Cytogenetics in the management of bone marrow failure syndromes: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

Bone marrow failure syndromes are rare disorders characterized by bone marrow hypocellularity and resultant peripheral cytopenias. The most frequent form is acquired, so-called aplastic anemia or idiopathic aplastic anemia, an auto-immune disorder frequently associated with paroxysmal nocturnal hemoglobinuria, whereas inherited bone marrow failure syndromes are related to pathogenic germline variants. Among newly identified germline variants, GATA2 deficiency and SAMD9/9L syndromes have a special significance. Other germline variants impacting biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, may cause major syndromes including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia. Acquired clonal cytogenetic abnormalities may be present before or at the onset of progression; some have prognostic value and/or represent somatic rescue mechanisms in inherited syndromes. On the other hand, the differential diagnosis between aplastic anemia and hypoplastic myelodysplastic neoplasm remains challenging. Here we discuss the value of cytogenetic abnormalities in bone marrow failure syndromes and propose recommendations for cytogenetic diagnosis and follow-up.

Optimizing diagnostic methods and stem cell transplantation outcomes in pediatric bone marrow failure: a 50-year single center experience.

Peripheral blood cytopenia, a frequent presenting symptom in pediatric patients, can be caused by bone marrow failure (BMF). Timely identification of patients with non-reversible BMF is of crucial importance to reduce the risks of invasive infections and bleeding complications. Most pediatric patients with severe persistent cytopenia, independent of the underlying cause, are offered allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy. Here we report on our management guidelines and HSCT outcomes of pediatric BMF patients to pinpoint improvements and future challenges. We formulated recommendations based on this 50 years' experience, which were implemented at our center in 2017. By analysis of the HSCT cohort of 2017-2023, the 5-year outcome data is presented and compared to historical outcome data. In addition, outcomes of patients transplanted for identified inherited bone marrow failure syndromes (IBMFS) are compared to severe aplastic anemia (SAA) outcomes to underline the often multiorgan disease in IBMFS with implications for long-term survival. Survival of pediatric patients with irreversible BMF has improved tremendously. SAA patients transplanted after 2017 had a superior 5-year overall (OS) and event-free survival (EFS) of 97% and 85% compared to 68% and 59% in the cohort transplanted before 2017 (p = 0.0011 and p = 0.017). A similar trend was seen for BMF, with an OS and EFS of 89% for those transplanted after 2017 compared to 62% and 59% (p > 0.05). This improvement is mainly related to better survival in the first months after HSCT. The long-term survival after HSCT is lower in IBMFS patients as compared to SAA patients due to secondary malignancies and multiorgan toxicity.   Conclusion: Unbiased protocolized in-depth diagnostic strategies are crucial to increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. A comprehensive approach to identify the cause of BMF can prevent treatment delay and be useful to tailor treatment and follow-up protocols. What is Known: • Irreversible BMF in pediatric patients can be caused by a wide spectrum of underlying diseases including (pre)malignant disease, IBMFS and AA. Identifying the exact underlying cause of BMF is crucial for tailored therapy, however often challenging and time-consuming. • Frontline allogeneic HSCT is offered to most pediatric patients with severe BMF as curative treatment. What is New: • Protocolized unbiased diagnostics, short time to treatment (< 3 months) and maximal supportive care until curative treatment can prevent complications with a negative effect on survival such as infection and bleeding. • Personalized follow-up protocols for IBMFS patients are essential to prevent a second decline in survival due to long-term treatment toxicity and extra-hematological disease complications.

Differential diagnosis of bone marrow failure syndromes guided by machine learning.

The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A-specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.

Inherited bone marrow failure syndromes: a review of current practices and potential future research directions.

