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Hong Y, Lee JM, Lee C, Na D, Jung J, Ahn A, Yoo JW, Lee JW, Chung NG, Kim M, Kim Y. Telomere Length and Genetic Variations in Acquired Pediatric Aplastic Anemia: A Flow-FISH Study in Korean Patients. Diagnostics (Basel) 2025; 15:931. [PMID: 40218281 PMCID: PMC11988933 DOI: 10.3390/diagnostics15070931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
Background: Aplastic anemia (AA) is a rare bone marrow failure syndrome characterized by notably short telomere length, which is associated with treatment responses. In this study, we measured telomere lengths in Korean pediatric AA patients using flow-fluorescence in situ hybridization (Flow-FISH) and explored their shortening in relation to disease characteristics, genetic conditions and patient outcomes. Methods: We analyzed peripheral blood samples from 75 AA patients and 101 healthy controls. Telomere lengths were measured using Flow-FISH, and relative telomere length (RTL) and delta RTL assessments were conducted. Genetic evaluations included karyotyping, chromosome breakage tests and clinical exome sequencing (CES) to identify inherited bone marrow failure syndrome (IBMFS)-associated genetic variants. Results: Telomere lengths in AA patients were significantly lower than those of age-adjusted healthy controls. Patients receiving immunosuppressive therapy tended to have long telomeres, as indicated by high delta RTL values. Patients with genetic abnormalities, including karyotype abnormalities (n = 2) and genetic variants (n = 11) such as carrier genes of IBMFS or variants of unclear significance, showed significantly short telomere lengths. Conclusions: This study reinforces the importance of telomere length as a biomarker in acquired AA. Utilizing Flow-FISH, we were able to accurately measure telomere lengths and establish confidence in this method as an appropriate laboratory test. We found significant reduction in telomere lengths in AA patients, and importantly, longer telomeres were correlated with better outcomes in immunosuppressive therapy. Additionally, our genetic analysis underscored the relevance of variants in IBMFS-associated genes to the pathophysiology of short telomeres.
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Affiliation(s)
- Yuna Hong
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jong-Mi Lee
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Chaeyeon Lee
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Duyeon Na
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jin Jung
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Ari Ahn
- Department of Laboratory Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Jae Won Yoo
- Department of Pediatrics, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.Y.); (J.W.L.)
| | - Jae Wook Lee
- Department of Pediatrics, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.Y.); (J.W.L.)
| | - Nack-Gyun Chung
- Department of Pediatrics, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.Y.); (J.W.L.)
| | - Myungshin Kim
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Yonggoo Kim
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
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Geppner AC. Aplastic anemia: A person-centered approach to diagnosis and treatment. JAAPA 2025; 38:18-27. [PMID: 40052724 DOI: 10.1097/01.jaa.0000000000000195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
ABSTRACT Aplastic anemia (AA) is an inherited, idiopathic, or acquired syndrome of bone marrow failure characterized by pancytopenia and ineffective hematopoiesis. Diagnosis, while crucial, is often difficult due to required exclusion of numerous inherited or acquired diseases with similar phenotypes. Mortality from severe AA without treatment approaches 70% within 2 years. The diagnostic algorithm for AA has increased in complexity, now incorporating molecular and genetic testing, and AA treatment guidelines have evolved to optimize patient outcomes. For individuals younger than age 50 years, a matched sibling allogeneic hematopoietic stem cell transplant remains the treatment of choice, and possible cure, for AA. For those without a donor, immunosuppressive therapy (IST) utilizing equine antithymocyte globulin, cyclosporine A, and eltrombopag is the mainstay of treatment. This article explores updated AA guidelines, covering presentation, diagnostic workup, differential diagnosis, IST, supportive care, and monitoring for appropriate dosing and adverse events.
