hidroxiureia/administração & dosagem , Pessoa de Meia-Idade , Anemia Falciforme/terapia , Azatioprina/uso terapêutico , Azatioprina/administração & dosagem , Adulto Jovem , Quimeras de Transplante , Alemtuzumab/uso terapêutico , Alemtuzumab/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/etiologia
4.
N Engl J Med ; 390(18): 1663-1676, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38657265

RESUMO

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.).


Assuntos
Hemoglobina Fetal , Edição de Genes , Transplante de Células-Tronco Hematopoéticas , Talassemia beta , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Adulto Jovem , Antígenos CD34 , Talassemia beta/terapia , Talassemia beta/genética , Transfusão de Sangue , Bussulfano/uso terapêutico , Sistemas CRISPR-Cas , Hemoglobina Fetal/biossíntese , Hemoglobina Fetal/genética , Edição de Genes/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas , Proteínas Repressoras/genética , Condicionamento Pré-Transplante , Transplante Autólogo , Agonistas Mieloablativos/uso terapêutico , América do Norte , Europa (Continente)
5.
Bone Marrow Transplant ; 59(6): 832-837, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38443706

RESUMO

Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable of curing these diseases. Allo-HCT has been also shown to be curative in benign hematologic disorders such as aplastic anemia, sickle cell disease, and thalassemia, among others. Recently, the American Society for Transplantation and Cellular Therapy (ASTCT) published standardized definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism. To attempt broader international consensus, a panel of adult and pediatric physician transplant experts was assembled from European Society for Blood and Marrow Transplantation (EBMT), ASTCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), and Asia-Pacific Blood and Marrow Transplantation (APBMT). Consensus was defined as ≥70% of voting members strongly agreeing or somewhat agreeing with a definition. With few exceptions, there was a consensus to endorse the prior ASTCT definitions. Importantly, we revised existing EBMT and CIBMTR data collection forms to align with these harmonized definitions that will facilitate research and international collaboration among transplant researchers and across transplant registries.


Assuntos
Rejeição de Enxerto , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Aloenxertos , Masculino , Feminino , Adulto , Quimeras de Transplante , Transplante Homólogo/métodos
6.
Blood ; 143(25): 2654-2665, 2024 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-38493482

RESUMO

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.


Assuntos
Anemia Falciforme , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro , Transplante Haploidêntico , Humanos , Transplante de Medula Óssea/métodos , Transplante de Medula Óssea/efeitos adversos , Masculino , Feminino , Criança , Adolescente , Adulto , Anemia Falciforme/terapia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante Haploidêntico/métodos , Pré-Escolar , Adulto Jovem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Condicionamento Pré-Transplante/métodos , Pessoa de Meia-Idade , Tiotepa/administração & dosagem , Tiotepa/uso terapêutico
7.
Br J Haematol ; 204(1): e1-e5, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37795523

RESUMO

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.


Assuntos
Anemia Falciforme , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Bussulfano/uso terapêutico , Irmãos , Vidarabina/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Condicionamento Pré-Transplante , Anemia Falciforme/terapia , Estudos Retrospectivos
8.
Blood Rev ; 61: 101097, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37263874

RESUMO

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome, usually caused by loss-of function variants in genes encoding ribosomal proteins. The hallmarks of DBA are anemia, congenital anomalies and cancer predisposition. Although DBA usually presents in childhood, the prevalence in later life is increasing due to an expanding repertoire of implicated genes, improvements in genetic diagnosis and increasing life expectancy. Adult patients uniquely suffer the manifestations of end-organ damage caused by the disease and its treatment, and transition to adulthood poses specific issues in disease management. To standardize and optimize care for this rare disease, in this review we provide updated guidance on the diagnosis and management of DBA, with a specific focus on older adolescents and adults. Recommendations are based upon published literature and our pooled clinical experience from three centres in the United Kingdom (U·K.). Uniquely we have also solicited and incorporated the views of affected families, represented by the independent patient organization, DBA U.K.