PURPOSE OF REVIEW: Recent advances in diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have significantly improved disease understanding and patient outcomes. Still, IBMFS present clinical challenges that require further progress. This review aims to provide an overview of the current state of diagnosis and treatment modalities of the major IBMFS seen in paediatrics and present areas of prioritization for future research. RECENT FINDINGS: Haematopoietic cell transplantation (HCT) for IBMFS has greatly improved in recent years, shifting the research and clinical focus towards cancer predispositions and adverse effects of treatment. Each year, additional novel genes and pathogenic variants are described, and genotype-phenotype mapping becomes more sophisticated. Moreover, novel therapeutics exploring disease-specific mechanisms show promise to complement HCT and treat patients who cannot undergo current treatment options. SUMMARY: Research on IBMFS should have short-term and long-term goals. Immediate challenges include solidifying diagnostic and treatment guidelines, cancer detection and treatment, and continued optimization of HCT. Long-term goals should emphasize genotype-phenotype mapping, genetic screening tools and gene-targeted therapy.

[Sternal bone marrow cell morphology evaluation utility for diagnostic categorization in patients with acquired hypocellular bone marrow failure syndromes].

Objective: Diagnostic value assessment of sternal bone marrow cell morphology in patients with acquired hypocellular bone marrow failure syndromes (BMFS) characterized by normal cytogenetics. Methods: A total of 194 eligible patients with an acquired hypocellular BMFS pre-sternum diagnosis in Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College from June 2014 to January 2019 were reviewed. Sternal bone marrow evaluation was performed, and a post-sternum diagnosis was made. Clinical characteristics and overall survival (OS) were then compared among patients with different post-sternum diagnosis. Binary logistic regression was used to develop a predictive scoring system. Results: In 152 patients with pre-sternum AA diagnosis, 29 patients with a pre-sternum idiopathic cytopenia of undetermined significance (ICUS) diagnosis, and 13 patients with a pre-sternum clonal cytopenia of undetermined significance (CCUS) diagnosis, sternal bone marrow evaluation resulted in a change of diagnosis to hypocellular myelodysplastic syndrome (hypo-MDS) in 42.8% (65/152) , 24.1% (7/29) , and 30.8% (4/13) , respectively. Patients with a post-sternum hypo-MDS diagnosis showed a significant difference in OS compared with patients with a post-sternum AA diagnosis (P=0.005) . Patients with ICUS/CCUS showed no difference in OS compared with AA and hypo-MDS (P=0.095 and P=0.480, respectively) . A 4-item predictive scoring system to identify hypocellular BMFS patients that need sternal bone marrow evaluation was developed, including age > 60 years old (OR=6.647, 95% CI 1.954-22.611, P=0.002, 2 points) , neutrophil alkaline phosphatase score ≤ 160 (OR=2.654, 95% CI 1.214-5.804, P=0.014, 1 point) , abnormal erythroid markers evaluated by flow cytometry on iliac bone marrow (OR=6.200, 95% CI 1.165-32.988, P=0.032, 2 points) , and DAT (DNMT3A, ASXL1, TET2) genes mutation (OR=4.809, 95% CI 1.587-14.572, P=0.005, 1 point) . The Akaike information criterin (AIC) was 186.1. Conclusion: Patients with a pre-sternum acquired hypocellular BMFS diagnosis characterized by normal cytogenetics may not reach accurate diagnostic categorization without sternal bone marrow cell morphology evaluation, which could be considered a diagnostic tool for this patient population. A predictive scoring system was developed, and when the total score is ≥ 2 points, sternal bone marrow evaluation should be performed for accurate diagnostic categorization that is critical to optimal patient care.

When to worry about inherited bone marrow failure and myeloid malignancy predisposition syndromes in the setting of a hypocellular marrow.

With our increasing understanding of inherited marrow failure and myeloid malignancy predisposition syndromes, it has become clear that there is a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of both children and adults with unexplained defects in hematopoiesis. Moreover, these conditions are not as rare as previously believed and may present as aplastic anemia, myelodysplastic syndrome, or malignancy over a range of ages. Establishing the correct diagnosis is essential because it has implications for treatment, medical management, cancer screening, and family planning. Our goal is to highlight insights into the pathophysiology of these diseases, review cryptic presentations of these syndromes, and provide useful references for the practicing hematologist.

