Adult Aplastic Anemia Research Articles

Proton Density Fat Fraction Quantification (PD-FFQ): Capability for hematopoietic ability assessment and aplastic anemaia diagnosis of adults

PurposeThe purpose of this study was to determine the capability of proton density with fat fraction (PD-FFQ) imaging to help assess hematopoietic ability and diagnose aplastic anemia in adults. MethodsBetween January 2021 and March 2023, patients diagnosed with aplastic anemia (AA: n = 14) or myelodysplastic syndrome (MDS: n = 14) were examined by whole-body PD-FFQ imaging, and 14 of 126 age and gender matched patients who had undergone the same PD-FFQ imaging were selected as control group. All proton density fat fraction (PDFF) index evaluations were then performed by using regions of interest (ROIs). Pearson's correlation was used to determine the relationship between blood test results and each quantitative index, and ROC-based positive test and discrimination analyses to compare capability to differentiate the AA from the non-AA group. Finally, sensitivity, specificity and accuracy of all quantitative indexes were compared by means of McNemar's test. ResultsMean PDFF, standard deviation (SD) and percentage of coefficient of variation (%CV) for vertebrae showed significant correlation with blood test results (−0.52 ≤ r ≤ −0.34, p < 0.05). Specificity (SP) and accuracy (AC) of %CV of PDFF in vertebrae were significantly higher than those of mean PDFF in vertebrae and the posterior superior iliac spine (SP: p = 0.0002, AC: p = 0.0001) and SD of PDFF in vertebrae (SP: p = 0.008, AC: p = 0.008). Moreover, AC of SD of PDFF in vertebrae was significantly higher than that of mean PDFF in vertebrae and the posterior superior iliac spine (p = 0.03). ConclusionWhole-body PD-FFQ imaging is useful for hematopoietic ability assessment and diagnosis of aplastic anemia in adults.

Clinical impact and characteristics of erythroid dysplasia in adult aplastic anaemia: Results from a multicentre registry.

Morphological dysplasia in haematopoietic cells, defined by a 10% threshold in each lineage, is one of the diagnostic criteria for myelodysplastic neoplasms. Dysplasia limited to the erythroid lineage has also been reported in some cases of aplastic anaemia (AA); however, its significance remains unclear. We herein examined the impact of erythroid dysplasia on immunosuppressive therapy responses and survival in AA patients. The present study included 100 eligible AA patients without ring sideroblasts. Among them, 32 had dysplasia in the erythroid lineage (AA with minimal dysplasia [mini-D]). No significant sex or age differences were observed between AA groups with and without erythroid dysplasia. In severe/very severe AA and non-severe AA patients, a response to anti-thymocyte globulin + ciclosporin within 12 months was observed in 80.0% and 60.0% of AA with mini-D and 42.9% and 90.0% of those without dysplasia, with no significant difference (p = 0.29 and p = 0.24 respectively). Overall survival and leukaemia-free survival did not significantly differ between the groups. Collectively, the present results indicate that the presence of erythroid dysplasia did not significantly affect clinical characteristics or outcomes in AA patients, suggesting that its presence in AA is acceptable. Therefore, erythroid dysplasia should not exclude an AA diagnosis.

Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline.

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.

Indigenous antithymocyte globulin-equine to treat aplastic anaemia in adults: a case series from two centres in northeast India

BackgroundImmunosuppressive therapy is the standard management of adults with aplastic anaemia. Antithymocyte globulin is used as first-line treatment of patients not eligible for bone marrow transplantation. This being a rare disease, available evidence in India is scarce. This study aimed to present experience in treating adult aplastic anaemia patients by immunosuppressive therapy using antithymocyte globulin-equine (Thymogam) in two tertiary care centres of northeast India. MethodsThis case series was conducted at the Health city hospital, Guwahati, and Excel Care Hospital, Guwahati from 2018 to 2020. Eighteen adult aplastic anaemia patients who were treated by immunosuppressive therapy with antithymocyte globulin-equine (Thymogam) and followed up for two years were included. Treatment response and relapse are described. ResultsAll the 18 patients, (14 severe, four very severe) were uniformly treated with immunosuppressive therapy (Thymogam 40 mg/kg/d for four days with oral Cyclosporine from Day-1). Cyclosporin A was used as a concomitant drug in 94.44 % of the patients. At two years of follow up, 66.7 % showed a response and the mortality rate was 11.1 %. ConclusionThe results of this case series substantiate the effectiveness of immunosuppressive therapy with a low-cost preparation of horse antithymocyte globulin (Thymogam) along with cyclosporin A in the management of aplastic anaemia patients not suitable for bone marrow transplantation.