Assuntos
Anemia de Diamond-Blackfan , Neoplasias , Adolescente , Humanos , Adulto , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/epidemiologia , Anemia de Diamond-Blackfan/genética , Doenças Raras , Proteínas Ribossômicas/genética , Suscetibilidade a Doenças , Mutação
9.
JMIR Res Protoc ; 11(7): e36780, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35793124

RESUMO

BACKGROUND: There are sparse data on the long-term and late effects of hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). OBJECTIVE: This study aims to establish an international registry of long-term outcomes post-HCT for SCD and demonstrate the feasibility of recruitment at a single site in the United States. METHODS: The Sickle Cell Transplantation Evaluation of Long-Term and Late Effects Registry (STELLAR) was designed to enroll patients with SCD ≥1 year post-HCT, their siblings without SCD, and nontransplanted controls with SCD to collect web-based participant self-reports of health status and practices by using the Bone Marrow Transplant Survivor Study (BMTSS) surveys, health-related quality of life (HRQOL) using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25 or Pediatric Profile-29 survey, chronic graft-versus-host disease (cGVHD) using the symptom scale survey, daily pain using an electronic pain diary, the economic impact of HCT using the financial hardship survey, sexual function using the PROMIS Sexual Function SexFSv2.0 survey, and economic productivity using the American Time Use Survey (ATUS). We also piloted retrieval of clinical data previously submitted to the Center for International Blood and Marrow Transplant Research (CIBMTR); recorded demographics, height, weight, blood pressure, waist and hip circumferences, timed up and go (TUG) test, and handgrip test; and obtained blood for metabolic screening, gonadal function, fertility potential, and biorepository of plasma, serum, RNA, and DNA. RESULTS: Of 100 eligible post-HCT patients, we enrolled 72 (72%) participants aged 9-38 (median 17) years. We also enrolled 19 siblings aged 5-32 (median 10) years and 28 nontransplanted controls with SCD aged 4-46 (median 22) years. Of the total 119 participants, 73 (61%) completed 85 sets of surveys and 41 (35%) contributed samples to the biorepository. We completed ATUS interviews of 28 (24%) participants. We successfully piloted retrieval of data submitted to the CIBMTR and expanded recruitment to multiple sites in the United States, Canada, the United Kingdom, and Nigeria. CONCLUSIONS: It is feasible to recruit subjects and conduct study procedures for STELLAR in order to determine the long-term and late effects of HCT for SCD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36780.

10.
Ann Hematol ; 101(3): 655-665, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34999929

RESUMO

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.


Assuntos
Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/uso terapêutico , Vidarabina/análogos & derivados , Talassemia beta/terapia , Adolescente , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Imunossupressores/uso terapêutico , Lactente , Masculino , Estudos Retrospectivos , Condicionamento Pré-Transplante , Vidarabina/uso terapêutico
12.
Transplant Cell Ther ; 28(2): 105.e1-105.e7, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34649020

RESUMO

Idiopathic aplastic anemia is a rare and life-threatening disorder, and hematopoietic stem cell transplantation (HSCT) from a matched sibling donor (MSD) is the standard treatment strategy for young patients. Alternative donor transplantation (ADT) from a matched unrelated donor or an HLA haploidentical donor is not commonly used in the frontline setting. This systematic review/meta-analysis was conducted to compare ADT as an upfront, rather than delayed, treatment strategy in the absence of an MSD to immunosuppressive therapy (IST) in severe aplastic anemia (SAA). We searched PubMed/MEDLINE and Embase (1998 to 2019) for studies that compared the outcomes of ADT with IST as upfront therapy in patients with SAA. We included studies with 5 patients or more in each arm. Studies that included patients with inherited forms of bone marrow failure syndromes were excluded. The primary outcome was the 5-year overall survival (OS) rate. Five studies met the inclusion criteria and were included in this meta-analysis. The pooled 5-year odds ratio (OR) for OS was statistically significant at 0.44 (95% confidence interval [CI], 0.23 to 0.85) in favor of upfront ADT. In addition, survival was compared between upfront ADT versus salvage ADT in 6 studies. The pooled 5-year OR for OS was statistically significant at 0.31 (95% CI, 0.15 to 0.64) in favor of upfront ADT. Although this analysis has some limitations, including the retrospective nature of the included studies, the lack of ethnic diversity, the predominantly pediatric population, and the relatively suboptimal IST regimen used in some of the studies, it indicates that upfront ADT is a potential alternative treatment option in young and pediatric SAA patients who lack an HLA identical sibling donor, particularly when optimal IST is not available. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.


Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Anemia Aplástica/terapia , Medula Óssea , Criança , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Terapia de Imunossupressão , Estudos Retrospectivos
13.
Transplant Cell Ther ; 27(12): 1004.e1-1004.e8, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34537420

RESUMO

Allogeneic hematopoietic stem cell transplantation (SCT) is the sole established curative treatment option for patients with sickle cell disease (SCD). However, a lack of HLA-identical sibling donors is a limiting factor. Haploidentical related donors are a promising donor pool, potentially extending SCT as a curative treatment option to a larger group of patients with no other meaningful treatment options for their severe SCD. In the present study, we aimed to systematically review the results of haploidentical SCT in patients with SCD. A comprehensive search was performed in MEDLINE/PubMed and Embase up to May 2021. Data were extracted by 2 reviewers independently, and the Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. Fourteen studies met our inclusion criteria. To provide an overview of the results of haploidentical SCT, we grouped the studies into myeloablative conditioning versus nonmyeloablative conditioning as well as into in vitro versus in vivo (ie, with post-transplantation cyclophosphamide) T cell depletion with a subgroup meta-analysis of proportions. All the included studies were observational cohort studies. Only 3 of these studies reported data for both matched sibling donor (MSD) SCT and haploidentical SCT. Based on a comparative meta-analysis of the 3 studies that included both haploidentical and MSD transplantation, graft failure was significantly higher in the haploidentical group than in the MSD group (odds ratio, 5.3; 95% confidence interval [CI], 1.0 to 27.6). Overall survival was not significantly different between the groups. A subgroup meta-analysis of the results of haploidentical SCT showed relatively low overall pooled proportions of graft failure (7%; 95% CI, 2% to 20%), acute graft-versus-host disease (GVHD) (4%; 95% CI, 2% to 12%), and chronic GVHD (11%; 95% CI, 7% to 16%). Overall survival (OS) was high in all the included studies (91%; 95% CI, 85% to 94%). Adjustments to the conditioning regimens, robust pretransplantation and post-transplantation T cell depletion, and improved supportive care have resulted in reduced graft failure and improved OS following haploidentical SCT in patients with SCD. We conclude that the safety of haploidentical SCT in SCD patients has improved significantly, and that this should be considered as a curative option in patients with severe SCD.


Assuntos
Anemia Falciforme , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Anemia Falciforme/terapia , Ciclofosfamida , Humanos , Condicionamento Pré-Transplante
14.
Sci Transl Med ; 13(610): eabf0113, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34516827

RESUMO

Ribosome dysfunction underlies the pathogenesis of many cancers and heritable ribosomopathies. Here, we investigate how mutations in either ribosomal protein large (RPL) or ribosomal protein small (RPS) subunit genes selectively affect erythroid progenitor development and clinical phenotypes in Diamond-Blackfan anemia (DBA), a rare ribosomopathy with limited therapeutic options. Using single-cell assays of patient-derived bone marrow, we delineated two distinct cellular trajectories segregating with ribosomal protein genotypes. Almost complete loss of erythroid specification was observed in RPS-DBA. In contrast, we observed relative preservation of qualitatively abnormal erythroid progenitors and precursors in RPL-DBA. Although both DBA genotypes exhibited a proinflammatory bone marrow milieu, RPS-DBA was characterized by erythroid differentiation arrest, whereas RPL-DBA was characterized by preserved GATA1 expression and activity. Compensatory stress erythropoiesis in RPL-DBA exhibited disordered differentiation underpinned by an altered glucocorticoid molecular signature, including reduced ZFP36L2 expression, leading to milder anemia and improved corticosteroid response. This integrative analysis approach identified distinct pathways of erythroid failure and defined genotype-phenotype correlations in DBA. These findings may help facilitate therapeutic target discovery.