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Affiliation(s)
- Alexis C Geppner
- Alexis C. Geppner practices in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, Tex. Alexis C. Geppner discloses that she is a consultant for AbbVie Inc., Bristol Myers Squibb, and Daiichi Sankyo
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Wang C, Li J, Liu K, Li J, Zhang F, Ma X, Li Y, Zhang C, Liu X, Qu Y, Zhao M, Li W, Huang W, Li YQ. Donkey-Hide Gelatin-Derived Carbon Dots Activate Erythropoiesis and Eliminate Oxidative Stress for Aplastic Anemia Treatment. ACS NANO 2025; 19:2922-2935. [PMID: 39772431 DOI: 10.1021/acsnano.4c16766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Aplastic anemia (AA) is a life-threatening hematologic disease with limited therapeutic options. Stalled erythropoiesis and oxidative stress-induced hemocyte apoptosis are the main pathological features of AA, yet therapeutic agents that address these issues remain elusive. In this study, we report distinctive donkey-hide gelatin-derived carbon dots (G-CDs) that enable erythropoiesis activation and oxidative stress elimination to tackle refractory AA. We demonstrate that G-CDs can promote the proliferation and erythroid differentiation of hematopoietic stem cells as well as erythrocyte maturation, activating the whole process of erythropoiesis. Moreover, G-CDs display multienzyme-like activities and dramatically alleviate the oxidative stress of bone marrow and peripheral blood via catalytic scavenging of multiple reactive oxygen species, reconstructing the hematopoietic microenvironment. Intravenously or orally administered to AA mice induced by chemotherapy drugs, G-CDs significantly boost the level of red blood cells and hemoglobin and lead to the complete recovery of hematopoietic function, showing better therapeutic performance than clinically approved erythropoietin (EPO) without adverse effects. By collaboratively addressing the issues of stalled erythropoiesis and oxidative stress, the G-CDs-based intervention strategy may offer a powerful paradigm for clinical AA management.
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Affiliation(s)
- Chunzhen Wang
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Jinghui Li
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Kehan Liu
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Junjin Li
- Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Fan Zhang
- Gastroenterology ICU, Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Xiaomin Ma
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Yuezheng Li
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Chengmei Zhang
- Laboratory Animal Center of Shandong University, Jinan 250012, China
| | - Xiangdong Liu
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Yuanyuan Qu
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Mingwen Zhao
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Weifeng Li
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
| | - Weimin Huang
- Orthopedic Department, 960 Hospital of People's Liberation Army, Jinan 250031, China
| | - Yong-Qiang Li
- Institute of Advanced Interdisciplinary Science, School of Physics, Shandong University, Jinan 250100, China
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Guo L, Zhang Y, Liu X, Xiao Y, Luo W, Fang S, Li Y, Lai J, Li Y, Li B. Sex-Biased CD3ζ 3'-UTR SNP Increased Incidence Risk in Aplastic Anemia. Int J Gen Med 2024; 17:6343-6353. [PMID: 39720574 PMCID: PMC11668313 DOI: 10.2147/ijgm.s489870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/12/2024] [Indexed: 12/26/2024] Open
Abstract
Purpose Aplastic anemia (AA) is a bone marrow failure syndrome with an unclear pathogenesis. Abnormal T cell immunity is one of the mechanisms involved in AA, and CD3ζ is an important signaling molecule for T cell activation. Single-nucleotide polymorphisms (SNPs) in CD3ζ 3'-untranslated region (3'-UTR) were associated with some immune-related disease occurrence and affect CD3ζ protein level. In this study, our aim was to analyze whether CD3ζ 3'-UTR SNPs were associated with AA susceptibility and had influence on CD3ζ protein level and provide new research data for exploring the pathogenesis of aplastic anemia. Patients and Methods We screened the genotypes of SNPs in 101 healthy individuals and 91 AA patients by PCR-RFLP and sequencing. In addition, the effect of specific CD3ζ 3'-UTR SNPs was analyzed by flow cytometry and dual luciferase assay. Results Four SNPs of CD3ζ 3'-UTR, 1184 C >G (rs3738212), 1292 delG (rs3831958), 1403 G >C (rs1052230) and 1410 A >T (rs1052231) were identified from Chinese healthy individuals and AA patients in which rs3738212 was not previously reported. Increased risk of AA was observed in female AA who with heterozygous genotype of linkage disequilibrium SNP (rs3831958, rs1052230 and rs1052231). Different genotypes of rs3738212 have sex-biases feature in AA, higher 1184 CC frequency in male AA and higher 1184 CG frequency in female AA. Furthermore, rs3738212 could upregulate CD3ζ protein level. Conclusion This study first identified sex-specific CD3ζ 3'-UTR SNPs that were associated with risk of AA. Our data also demonstrated that rs3738212 could upregulate CD3ζ protein level.