Salidroside affects the Th17/Treg cell balance in aplastic anemia via the STAT3/HIF-1α/RORγt pathway

ABSTRACTBackgroundAcquired aplastic anemia (AA) is a life-threatening disease associated with an imbalance in Th17/Treg cells. Regulating this balance may be an effective treatment approach for AA. Rhodiola rosea has shown efficacy in AA treatment, but its mechanisms remain unclear.PurposeWe investigated salidroside's effect (a component of Rhodiola rosea) on Th17/Treg balance in adult AA patients and a mouse model.MethodsHIF-1α mRNA and protein levels were measured in AA patients' peripheral blood. Flow cytometry, qRT-PCR, and WB analyzed salidroside's impact on T cell differentiation, Th17 cells, Treg cells, STAT3, HIF-1α, and RORγt expression. ELISA measured hematopoietic growth factors in mouse serum.ResultsAA patients exhibited elevated HIF-1α levels. Salidroside improved hematopoietic function, increasing blood cell count and enhancing bone marrow. Salidroside induced SCF, TPO, and IL-3 expression while inhibiting IL-2 in mice. Salidroside reduced STAT3, HIF-1α, RORγt, and IL-17a, while increasing FoxP3 expression, correcting the Th17/Treg imbalance in vitro and in vivo.ConclusionSalidroside has potential as a novel AA treatment by correcting the Th17/Treg imbalance through the STAT3/HIF-1α/RORγt pathway.

SEVERITY AND CLINICO-HAEMATOLOGICAL FEATURES OF APLASTIC ANEMIA IN ADULTS PRESENTING TO PUBLIC SECTOR TERTIARY CARE HOSPITAL OF LAHORE: A DESCRIPTIVE CROSS SECTIONAL STUDY

Background &amp; Objective: Aplastic anemia is a rare and heterogeneous disorder. Literature shows inconsis- tencies in frequency and its clinico-hematological findings. Objective of this study was to assess frequency of different severity grades and clinico-hematological features in newly diagnosed cases of aplastic anemia in adults.&#x0D; Methods: In this descriptive, cross-sectional study, conducted in Allama Iqbal Medical College Lahore from October 2021 through April 2022, a total of 100 diagnosed cases of acquired aplastic anemia were included. Modified Camitta's criteria were applied to assess the severity of aplastic anemia. Clinical features such as pallor, fever and bleeding manifestations were determined by history and physical examination. About 3ml whole blood was collected in EDTA vial and run for complete blood count on automated hematology analyzer for hematological Parameters (Hb, Platelets, total leukocyte count and absolute Neutrophil count). Data were entered and analyzed using SPSS version 20. Quantitative variables like age, Hb, TLC and platelet count were expressed as mean ±Standard deviation. Qualitative variables such as gender, severity of aplastic anemia and clinical features were expressed as percentages.&#x0D; Results: In this study, 55% participants were male and 45% were female. All patients had pallor, 61% had fever and 66% had bleeding on presentation. Regarding severity of aplastic anemia, 56% were categorized as severe, 24% as very severe and 20% were as non severe aplastic anemia.&#x0D; Conclusion: Severe aplastic anemia is frequent among male population and at younger age. This information has prognostic implications. Therefore, all patients with aplastic anemia should be assessed for severity for further clinical management.

High-Dimensional Mass Cytometric Analysis of the Bone Marrow Compartment Identifies a Disease-Specific Immune Cell Network in Aplastic Anemia