Assuntos
Anemia de Diamond-Blackfan , Medula Óssea , Eritropoese , Humanos , Proteínas Ribossômicas
17.
Bone Marrow Transplant ; 56(10): 2518-2532, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34011966

RESUMO

Aplastic anemia is a relatively rare but potentially fatal disorder, with a reported higher incidence in developing countries in comparison to the West. There are significant variations in epidemiological as well as etiological factors of bone marrow failure syndromes in the developing countries in comparison to the developed world. Furthermore, the management of bone marrow failure syndromes in resource constraint settings has significant challenges including delayed diagnosis and referral, limited accessibility to healthcare facilities, treatment modalities as well as limitations related to patients who require allogeneic stem cell transplantation. Here we will provide a review of the available evidence related to specific issues of aplastic anemia in the developing countries and we summarize suggested recommendations from the Eastern Mediterranean blood and bone marrow transplantation (EMBMT) group and the severe aplastic anemia working party of the European Society of blood and marrow transplantation (SAAWP of EBMT) related to the diagnosis and therapeutic options in countries with restricted resources.


Assuntos
Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Transplante de Medula Óssea , Humanos , Condicionamento Pré-Transplante
18.
Transplant Cell Ther ; 27(2): 167.e1-167.e12, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33830027

RESUMO

Sickle cell disease (SCD) affects more than 300,000 children annually worldwide. Despite improved supportive care, long-term prognosis remains poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is the sole validated curative option, resulting in sustained resolution of the clinical phenotype. The medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated allo-HCT efficacy in adults. Here, we conducted a systematic review/meta-analysis to assess the totality of evidence on the efficacy, or lack thereof, of allo-HCT in treating SCD. We performed a comprehensive literature search using PubMed/Medline, Embase, and Cochrane library databases on November 13, 2019. Four authors independently extracted data on clinical outcomes related to benefits (overall survival [OS] and disease-free survival [DFS]) and harms (acute graft-versus-host disease [aGVHD], chronic graft-versus-host disease [cGVHD], nonrelapse mortality [NRM], and graft failure [GF]). Our search identified a total of 1906 references. Only 33 studies (n= 2853 patients) met our inclusion criteria. We also performed a subset analysis by age. Analyses of all-age groups showed pooled rates of 96% for OS, 90% for DFS, 20% for aGVHD, 10% for cGVHD, 4% for NRM, and 5% for GF. In the pediatric population, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 97%, 91%, 26%, 11%, 5%, and 3%, respectively. In adults, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 98%, 90%, 7%, 1%, 0%, and 14%, respectively. Our data show that allo-HCT is safe and effective, yielding pooled OS rates exceeding 90%. The high GF rate of 14% in adults is concerning and emphasizes the need to evaluate new strategies.


Assuntos
Anemia Falciforme , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Anemia Falciforme/terapia , Medula Óssea , Criança , Humanos , Condicionamento Pré-Transplante
19.
Transplant Cell Ther ; 27(3): 274.e1-274.e5, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781541

RESUMO

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.


Assuntos
Anemia Aplástica , Anemia de Diamond-Blackfan , Transplante de Células-Tronco Hematopoéticas , Anemia Aplástica/terapia , Anemia de Diamond-Blackfan/terapia , Medula Óssea , Criança , Humanos , Estudos Retrospectivos
20.
J Exp Med ; 218(2)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416891

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a "first hit," (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.


Assuntos
Células-Tronco Hematopoéticas/patologia , Leucemia Mielomonocítica Juvenil/patologia , Animais , Biomarcadores Tumorais/genética , Linhagem Celular , Feminino , Humanos , Leucemia Mielomonocítica Juvenil/genética , Masculino , Camundongos , Mutação/genética , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/genética , Regulação para Cima/genética
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