When does a PNH clone have clinical significance?

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired blood disease caused by somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene required to produce glycophosphatidyl inositol (GPI) anchors. Although PNH cells are readily identified by flow cytometry due to their deficiency of GPI-anchored proteins, the assessment of the clinical significance of a PNH clone is more nuanced. The interpretation of results requires an understanding of PNH pathogenesis and its relationship to immune-mediated bone marrow failure. Only about one-third of patients with PNH clones have classical PNH disease with overt hemolysis, its associated symptoms, and the highly prothrombotic state characteristic of PNH. Patients with classical PNH benefit the most from complement inhibitors. In contrast, two-thirds of PNH clones occur in patients whose clinical presentation is that of bone marrow failure with few, if any, PNH-related symptoms. The clinical presentations are closely associated with PNH clone size. Although exceptions occur, bone marrow failure patients usually have smaller, subclinical PNH clones. This review addresses the common scenarios that arise in evaluating the clinical significance of PNH clones and provides practical guidelines for approaching a patient with a positive PNH result.

The clinical and laboratory evaluation of patients with suspected hypocellular marrow failure.

The overlap in clinical presentation and bone marrow features of acquired and inherited causes of hypocellular marrow failure poses a significant diagnostic challenge in real case scenarios, particularly in nonsevere disease. The distinction between acquired aplastic anemia (aAA), hypocellular myelodysplastic syndrome (MDS), and inherited bone marrow failure syndromes presenting with marrow hypocellularity is critical to inform appropriate care. Here, we review the workup of hypocellular marrow failure in adolescents through adults. Given the limitations of relying on clinical stigmata or family history to identify patients with inherited etiologies, we outline a diagnostic approach incorporating comprehensive genetic testing in patients with hypocellular marrow failure that does not require immediate therapy and thus allows time to complete the evaluation. We also review the clinical utility of marrow array to detect acquired 6p copy number-neutral loss of heterozygosity to support a diagnosis of aAA, the complexities of telomere length testing in patients with aAA, short telomere syndromes, and other inherited bone marrow failure syndromes, as well as the limitations of somatic mutation testing for mutations in myeloid malignancy genes for discriminating between the various diagnostic possibilities.

COVID-19 in 96 Patients With Hematologic Disease: The First Single-center Experience From the Czech Republic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) represents an important infectious complication associated with high mortality rates in patients with hematologic diseases. There have not been published any epidemiologic studies from Czech Republic so far. PATIENTS AND METHODS: This study is the first analysis of patients with hematologic malignancies and bone marrow failure syndromes treated at single hematology center in the Czech Republic between March 1 and December 31, 2020, in whom COVID-19 infection was confirmed. RESULTS: The sample comprised 96 patients aged 26 to 84 years (median, 66.0 years). At the time of their COVID-19 diagnosis, 75 patients (78.1%) were treated for hematologic diseases. Twenty-seven patients (28.1%) in the sample had complete remission (CR) of their hematologic disease. They were nonsignificantly more likely to have asymptomatic to moderate COVID-19 infection than those who failed to achieve CR (74.1% vs. 56.5%; P = .06). A more severe course of the infection was significantly correlated with older age (P = .047). Lung involvement was also statistically significantly associated with older age (P = .045). Over the study period, a total of 15 patients died. Age greater than 60 years was significantly associated with deaths from COVID-19 (P = .036), with failure to achieve CR having a statistically nonsignificant impact on mortality (P = .22). CONCLUSION: These results confirm the prognostic significance of age for achieving treatment response of hematologic disease as well as the severity and mortality of COVID-19 in hematology patients.

High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders.

Telomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter- and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5-20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy.

Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes.

Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndrome (median age 24 years, range 3 months - 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12/23), 53% (25/47) and 56% (25/45) respectively. Genomic characterization resulted in a change of diagnosis in 30/115 (26%) including the identification of germline causes for 3/47 and 16/45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.

