Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management
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SUBMITTER: Vissers L
PROVIDER: S-EPMC10672506 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with ≥1 extrahematopoietic abnormalities. BM failure, which can involve ≥1 cell lineages, often presents in the pediatric age group. Furthermore, some children initially labeled as having idiopathic aplastic anemia or myelodysplasia represent cryptic cases of inherited BM failure. Significant advances in the genetics of these syndromes have been made, identifying more than 100 disease genes, giving insights into normal hematopoiesis and how it is disrupted in patients with BM failure. They have also provided important information on fundamental biological pathways, including DNA repair: Fanconi anemia (FA) genes; telomere maintenance: dyskeratosis congenita (DC) genes; and ribosome biogenesis: Shwachman-Diamond syndrome and Diamond-Blackfan anemia genes. In addition, because these disorders are usually associated with extrahematopoietic abnormalities and increased risk of cancer, they have provided insights into human development and cancer. In the clinic, genetic tests stemming from the recent advances facilitate diagnosis, especially when clinical features are insufficient to accurately classify a disorder. Hematopoietic stem cell transplantation using fludarabine-based protocols has significantly improved outcomes, particularly in patients with FA or DC. Management of some other complications, such as cancer, remains a challenge. Recent studies have suggested the possibility of new and potentially more efficacious therapies, including a renewed focus on hematopoietic gene therapy and drugs [transforming growth factor-β inhibitors for FA and PAPD5, a human poly(A) polymerase, inhibitors for DC] that target disease-specific defects.
| S-EPMC9373017 | biostudies-literature
Project description:The inherited marrow failure syndromes are a diverse set of genetic disorders characterized by hematopoietic aplasia and cancer predisposition. The clinical phenotypes are highly variable and much broader than previously recognized. The medical management of the inherited marrow failure syndromes differs from that of acquired aplastic anemia or malignancies arising in the general population. Diagnostic workup, molecular pathogenesis, and clinical treatment are reviewed.
| S-EPMC3733544 | biostudies-literature
Project description:PurposeAllogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS).MethodsWe report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months-21 years).ResultsWith a median follow-up of 26 months (range 7 months-9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III-IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%.ConclusionThis alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS.Trial registrationClinicalTrials.gov Identifier: NCT04232085.
| S-EPMC7647188 | biostudies-literature
Project description:Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective was to evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naïve relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.
| S-EPMC10196963 | biostudies-literature
Project description:Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia (DBA), and Shwachman-Diamond syndrome (SDS) are characterized by the progressive development of bone marrow failure. Overproduction of tumour necrosis factor-α (TNF-α) from activated bone marrow T-cells has been proposed as a mechanism of FA-related aplasia. Whether such overproduction occurs in the other syndromes is unknown. We conducted a comparative study on bone marrow mononuclear cells to examine the cellular subset composition and cytokine production. We found lower proportions of haematopoietic stem cells in FA, DC, and SDS, and a lower proportion of monocytes in FA, DC, and DBA compared with controls. The T- and B-lymphocyte proportions were similar to controls, except for low B-cells in DC. We did not observe overproduction of TNF-α or IFN-γ by T-cells in any patients. Induction levels of TNF-α, interleukin (IL)-6, IL-1β, IL-10, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in monocytes stimulated with high-dose lipopolysaccharide (LPS) were similar at 4 h but lower at 24 h when compared to controls. Unexpectedly, patient samples showed a trend toward higher cytokine level in response to low-dose (0·001 μg/ml) LPS. Increased sensitivity to LPS may have clinical implications and could contribute to the development of pancytopenia by creating a chronic subclinical inflammatory micro-environment in the bone marrow.
| S-EPMC3930339 | biostudies-literature
Project description:Bone marrow suppression, including neutropenia, is a major adverse effect of prolonged antibiotic use that impairs the clinical care and outcomes of patients with serious infections. The mechanisms underlying antibiotic-mediated bone marrow suppression remain poorly understood, with initial evidence indicating that depletion of the intestinal microbiota is an important factor. Based on our earlier studies of blood and bone marrow changes in a mouse model of prolonged antibiotic administration, we studied whether changes in megakaryocytes or regulatory T cells (Tregs), two cell types that are critical in the maintenance of hematopoietic stem cells, contribute to antibiotic-mediated bone marrow suppression. Despite increased platelet numbers, megakaryocytes were unchanged in the bone marrow of antibiotic-treated mice; however, Tregs were found to be significantly depleted. Exogenous addition of Tregs was insufficient to rescue the function of bone marrow from antibiotic-treated mice in both colony formation and transplantation assays. These findings indicate that the intestinal microbiota support normal Treg development to protect healthy hematopoiesis, but that the restoration of Tregs alone is insufficient to restore normal bone marrow function.