Idiopathic acquired aplastic anemia (AA) is considered an immune-mediated syndrome of bone marrow failure since approximately 70% of patients respond to immunosuppressive therapy (IST). However, the immune response that underlies the pathogenesis of AA remains incompletely understood. Previous studies have extensively studied the immune cell composition in peripheral blood in AA, but a comprehensive overview of the immune landscape at the site of hematopoietic stem and progenitor cell (HSPC) destruction, the bone marrow, is lacking. We investigated the immune composition of the bone marrow in AA to interrogate which immune populations may be implicated in the pathogenesis of AA. A mass cytometric analysis of bone marrow aspirates was performed using a 39-marker panel for broad immunophenotyping of all major immune lineages and HSPCs. Cryopreserved bone marrow nuclear cells from adult AA patients (n=7) before start of first-line IST with horse-derived anti-thymocyte globulin (hATG) in combination with ciclosporin and age- and sex-matched healthy donors (HDs, n=7) were studied. 6 of 7 AA patients responded to IST. For 3 IST responders paired bone marrow samples taken at six months after start of IST were also included. A Hierarchical Stochastic Neighborhood Embedding (HSNE) analysis in Cytosplore revealed that the bone marrow in AA pre-IST features a distinct immune cell composition compared to HDs. At the major immune lineage level, HSPC and myeloid cell depletion (0.6% vs 33% of all immune cells, p<0.001), decreased B-cell frequencies (9% vs 16%, p=0.007), increased CD4+ T-cell frequencies (37% vs 28%, p=0.04) and increased CD8+ T-cell frequencies (37% vs 20%, p=0.007) were observed. Detailed analysis of these 4 lineages identified 121 phenotypically distinct cell clusters, 45 of which were differentially present (p<0.05) in AA patients pre-IST compared to HDs. To capture the relationships between these 45 immune clusters a Spearman's rank correlation analysis was performed using the cluster frequencies. Two cell networks were identified (Figure 1A), one of which (network AA) was significantly increased in frequency in AA pre-IST (22% vs 5% of all immune cells, p=0.001; Figure 1B). This network consisted of CD16+ myeloid cells, CCR6++ B-cells, Th17-like CCR6+ memory CD4+ T-cells and KLRG1+ terminally differentiated effector memory (EMRA) CD8+ T-cells, compatible with a state of chronic inflammation. Successful treatment with IST largely normalized the immune cell composition at the immune lineage level and strongly reduced the levels of CD16+ myeloid cells. However, at six months after start of IST the frequencies of CCR6++ B-cells, CCR6+ memory CD4+ T-cells and KLRG1+ EMRA CD8+ T-cells were not normalized, which could indicate that ciclosporin is still needed. This study provides a unique overview of the immune landscape in bone marrow in AA pre- and post-IST at a single-cell level. Previously reported cell subsets could be further defined and possible new players that contribute to the pathogenesis of AA were identified. Our findings show that AA is characterized by high frequencies of immune cells compatible with a state of chronic inflammation and provide a basis for future studies to characterize the function of the identified subsets in the pathogenesis of AA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genomic-Based Machine Learning Towards Prediction of the Etiology of Bone Marrow Failure Syndromes

Genetic testing has been increasingly used to assist with differential diagnosis of acquired vs inherited bone marrow failure syndromes (IBMFS), a group of rare and heterogeneous diseases. However, the assay is still costly and not routinely available for many hematologists. To improve decision-making for genetic testing, we developed a genomic-based machine-learning model based on a two-step data-driven clustering and classification process to predict the likelihood of BMF patients having either an acquired or inherited disease based on 27 clinical and laboratory variables recorded at initial clinical encounter.Clinical records from two independent cohorts of patients screened for pathogenic variants in genes associated with IBMFS were included in this study: the NIH cohort with 441 consecutive patients followed at the NHLBI and NCI, and the USP cohort with 172 consecutive patients from the Medical School of Ribeirão Preto/USP. In a binary target classification, cases were labeled as inherited if they had a pathogenic/likely pathogenic disease-causing variant and as acquired when they had benign or likely benign variants or negative genetic test, regardless of patients' clinical diagnoses. K-means clustering was first applied to resolve our highly dimensional data into two main clusters (Clusters A and B). An optimized bootstrap aggregation ensemble Cluster A specific was trained with cases from the NIH cohort (n=359). The model was then validated with Cluster A cases from the external USP cohort (n=127). The binary classification task was utilized to predict the etiology of BMF cases, labeled as acquired or inherited depending on patients' genomic data.At first, unsupervised clustering separately grouped datasets into Cluster A, the largest group mostly represented by aplastic anemia (AA), and Cluster B, those underrepresented in our cohort including some classical IBMFS at early disease onset. The ensemble model Cluster A-specific was accurate to predict the BMF etiology in 88% of cases, correctly predicting inherited and likely immune BMF in 72% and 92% of cases, respectively. Out of the 27 initial clinical variables included in the model, 25 were found to be important for prediction. Telomere length (TL), age, and clinical variables were most important for the model's predictive accuracy, highlighting that a comprehensive history and physical examination encompassing all organ systems is imperative. Based on our model, genetic testing must be considered for patients in Cluster A predicted to have inherited disease and also for patients in Cluster B as no specific model was available but they were more likely to have IBMFS in comparison to Cluster A (50% vs 30%). We also recommend genetic screening in patients from Cluster A predicted to have acquired disease who are children (age <18 years who may not have clinical signs of IBMFS), have consanguinity in the family, have a diagnosis of myelodysplastic syndromes with or without suspicion for familial predisposition to myeloid malignancies (all cases where the model had limited prediction). A model without TL, an assay that can also be limited in low-resource centers, underperformed for prediction of inherited cases with sensitivity of 55%, highlighting the importance of TL measurement for the model's performance.Our machine-learning model reproduced the clinical knowledge used by clinicians specialized in BMF and accurately predicted BMF etiology in 88% of cases. The model was particularly accurate for differential diagnosis of immune AA in adults, which may allow for selections of patients in whom rapidly starting immunosuppression rather than waiting weeks for genetic results is preferable. Clinical variables were strong predictors and adult patients with severe AA rarely had an inherited disease without a positive family history, a suggestive phenotype of IBMFS, or consanguinity being present. The generalizability of our model indicates that this tool can be used by hematologists not specialized in BMF to prioritize patients that would benefit from genetic testing. TL was a top predictor and a key variable for this model's accuracy. Implementation of TL measurement may be critical for differential diagnosis of BMF, especially in low-resource centers where genetic testing is not feasible or readily available. We plan to continue adding to the model to better predict IBMFS cases that were underrepresented in the current cohort. DisclosuresCalado: Instituto Butantan: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Alexion Brasil: Consultancy; Novartis Brasil: Honoraria; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees; AA&MDS International Foundation: Research Funding. Young: Novartis: Research Funding.