Next-generation sequencing in hypoplastic bone marrow failure: What difference does it make?

Hypoplastic bone marrow failure is a diagnostic feature of multiple haematological disorders, which also share a substantial overlap of clinical symptoms. Hence, discrimination of underlying disorders in patients presenting with hypoplastic bone marrow failure remains a major challenge in the clinic. Recent next-generation sequencing (NGS) studies have broadened our understanding of the varying molecular mechanisms and advanced diagnostics of disorders exhibiting hypoplastic bone marrow failure. In this article, we present a literature review of NGS studies of haematological disorders associated with hypoplastic bone marrow failure and highlight the relevance of NGS for improved clinical diagnostics and decision-making.

The clinical significance of PNH-phenotype cells accounting for < 0.01% of total granulocytes detected by the Clinical and Laboratory Standards Institute methods in patients with bone marrow failure.

Small populations of glycosylphosphatidylinositol-anchored protein-deficient (GPI[-]) cells accounting for up to 0.01% of total granulocytes can be accurately detected by a high-sensitivity flow cytometry (FCM) assay established by the Clinical and Laboratory Standards Institute (CLSI method) and have a prognostic value in bone marrow failure (BMF); however, the significance of GPI(-) granulocytes accounting for 0.001-0.009% of granulocytes remains unclear. To clarify this issue, we examined the peripheral blood of 21 BMF patients in whom minor (around 0.01%) populations of GPI(-) granulocytes had been previously detected by a different high-resolution FCM method (OPTIMA method, which defines ≥ 0.003% GPI(-) granulocytes as an abnormal increase) using both the CLSI and OPTIMA methods simultaneously. These two methods detected an "abnormal increase" in GPI(-) granulocytes in 10 patients (48%) and 17 patients (81%), respectively. CLSI detected 0.002-0.005% (median, 0.004%) GPI(-) granulocytes in 7 patients who were deemed positive for PNH-type cells according to the OPTIMA method, which detected 0.003-0.012% (median 0.006%) GPI(-) granulocytes. The clone sizes of GPI(-) cells detected by each assay were positively correlated (r = 0.994, p < 0.001). Of the seven patients who were judged positive for PNH-type cells by OPTIMA alone, five received immunosuppressive therapy, and all of them achieved a partial or complete response. GPI(-) granulocytes detected in BMF patients by the CLSI method should thus be considered significant, even at percentages of < 0.01%.

Desenlace de los pacientes pediátricos con falla medular tratados en un centro de alta complejidad / Outcomes in pediatrics patients diagnosed with bone marrow failure disorders treated in a tertiary care center

INTRODUCCIÓN: Los síndromes de falla medular (SFM) son trastornos infrecuentes, con una incidencia anual de 2-4 casos por millón. Las opciones de tratamiento incluyen terapia de inmunosupresión (TIS) y restaura ción de la hematopoyesis con trasplante de progenitores hematopoyéticas (TPH). OBJETIVO: Analizar los desenlaces de pacientes pediátricos diagnosticados con SFM tratados en una institución de alta complejidad. PACIENTES Y MÉTODO: Estudio retrospectivo de pacientes pediátricos con diagnóstico de SFM que consultaron a la Fundación Valle del Lili, Cali. Se realizo análisis estadístico descriptivo según SFM adquirida (SFMA) y SFM congénita (SFMC). Los desenlaces incluyeron: tratamiento, complicaciones, supervivencia global (SG) en los trasplantados, calculada con el método Kaplan Meier. RESULTADOS: Se incluyeron 24 pacientes con SFM, edad 6,5 ± 4 años, 50% mujeres. El 58% fue ron SFMC, 9 con anemia de Fanconi, 2 disqueratosis congénita, 2 trombocitopenia amegacariocítica congénita, uno anemia Diamond-Blackfan. Doce pacientes con TPH tuvieron SG a 5 años de 83%. SFMA correspondió al 42%, 6 recibieron TIS-TPH, 3 TIS y 1 TPH, la SG del grupo con TIS-TPH fue 86%. Seis pacientes fallecieron, 4/6 relacionadas con infección. CONCLUSIONES: En esta serie fue mayor el número de casos con SFMC. La SG de los pacientes llevados a TPH es comparable con la reportada en estudios recientes. La causa de muerte predominante fue infecciosa que también se ha reportado previamente. El tratamiento instaurado en los pacientes de esta serie mostró resultados favorables en un centro de alta complejidad en un país latinoamericano.