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Affiliation(s)
- Lixing Guo
- Department of Hematology and Oncology, The Fifth Affiliated Hospital of Jinan University, Heyuan, People’s Republic of China
| | - Yuping Zhang
- Department of Hematology, Guangzhou First People’s Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou, People’s Republic of China
| | - Xiaoen Liu
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, People’s Republic of China
| | - Yankai Xiao
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, People’s Republic of China
| | - Weifeng Luo
- Department of Management, Guangzhou Blood Center, Guangzhou, People’s Republic of China
| | - Su Fang
- Institute of Hematology, Xi’an Children’s Hospital, Xi’an, People’s Republic of China
| | - Yan Li
- Department of Cardiology, First Affiliated Hospital, Jinan University, Guangzhou, People’s Republic of China
| | - Jing Lai
- Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, People’s Republic of China
| | - Yangqiu Li
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, People’s Republic of China
- Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, People’s Republic of China
| | - Bo Li
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, People’s Republic of China
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Guo H, Liu C, Kang L, Liu C, Liu Y. Safety and efficacy of eltrombopag in patients with aplastic anemia: a systematic review and meta-analysis of randomized controlled trials. Hematology 2024; 29:2335419. [PMID: 38553907 DOI: 10.1080/16078454.2024.2335419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 03/21/2024] [Indexed: 04/02/2024] Open
Abstract
OBJECTIVE This article conducts a systematic review of eltrombopag combined with immunosuppressive therapy for the treatment of aplastic anemia (AA), to demonstrate the effectiveness and safety of eltrombopag. METHODS PubMed, Cochrane Library, Embase, OVID, Web of Science, China National Knowledge Infrastructure, and Wanfang databases were searched. Studies that met the inclusion criteria were collected, ranging from the establishment of the database to August 2023. Two reviewers performed meta-analyses using the Cochrane systematic review method and RevMan 5.3 software. RESULTS This meta-analysis enrolled 5 studies with a total of 542 AA patients, including 274 in the experimental group and 268 in the control group. Meta-analyses were performed for efficacy and adverse reactions. The endpoint of effects included 6-month complete response (CR), 6-month partial response (PR), and 6-month overall response (OR). Eltrombopag combined with immunotherapy showed significant improvements in 6-month CR (OR: 2.20; 95% CI;1.54-3.12; P < 0.0001) and 6-month OR (OR = 3.66, 95% CI 2.39-5.61, P < 0.001)compared to immunosuppressive therapy for AA patients. In terms of safety, eltrombopag combined with immunosuppressive therapy showed significantly increased pigment deposition and abnormal liver function compared to immunosuppressive therapy alone. CONCLUSION Compared to immunosuppressive therapy alone, eltrombopag combined with immunosuppressive therapy showed significant improvements in 6-month CR and 6-month OR. However, it also resulted in increased pigment deposition and abnormal liver function in terms of safety.
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Affiliation(s)
- Huaipeng Guo
- Department of Hematopathology, Second Affiliated Hospital of Air Force Medical University, Xi'an, People's Republic of China
| | - Cangchun Liu
- Department of Hematopathology, Second Affiliated Hospital of Air Force Medical University, Xi'an, People's Republic of China
| | - Lei Kang
- Department of Cardiology, Second Affiliated Hospital of Air Force Medical University, Xi'an, People's Republic of China
| | - Cong Liu
- Department of Hematopathology, Xi'an International Medical Center Hospital, Xi'an, People's Republic of China
| | - Ying Liu
- Department of Hematopathology, Xi'an International Medical Center Hospital, Xi'an, People's Republic of China
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Wong RSM, Ho Jang J, Wong LLL, Kim JS, Rojnuckarin P, Goh YT, Ueda Y, Chou WC, Lee JW, Kanakura Y, Chiou TJ. Monitoring and Treatment of Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia in Asia: An Expert Consensus. Int J Mol Sci 2024; 25:12160. [PMID: 39596227 PMCID: PMC11594386 DOI: 10.3390/ijms252212160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/05/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) clones can be identified in a significant proportion of patients with aplastic anemia (AA). Screening for PNH clones at the time of an AA diagnosis is recommended by national and international guidelines. In this report, an expert panel of physicians discusses current best practices and provides recommendations for managing PNH in patients with AA in the Asia-Pacific region. Plasma/serum lactate dehydrogenase (LDH) levels and reticulocyte count should be measured with every blood test. PNH clone size should be monitored regularly by flow cytometry, with on-demand testing in the event of a rise in LDH level ± reticulocyte count or development of symptoms such as thrombosis. Monitoring for PNH clones can guide the choice of initial AA treatment, although flow cytometry has resource implications which may present a challenge in some Asia-Pacific countries. The treatment of patients with both PNH and AA depends on which condition predominates; following PNH treatment guidelines if hemolysis is the main symptom and AA treatment guidelines if bone marrow failure is severe (regardless of whether hemolysis is mild or moderate). The expert panel's recommendations on the monitoring and treatment of PNH in patients with AA are practical for healthcare systems in the Asia-Pacific region.