Total body irradiation-containing conditioning regimens without antithymocyte globulin in adults with aplastic anemia undergoing umbilical cord blood transplantation.

Thus far, there have been no large cohort studies on total body irradiation (TBI)-containing conditioning regimens without antithymocyte globulin (ATG) in adults with aplastic anemia (AA) undergoing umbilical cord blood (UCB) transplantation (UCBT). We retrospectively analyzed 115 adults with idiopathic AA undergoing UCBT using TBI-containing reduced-intensity conditioning (RIC) regimens without ATG between 2000 and 2018 on behalf of the Adult Aplastic Anemia Working Group of the Japanese Society for Hematopoietic Cell Transplantation. We then compared transplantation outcomes between a fludarabine (Flu)- and melphalan (Mel)-based regimen (FM) and a Flu- and cyclophosphamide (Cy)-based regimen (FC). The median patient age at UCBT was 41years. The median total nucleated cell and total CD34+ cell doses in a UCB unit at cryopreservation were 2.5 × 107/kg and 0.7 × 105/kg, respectively. The median follow-up period for survivors was 47months. The cumulative incidence rate of neutrophil engraftment was 76.5%, and the 4-year overall survival (OS) rate was 64.3%. In multivariate analysis, the covariates that were significantly associated with a higher neutrophil engraftment were total CD34+ cell dose in an UCB unit (≥ 0.7 × 105/kg; hazard ratio, 0.57, P = 0.01) and total dose of TBI (4Gy of TBI; hazard ratio, 0.32, P = 0.01). There was no significant difference in the cumulative incidence of neutrophil engraftment and the 4-year OS between the FM and FC groups. In conclusion, TBI-containing RIC regimens without ATG are suitable for adults with AA undergoing UCBT. There were no significant differences in transplantation outcomes between the FM and FC groups.

Adult aplastic anemia in Thailand: incidence and treatment outcome from a prospective nationwide population-based study