INTRODUCTION: Bone marrow failure (BMF) syndromes are rare disorders with an annual incidence of 2-4 cases per million. Treatment options include immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To analyze the outcomes of pediatric patients diagnosed with BMF treated in a tertiary care center. PATIENTS AND METHODP: Retrospective study of pediatric patients diagnosed with BMF who consulted at Fundación Valle de Lili, Cali. Descriptive statistical analysis was performed according to Acquired BMF (ABMF) and Inherited BMF (IBMF). The outcomes include treatment, complications, overall survival (OS) in transplant patients, calculated using the Kaplan Meier method. RESULTS: We included 24 patients with BMF, average age 6.5 ± 4 years, and 50% were women. 58% presented IBMF, 9 with Fanconi anemia (FA), 2 dyskeratosis congenita, 2 congenital amegakaryocytic thrombocytopenia, and 1 presented Diamond-Blackfan anemia. 12 patients treated with HSCT had a 5-year OS of 83%. ABMF represented 42%. 6 patients received IST-HSCT, 3 received IST, and 1 received HSCT. The OS of the IST-HSCT group was 86%. Six patients died, four of them related to infection. CONCLUSIONS: In this series, there was a higher number of cases with IBMF. The OS of patients treated with HSCT is similar to that reported in recent studies. The most frequent cause of death was of infectious origin which has also been previously reported. The treatment esta blished in the patients showed favorable results in a Latin American tertiary care center.

Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline. RESEARCH QUESTION: What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient? STUDY DESIGN AND METHODS: We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family. RESULTS: We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease. INTERPRETATION: Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.

Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry.

The International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry (NCT01374360) was initiated to optimize patient management by collecting data regarding disease burden, progression, and clinical outcomes. Herein, we report updated baseline demographics, clinical characteristics, disease burden data, and observed trends regarding clone size in the largest cohort of Registry patients. Patients with available data as of July 2017 were stratified by glycosylphosphatidylinositol (GPI)-deficient granulocyte clone size (< 10%, ≥ 10%-< 50%, and ≥ 50%). All patients were untreated with eculizumab at baseline, defined as date of eculizumab initiation or date of Registry enrollment (if never treated with eculizumab). Outcomes assessed in the current analysis included proportions of patients with high disease activity (HDA), history of major adverse vascular events (MAVEs; including thrombotic events [TEs]), bone marrow failure (BMF), red blood cell (RBC) transfusions, and PNH-related symptoms. A total of 4439 patients were included, of whom 2701 (60.8%) had available GPI-deficient granulocyte clone size data. Among these, median clone size was 31.8% (1002 had < 10%; 526 had ≥ 10%-< 50%; 1173 had ≥ 50%). There were high proportions of patients with HDA (51.6%), history of MAVEs (18.8%), BMF (62.6%), RBC transfusion (61.3%), and impaired renal function (42.8%). All measures except RBC transfusion history significantly correlated with GPI-deficient granulocyte clone size. A large proportion of patients with GPI-deficient granulocyte clone size < 10% had hemolysis (9.7%), MAVEs (10.2%), HDA (9.1%), and/or PNH-related symptoms. Although larger GPI-deficient granulocyte clone sizes were associated with higher disease burden, a substantial proportion of patients with smaller clone sizes had history of MAVEs/TEs.