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Affiliation(s)
- Raymond Siu Ming Wong
- Sir Y.K. Pao Centre for Cancer & Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR, China
| | - Jun Ho Jang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 2066 Seobu-Ro, Suwon 16419, Republic of Korea
| | - Lily Lee Lee Wong
- Queen Elizabeth Hospital, 13a, Jalan Penampang, Kota Kinabalu 88200, Sabah, Malaysia
| | - Jin Seok Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, 50-1 Yonsei-ro, Sinchon-dong, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Ponlapat Rojnuckarin
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, 1873 Rama IV Rd, Pathum Wan, Bangkok 10330, Thailand;
- Research Unit in Translational Hematology, Chulalongkorn University, 254 Phaya Thai Rd, Khwaeng Wang Mai, Pathum Wan, Bangkok 10330, Thailand
| | - Yeow-Tee Goh
- Department of Haematology, Singapore General Hospital, Outram Rd, Singapore 169608, Singapore
| | - Yasutaka Ueda
- Department of Hematology and Oncology, Graduate School of Medicine, Faculty of Medicine, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan;
| | - Wen-Chien Chou
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, No.7, Chung Shan S. Rd. (Zhongshan S. Rd), Zhongzheng Dist., Taipei City 100225, Taiwan
| | - Jong Wook Lee
- Division of Hematology-Oncology, Hanyang University Seoul Hospital, 222-1 Wangsimni-ro, Seong-dong-gu, Seoul 04763, Republic of Korea
| | - Yuzuru Kanakura
- Department of Hematology, Sumitomo Hospital, 5-chōme-3-20 Nakanoshima, Kita Ward, Osaka 530-0005, Japan
| | - Tzeon-Jye Chiou
- Cancer Center, Division of Hematology and Oncology, Department of Medicine, Taipei Municipal Wanfang Hospital, Taipei Medical University, No. 111, Section 3, Xinglong Rd, Wenshan District, Taipei City 11696, Taiwan;
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Benmoussa A, Assernannas I, Maatoui-Belabbes H, Dahmaoui N, Qachouh M, Cherkaoui S, Lamchaheb M, Rachid M, Madani A, Khoubila N. [Acquired bone marrow aplasia in children and young adults under the age of 30: Experience of the Pediatric Hematology and Oncology Department of the 20 August Hospital, Casablanca]. Bull Cancer 2024; 111:944-954. [PMID: 39242252 DOI: 10.1016/j.bulcan.2024.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/20/2024] [Accepted: 06/11/2024] [Indexed: 09/09/2024]
Abstract
Bone marrow aplasia is a rare and serious hematologic disorder. Although benign, it is a hematologic disorder whose prognosis can be poor and whose spontaneous development can be fatal. Treatment is long, difficult and costly. In developing countries, the mortality rate is high due to the difficulties of therapeutic management, both supportive and specific. We conducted a retrospective study of 92 cases of AM identified in the Pediatric Hematology and Oncology Department of the 20 Août University Hospital in Casablanca over a 10-year period (January 2010-January 2020). In this work, we present an overview of the situation and highlight the difficulties encountered in the management of AM in the Pediatric Hematology and Oncology Department of the University Hospital of Casablanca. In our study, the mean age was 19 years, ranging from 3 months to 29 years, with a peak in the 15-20 age group. The sex ratio (M/F) was 2.06, with a male predominance of 67%. In our series, only 35% of patients had complete bone marrow failure. An anemic syndrome was present in 92% of patients, and hemorrhagic and infectious syndromes were present in 70% and 41% of patients, respectively. The median time from diagnosis to treatment was 82 days. According to the Camitta score, 31% of our patients had mild AM, 41% had severe AM, and 28% had very severe AM. After etiologic evaluation, we concluded that 90% of the patients had idiopathic bone marrow aplasia, 2% had constitutional bone marrow aplasia, and 8% of the patients were suspected to have secondary bone marrow aplasia: post-hepatitis (3 cases), toxic (2 cases), drug-induced (1 case), and aplastic PNH (1 case). Mortality in the first three months after diagnosis was 21%. Sixty-nine percent of our patients received specific treatment: 28 were treated with cyclosporin (CIS) alone as first-line therapy, 20 received a combination of antilymphocyte serum (ALS) and cyclosporin, 2 received hematopoietic stem cell transplantation (HSCT), while 3 were treated with androgens alone. The overall response rate was 30% with CIS, 42% with ALS+CIS and 100% with HSCT. In our study, the overall death rate was 44%, while the one-year survival rate was 40%. It is important to note that septic shock was the leading cause of death (53% of deaths), followed by hemorrhagic shock (24%). This highlights the lack of hemodynamic resuscitation and symptomatic treatment. Our multivariate study defined the following risk factors as predictive of worse survival: age greater than 16 years (RR: 3.28; CI: 1.29-8.33; P=0.012), PNN less than 200 or very severe bone marrow aplasia (RR: 3.01; 1.1-8.08; P=0.028), and failure to receive any specific treatment (RR: 4.07; 1.77-9.35; P=0.0003). The high overall mortality in our series was due to several factors: inaccessibility to effective therapies, delayed diagnosis, failure to initiate specific treatment, inadequate symptomatic treatment, and geographical and financial inaccessibility.