The incidence and outcomes of aplastic anemia (AA) in Asia remain limited. This study aimed to explore the incidence and outcomes of patients with adult AA across the country of Thailand. This is a prospective multi-center nationwide population-based observational study of AA patients aged at least 15 years old, diagnosed from August 2014 to July 2016, with a longitudinal follow-up period over 2 years. There were 348 newly diagnosed adult AA patients during the enrollment period, giving an annual incidence of 4.6 per million. The incidence of severe (SAA) and very severe aplastic anemia (VSAA) (3.8 per million) was higher than non-severe AA (NSAA, 0.8 per million). The peak incidence was observed in the patients aged from 80 to 89 years old (14.4 per million). The 2-year overall survival (OS) in NSAA, SAA, and VSAA were 65.5%, 49.3%, and 20.1%, respectively (P < 0.001). With regard to the response to immunosuppressive therapy, the overall response rate (ORR) in SAA/VSAA treated with rabbit anti-thymocyte globulin with/without cyclosporin A (rATG ± CsA) were significantly superior to those treated with CsA alone, or anabolic steroids (44.4% vs 36.4% and 31.2%, respectively, P < 0.001). The 2-year OS in SAA/VSAA treated with rATG ± CsA, CsA, and anabolic steroids were 54.8%, 54.5%, and 37.6% (P = 0.037), respectively. The incidence of adult AA in Thailand is higher than those in Western countries, and the peak incidence is in the elderly. rATG ± CsA provided a better response than anabolic steroids, translating to the superior survival in SAA/VSAA treated with rATG ± CsA.

COVID-19 and Aplastic Anemia: Friend or Foe

Aplastic Anemia is a rare hematological disorder caused by bone marrow failure leading to pancytopenia. These patients are frequently treated with immunosuppressive therapy which may protect them in developing hyper-inflammatory response which is commonly seen in moderate and severe COVID-19 patients. On the other hand these patients are at high risk for infection and infection related complications. Here we are reporting an adult aplastic anemia patient who developed uncomplicated course of COVID-19 pneumonia.

Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series

First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.

Negative Impact of Cytomegalovirus Reactivation on Survival in Adult Patients with Aplastic Anemia after an Allogeneic Hematopoietic Stem Cell Transplantation: A Report from Transplantation-Related Complication and Adult Aplastic Anemia Working Groups of the Japan Society for Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) infection is a major infectious complication following an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent large-scale retrospective studies reported that CMV reactivation is an independent risk factor for poor post-transplant outcomes, although the development of CMV end-organ disease is suppressed by the CMV antiviral preemptive therapy, which has been mainly analyzed for hematopoietic malignancies, such as acute leukemia. However, it remains unclear whether CMV reactivation also has a negative effect on post-transplant outcomes in aplastic anemia (AA). Therefore, we evaluated the clinical relevance of CMV reactivation in patients with AA using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Adult patients with AA who underwent their first allo-HSCT between 2005 and 2017 and who survived with neutrophil engraftment until 100 days post-transplantation were analyzed (n=672). Patients were monitored using pp65 antigenemia since the time of engraftment, and CMV reactivation in the analysis of this study was defined as the beginning of CMV preemptive or definitive therapy within 100 days post-transplantation. CMV reactivation occurred in 372 (55%) patients, including 19 with CMV end-organ disease. In time-dependent multivariate analysis, patients aged ≥40 years (hazard ratio [HR], 1.89; P=.003) who underwent transplantation from HLA-matched related peripheral blood stem cells (HR, 2.85; P=.008), HLA-matched unrelated bone marrow (BM) (HR, 2.01; P=.036), and other stem cell sources (HR, 2.32; P=.007) compared to HLA-matched related BM, CMV reactivation (HR 1.65; P=.042), grade II to IV acute graft-versus-host disease (HR 1.73; P=.013), and secondary graft failure (HR 7.09; P < .001) had independent risk factors that significantly decreased overall survival, indicating that CMV reactivation, one of the early events at post-transplantation, had a significant negative impact on the long-term prognosis at post-transplantation. This effect was more pronounced in patients aged ≥40 years who received a graft from other than HLA-matched related BM. Comparing the causes of death with and without CMV reactivation, no significant difference in the frequency of each cause of death was observed between the 2 groups (P=.453). Improvement of post-transplant CMV management that effectively suppresses CMV reactivation in the early stage at post-transplantation will be required to improve post-transplant outcomes, especially in high-risk patients.