Outcomes in pediatrics patients diagnosed with bone marrow failure disorders treated in a tertiary care center. / Desenlace de los pacientes pediátricos con falla medular tratados en un centro de alta complejidad.

INTRODUCTION: Bone marrow failure (BMF) syndromes are rare disorders with an annual incidence of 2-4 cases per million. Treatment options include immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To analyze the outcomes of pediatric patients diagnosed with BMF treated in a tertiary care center. PATIENTS AND METHOD: Retrospective study of pediatric patients diagnosed with BMF who consulted at Fundación Valle de Lili, Cali. Descriptive statistical analysis was performed according to Acquired BMF (ABMF) and Inherited BMF (IBMF). The outcomes include treatment, complications, overall survival (OS) in transplant patients, calculated using the Kaplan Meier method. RESULTS: We included 24 patients with BMF, average age 6.5 ± 4 years, and 50% were women. 58% presented IBMF, 9 with Fanconi anemia (FA), 2 dyskeratosis congenita, 2 congenital amegakaryocytic thrombocytopenia, and 1 presented Diamond-Blackfan anemia. 12 patients treated with HSCT had a 5-year OS of 83%. ABMF represented 42%. 6 patients received IST-HSCT, 3 received IST, and 1 received HSCT. The OS of the IST-HSCT group was 86%. Six patients died, four of them related to infection. CONCLUSIONS: In this series, there was a higher number of cases with IBMF. The OS of patients treated with HSCT is similar to that reported in recent studies. The most frequent cause of death was of infectious origin which has also been previously reported. The treatment esta blished in the patients showed favorable results in a Latin American tertiary care center.

Soluble NKG2D Ligands Are Potential Biomarkers and Sentinels of Immune-Mediated Bone Marrow Injury in Bone Marrow Failure Syndromes.

Immune-mediated processes are considered important in the pathogenesis of bone marrow failure syndromes (BFS). We previously reported that natural killer group 2D (NKG2D) ligands were expressed on pathological blood cells of patients with BFS and that NKG2D immunity may be involved in bone marrow failure. In addition to membranous NKG2D ligands on the cell surface, soluble NKG2D ligands can exist in plasma. We therefore examined the relationship between soluble NKG2D ligands and blood cell counts in 86 patients with BFS, including aplastic anemia, myelodysplastic syndrome with single lineage dysplasia, and paroxysmal nocturnal hemoglobinuria. Approximately half of the BFS patients were positive for soluble NKG2D ligands in the plasma by enzyme-linked immunosorbent assay, and soluble NKG2D ligand-positive BFS patients exhibited severe cytopenia regardless of membranous NKG2D ligand expression. In vitroanalyses demonstrated that soluble ULBP1, an NKG2D ligand, down-regulated NKG2D receptors on CD2-positive cells in peripheral blood. Moreover, soluble ULBP1 attenuated the cytotoxic effects of peripheral blood mononuclear cells on K562, which express membranous ULBP1. Our results suggest that soluble NKG2D ligands can be easy-to-measure biomarkers for the prediction of activity of immune-meditated bone marrow injury in BFS and that soluble NKG2D ligands suppress redundant immune-mediated bone marrow injury.

Bone Marrow Failure in Children: Approach to Diagnosis and Treatment.

Bone marrow failure has many different etiologies, including genetic defects which manifest with specific syndromes, as well as acquired conditions as a result of insults to the bone marrow leading to aplasia. The clinical picture is varied and clues for the underlying cause may or may not be evident at the time of presentation, frequently leading to a complex workup with a battery of tests often done to rule out genetic defects. The treatment approach for bone marrow failure is very dependent on the underlying cause, which makes it all the more critical to have an accurate diagnosis. First line management essentially consists of either hematopoietic stem cell transplant or immunosuppressive therapy. In this review authors will provide a broad look at the causes of bone marrow failure, the stepwise diagnostic algorithm and the approach to decision making for treatment. Fine details of each cause, and of each treatment modality are beyond the scope of this review which aims to provide an overview.