| S-EPMC7911786 | biostudies-literature
Project description:Bone marrow failure syndromes encompass a range of inherited and acquired hematological diseases that result in insufficient blood cell production, which leads to severe complications including anemia, weakening of the immune system, impaired coagulation, and increased risk of cancer. Within inherited bone marrow failure syndromes, a number of genetically distinct diseases have been described including Shwachman-Diamond syndrome and Fanconi anemia. Given the genetic complexity and poor prognosis of these inherited bone marrow failure syndromes, there is increasing interest in both characterizing the genetic landscapes of these diseases and developing novel gene therapies to effectively monitor and cure patients. These topics were the focus of the winter 2021 International Society for Experimental Hematology New Investigator Webinar, which featured presentations by Dr. Akiko Shimamura and Dr. Paula Río. Here, we review the topics covered within this webinar.
| S-EPMC9165438 | biostudies-literature
Project description:BackgroundERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto.MethodsClinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations.ResultsAll six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication.ConclusionsERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.
| S-EPMC6014454 | biostudies-literature
Project description:BACKGROUND:The management of children with pediatric mastocytosis poses a challenge. This is because there is limited information as to the application of clinical and laboratory findings and bone marrow histopathology as they relate to medical intervention and communication. OBJECTIVE:We sought to examine clinical aspects of pediatric mastocytosis in relationship to serum tryptase levels and bone marrow pathology to provide practical guidance for management. METHODS:Between 1986 and 2012, 105 children were evaluated at the National Institutes of Health. Organomegaly was confirmed by means of ultrasound. Baseline tryptase levels and at least 1 subsequent tryptase measurement was available in 84 and 37 of these children, respectively. Fifty-three children underwent a bone marrow examination. These data were used to examine relationships between clinical findings, tryptase levels, and marrow histopathology. RESULTS:In patients with high tryptase levels and severe mediator symptoms, all with organomegaly had systemic disease, and none without organomegaly had systemic disease. Serum tryptase levels differed significantly between patients with urticaria pigmentosa and those with diffuse cutaneous (P < .0001) and systemic mastocytosis (P < .0001) and in all 3 categories versus control subjects (P < .0001). Tryptase levels and symptoms decreased over time in most patients, and tryptase levels correlated with bone marrow mast cell burden in patients with systemic mastocytosis (P < .0001). There was a significant relationship between clinical resolution and the percentage decrease in tryptase levels (P = .0014). CONCLUSIONS:The majority of children experienced major or complete disease resolution (57%), whereas the remainder exhibited partial improvement. Organomegaly was a strong indicator of systemic disease. Serum tryptase levels furthered classification and reflected clinicopathologic findings, while sequential tryptase measurements were useful in supplementing clinical judgment as to disease course.
| S-EPMC4984538 | biostudies-literature
Project description:Background/Objectives Most of the studies on functional outcomes in pediatric survivors of cancers and bone marrow failure disorders have been conducted in North American, European, and Oceanian populations, with few studies having been performed in China. The objective of this study was to evaluate psychosocial outcomes in a cohort of Chinese pediatric survivors diagnosed with cancer or conditions requiring hematopoietic stem cell transplantation (HSCT), and to identify clinical and behavioral factors associated with adverse psychosocial outcomes. Methods This was a cross-sectional survey study. We recruited pediatric survivors of cancer or inherited disorder requiring HSCT at ≤18 years old and were ≥6 months post-treatment. Parents completed the St. Jude Children’s Research Hospital After Completion of Therapy questionnaire to report their child’s emotional functioning, social functioning, attention/concentration and behavior. Multivariable general linear modeling was used to identify clinical, treatment and behavioral factors associated with psychosocial outcomes, adjusting for sex, age and cancer diagnoses. Results Ninety-five pediatric survivors were recruited (62.1% male; mean [standard deviation] age 9.7 [3.4] years; 4.1 [2.6] years post-diagnosis). They were diagnosed with bone marrow failure disorders (23.2%), hematological malignancies (45.3%) or solid tumors (23.2%). Compared with survivors with no current health problems, those with more than one current health problem performed worse in emotional functioning (Estimate = 2.42, SE = 0.88, P = 0.008) and social functioning (Estimate = 2.90, SE = 1.64, P = 0.03). Higher pain interference was significantly associated with worse emotional functioning (Estimate = 0.19, SE = 0.08, P = 0.03) and attention functioning (Estimate = 0.26, SE = 0.11, P = 0.03). Compared with survivors who reported less sleep problems, those who had more sleep problems demonstrated poorer emotional functioning (Estimate = 0.30, SE = 0.08, P = 0.001). Survivors who had a longer duration of screen usage per day reported more impairment on attention and behavior functioning than those who had a shorter duration of screen usage per day (both P<0.5). Conclusion Survivors who were diagnosed at a younger age or had unaddressed/untreated health problems may require additional psychological evaluation. The implementation of psychosocial assessments during routine long-term follow-up care may help to identify high-risk patients during the early phase of survivorship. Rehabilitation interventions should address modifiable behavioral factors (e.g. sleep habits, screen time and chronic pain).
| S-EPMC9746993 | biostudies-literature