Utilization & Barriers to Curative Therapies Among Adult Aplastic Anemia Patients in a Multiethnic Urban Underserved Cohort

Introduction Acquired Aplastic Anemia (AA) is a rare life-threatening immune-mediated bone marrow disorder. AlloHSCT is the only available curative therapy for SAA with a 3 year survival probability for adults between 72-80% in the United States. (D'Souza et all, Biol BMT 2020). The management of AA is complex and requires complicated regimens, recruitment of a BM donor, supportive care and close monitoring of hematopoietic response to therapy. Patients unable to follow closely with their physician or who lack sufficient social support are often deemed inappropriate candidates for BMT. The Bronx is one of the poorest urban counties in the US. 27.4% of Bronx residents live below the poverty line and 59% speak a language other than English at home. The socioeconomic circumstances for many Bronx residents present a multitude of health challenges that lead to poor health outcomes. Delivering the complex diagnosis and treatment strategies required for AA, a rare disease, can be particularly challenging for this population. Through this retrospective cohort study, we sought to find out the rate of utilization of curative therapies among patients with severe aplastic anemia in the Bronx, NY and to identify barriers to their care. We hypothesized that despite several social &amp; financial barriers, SAA patients that can avail of IST +/- AlloHSCT at a tertiary care center will have similar survival trends as the national standard. Methods Our study used a data search tool called Clinical Looking Glass to identify adult patients diagnosed with AA at Montefiore Medical Center (MMC) between 2000 and 2018. Under an IRB approved protocol, we extracted all patients with a bone marrow biopsy performed between 2000 and 2018 and an ICD-9 diagnosis code of AA. Only patients aged 17 and above at the time of the index date (BM biopsy) were included. We also reviewed each chart to ensure the diagnosis of AA was confirmed by the BM biopsy. We performed a retrospective chart review of each patient in our cohort using our electronic medical records. Clinical data collected included patient demographic information, AA classification, date of diagnosis, date of last follow up or date of death, type of therapy received, and identification of socioeconomic barriers to receiving appropriate care. Results Thirty three adult patients (aged 17 and above at time of BM biopsy-confirmed diagnosis) were diagnosed with AA at Montefiore Medical Center between 2000 and 2018. Age at diagnosis ranged from 17-79, with a mean age of 36 and median age 28. Fifty five percent of patients were younger than 30 at the time of diagnosis. Forty two percent of patients were female and 57.6% were male. Fifty two percent of patients were African American or Black, 27.3% were Hispanic, 12.1% were White, and 9.1% were Asian or Asian Indian. Forty two percent of cases were non-severe, 18.2% were severe, and 36.4% were very severe. Additionally, approximately 70% of our cohort was unmarried. Thirty (90%) of the patients were treated with IST (CSA + ATG), and ten (30.3%) were also treated with eltrombopag. Of the 18 patients with severe and very severe disease, seven patients (38.9%) underwent AlloHSCT. Twenty five patients (76%) were noted to be alive at the time of data-cut off for analysis (March 2020), 4 of which were post-AlloHSCT. 45% of patients in our cohort noted significant social &amp; financial barriers to their care. Discussion: Our study demonstrates that despite significant socio-economic barriers to care, adult patients with SAA that are treated with IST +/- AlloHSCT when indicated, have overall survival that equals the national standard. Notably, our patient cohort was more than 75% Black and Hispanic.Race in the US is strongly correlated to socioeconomic status, education, and health insurance status. Some specific social barriers were identified in provider notes. These included difficulty finding a donor match, recent immigration, housing &amp; financial insecurity, difficulty keeping follow up appointments due to transportation issues, lack of adequate health insurance. We believe the first step toward addressing the inequities in AA treatment is the continued acknowledgement of social barriers to care and addressing them in a timely manner. Socio-demographic research should inform health policy and guide interventions to ultimately reduce inequities in access and treatment for rare diseases in some of the most vulnerable in our population. Figure Disclosures No relevant conflicts of interest to declare.

Adult aplastic anemia patients can maintain remission after allogeneic hematopoietic stem cell transplantation in a mixed chimeric state

Aim: Allogeneic stem cell transplantation (allo-SCT) is performed as a curative treatment in young, fit, severe aplastic anemia (SAA) and very severe aplastic anemia (VSAA) patients. Age is one of the most significant factors that impact survival after transplantation. With advancing age, survival rates decrease, therefore it is crucial to perform allo-SCT without any delay in appropriate SAA and VSAA patients. Mixed chimerism (MC) in the post-allo-SCT period may be a sign of relapse or graft failure. In this study, we aimed to evaluate the outcome of allo-SCT in adult SAA and VSAA patients and the significance of chimerism monitoring in follow up. Methods: The data of 16 adult AA patients who underwent allo-SCT at our center were included in this observational study. HLA match, conditioning regimens, chimerism and remission status were recorded. Results: Median PFS was 70.4 months and median OS was 89.7 months in all patients. During the follow-up period, 9 patients remained fully chimeric whereas 6 patients had MC. The chimerism level of one patient, who had engraftment failure, was

Treatment of aplastic anemia in adults

Treatment of aplastic anemia in adults

Efficacy and Safety of Romiplostim in Patients with Acquired Aplastic Anemia Ineligible or Refractory to Immunosuppressive Therapy: Interim Analysis of Phase 2/3 Clinical Trial

Efficacy and Safety of Romiplostim in Patients with Acquired Aplastic Anemia Ineligible or Refractory to Immunosuppressive Therapy: Interim Analysis of Phase 2/3 Clinical Trial

189 - Promising Outcomes of Urgent Cord Blood Transplantation for Fulminant Aplastic Anemia in Adults

189 - Promising Outcomes of Urgent Cord Blood Transplantation for Fulminant Aplastic Anemia in Adults

Outcome of Immune-Suppressive Therapy (IST) and Hematopoietic Stem Cell Transplantation (SCT) in Patients with Aplastic Anemia: A Retrospective Single Center Experience

BackgroundAplastic anemia (AA), characterized by bone marrow failure resulting in pancytopenia, is a rare condition with an incidence rate of 2-3 cases per million per year internationally(Montane et al., 2008). Treatment consists of immune-suppressive therapy (IST), hematopoietic stem cell transplantation (SCT), or both depending on patient factors such as age and comorbidities. Some studies suggest patients who received SCT from alternative transplant donor, specifically matched unrelated donor (MUD), may experience similar outcomes as the time-tested matched related donor (MRD)(Kennedy-Nasser et al., 2006, Buchholz et al., 2008). We compare the survivals of our patients under different treatments and further examine how transplant donor types affect outcomes.MethodsWe retrospectively retrieved the medical records of patients with the ICD-9 and ICD-10 code of aplastic anemia in their diagnosis seen at the University of Arizona Cancer Center/University Medical Center at Tucson, Arizona from 1990 to 2016. There are 104 patients returned with these search criteria. After chart review, patients who did not have aplastic anemia or with insufficient data for analysis were removed, leaving a total of 65 patients in the cohort. Survival analyses with 95% confidence intervals (CI) were estimated by Kaplan-Meier method and compared by log-rank test. P-values less than 0.05 were considered to be statistically significant. All statistical analyses were performed using R Statistical Software (Foundation for Statistical Computing, Vienna, Austria).ResultsA total of 65 patients were included in the study with 25 males (38%) and 40 female (62%). Median age at diagnosis was 22 years ranging from 1 to 64 years. Overall survival (OS) was 70%+/-7.2 (95% CI, 56.8-85.3). Patients were divided into 3 treatment categories including those who had received IST only (13/65, 20%), transplant only (41/65, 63%), and combination (11/65, 17%). OS for each category was 92%+/-7.4, 64%+/-8.5, and 82%+/-11.6, respectively as shown in Figure1A(p=0.321). Applying the same analysis on patients who had received treatment in the last decade from 2007 and beyond showed improved outcomes for those who had received transplant only (9/29, 31%) with OS of 73%+/-17% as demonstrated in Figure1B(p<0.001). Further analysis by comparing OS in patients with various types of transplant donor including MRD (33/65, 51%), MUD (7/65, 11%), umbilical cord blood (UCB) (3/65, 5%), and mismatched (9/65, 14%) showed OS of 76%+/-9%, 71%+/-17%, 67%+/-27%, and 33%+/-16%, respectively as shown in Figure 2 (p=0.012). No significant correlations were found between the amount of CD34 transfused and survival.ConclusionsOur findings suggest IST remains the treatment method with the highest OS for those who are eligible. Advances in supportive care during transplant period in the last decade translate to better outcomes for these patients. For those who are appropriate for SCT, MRD is the optimal donor choice.ReferencesBUCHHOLZ, S., DAMMANN, E., KOENECKE, C., STADLER, M., FRANZKE, A., BLASCZYK, R., BREMER, M., KRAUTER, J., HERTENSTEIN, B., GANSER, A. & EDER, M. 2008. Allogeneic stem cell transplantation from related and unrelated donors for aplastic anaemia in adults–a single-centre experience. Ann Hematol, 87, 551-6.KENNEDY-NASSER, A. A., LEUNG, K. S., MAHAJAN, A., WEISS, H. L., ARCE, J. A., GOTTSCHALK, S., CARRUM, G., KHAN, S. P., HESLOP, H. E., BRENNER, M. K., BOLLARD, C. M. & KRANCE, R. A. 2006. Comparable outcomes of matched-related and alternative donor stem cell transplantation for pediatric severe aplastic anemia. Biol Blood Marrow Transplant, 12, 1277-84.MONTANE, E., IBANEZ, L., VIDAL, X., BALLARIN, E., PUIG, R., GARCIA, N., LAPORTE, J. R., CATALAN GROUP FOR STUDY OF, A. & APLASTIC, A. 2008. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica, 93, 518-23. [Display omitted] [Display omitted] [Display omitted] DisclosuresAnwer:Seattle Genetics: Other: Advisory Board Participant; Incyte: Speakers Bureau.

Suggestion of MUC16 (c.39169C>T) Mutation As a Potential Candidate for Predisposition to Myeloid Malignancy Associated with Trisomy 21

While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. Germline testing for the predisposition to myeloid malignancies is becoming more common with the recognition of multiple familial syndromes. In USA, Clinical Laboratory Improvement Amendments (CLIA) approved testing exists for mutations in RUNX1, GATA2, CEBPA and the other genes of inherited bone marrow failure syndromes. Meanwhile, GATA1 mutation is almost associated with Down syndrome and in acute myeloid leukemia (AML) with acquired trisomy 21. We experienced a case of infant AML with trisomy 21 and coexisting mutation of MUC16.We experienced infant leukemia (FAB classification, AML M7, Acute megakaryoblasticleukemia) with trisomy 21 and coexisting MUC16, SCRIB, and CEBPA mutation in a 7-month-old boy. Peripheral blood (PB) was taken from the boy every day during hospitalization. Bone marrow (BM) examination was performed at initial diagnosis and after remission. All of PB and BM samples were collected with informed consent, and the study was reviewed and approved by the Institutional Review Board of Seoul National University College of Medicine. The selected five PB samples are demonstrated on Fig. 1. G-banding revealed trisomy 21 and fluorescent in situ hybridization (FISH) for chromosome enumeration 21 revealed 71% with trisomy 21 cells in his diagnosis. At first, we suspected transient abnormal myeloproliferative disease associated with mosaic Down syndrome and serially monitored the proportion of cells with trisomy 21 by FISH and the percentage of blast during hospitalization. Cells with trisomy 21 decreased as blast disappeared in PB during chemotherapy, suggesting trisomy 21 is acquired abnormality in leukemic cells.We performed target gene sequencing of 359 genes related to the hematologic neoplasm, bone marrow failure syndrome, and cancer susceptibility to selected five PB. In addition, to search for the inherited predisposition gene to AML, we also performed whole genome sequencing (WGS) with BM specimen at initial diagnosis and after achieving remission. These next generation sequencing (NGS) with the Illumina HiSeq2500 platform revealed MUC16 (c.39169C>T) is the only significant mutation that persisted throughout from initial diagnosis to post-remission status. Mutations which were seen at initial diagnosis but disappeared after achieving remission were SCRIB (c.2197G>A, p.Arg733Trp) and CEBPA (c.371G>A, p.Ala124Val).To investigate whether MUC16 (c.39169C>T) mutation is rare variant which can be detected in normal person, we screened MUC16 mutation in healthy control (n=365) and in patients with other hematologic diseases (adult myelodysplastic syndrome, n=155; adult aplastic anemia, n=57; adult myeloproliferative neoplasm, n=44; childhood myeloid neoplasm, n=26; inherited bone marrow failure syndrome, n=21; idiopathic eosinophilia, n=4; familiar hemophagocytic lymophohistiocytosis, n=10; congenital neutropenia, n=1) using allele-specific PCR. MUC16 (c.39169C>T) was found in none of them. Discovered site of MUC16 (c.39169C>T) was not reported in solid tumor as well, though the other sites of MUC16 were frequently reported. It is generally known that AML with trisomy 21 accompanies GATA1 mutation, but the infant AML in this study did not accompany GATA1 mutation, but rather, MUC16 mutation.In this patient, GATA1 mutation was not found throughout hospital course. Instead, here we suggest that the constitutional MUC16 (c.39169C>T) mutation coexerts with acquired trisomy 21 in the development of infant AML and that MUC16 (c.39169C>T) mutation is a potential candidate gene for predisposition to AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.