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Affiliation(s)
- Amine Benmoussa
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc.
| | - Imane Assernannas
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
| | - Hajar Maatoui-Belabbes
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
| | - Nizar Dahmaoui
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
| | - Maryam Qachouh
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
| | - Siham Cherkaoui
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
| | - Mouna Lamchaheb
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
| | - Mohamed Rachid
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
| | - Abdellah Madani
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
| | - Nisrine Khoubila
- Service d'hématologie clinique et d'oncologie pédiatrique, faculté de médecine et de pharmacie de Casablanca, centre hospitalier universitaire 20 Août de Casablanca, Casablanca, Maroc
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Lendrum EC, Smart LR, Vukovic AA. Pancytopenia in the Emergency Department. J Pediatr 2024; 272:114111. [PMID: 38768892 DOI: 10.1016/j.jpeds.2024.114111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/07/2024] [Accepted: 05/15/2024] [Indexed: 05/22/2024]
Affiliation(s)
- Elizabeth C Lendrum
- Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
| | - Luke R Smart
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH; Global Health Center, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH
| | - Adam A Vukovic
- Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
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Guarina A, Farruggia P, Mariani E, Saracco P, Barone A, Onofrillo D, Cesaro S, Angarano R, Barberi W, Bonanomi S, Corti P, Crescenzi B, Dell'Orso G, De Matteo A, Giagnuolo G, Iori AP, Ladogana S, Lucarelli A, Lupia M, Martire B, Mastrodicasa E, Massaccesi E, Arcuri L, Giarratana MC, Menna G, Miano M, Notarangelo LD, Palazzi G, Palmisani E, Pestarino S, Pierri F, Pillon M, Ramenghi U, Russo G, Saettini F, Timeus F, Verzegnassi F, Zecca M, Fioredda F, Dufour C. Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP). Blood Cells Mol Dis 2024; 108:102860. [PMID: 38889660 DOI: 10.1016/j.bcmd.2024.102860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/20/2024]
Abstract
Acquired aplastic anemia (AA) is a rare heterogeneous disorder characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3 per million population per year in the Western world, but 3 times higher in East Asia. Survival in severe aplastic anemia (SAA) has improved significantly due to advances in hematopoietic stem cell transplantation (HSCT), immunosuppressive therapy, biologic agents, and supportive care. In SAA, HSCT from a matched sibling donor (MSD) is the first-line treatment. If a MSD is not available, options include immunosuppressive therapy (IST), matched unrelated donor, or haploidentical HSCT. The purpose of this guideline is to provide health care professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary evidence-based document prepared by a group of pediatric hematologists of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Hemato-Oncology (AIEOP) was discussed, modified and approved during a series of consensus conferences that started online during COVID 19 and continued in the following years, according to procedures previously validated by the AIEOP Board of Directors.
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Affiliation(s)
- A Guarina
- Pediatric Onco-Hematology Unit, A.R.N.A.S. Civico Hospital, Palermo, Italy
| | - P Farruggia
- Pediatric Onco-Hematology Unit, A.R.N.A.S. Civico Hospital, Palermo, Italy
| | - E Mariani
- Scuola di Specializzazione in Pediatria, University of Milano-Bicocca, Milan, Italy; Pediatric Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - P Saracco
- Hematology Unit, "Regina Margherita" Children's Hospital, Turin, Italy
| | - A Barone
- Pediatric Onco-Hematology Unit, University Hospital, Parma, Italy
| | - D Onofrillo
- Hematology Unit, Hospital of Pescara, Pescara, Italy
| | - S Cesaro
- Pediatric Hematology Oncology Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - R Angarano
- Pediatric Oncology-Hematology Unit, AOU Policlinico, Bari, Italy
| | - W Barberi
- Hematology, Department of Hematology, Oncology and Dermatology, AOU Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - S Bonanomi
- Pediatric Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - P Corti
- Pediatric Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - B Crescenzi
- Hematology and Bone Marrow Transplantation Unit, Hospital of Perugia, Perugia, Italy
| | - G Dell'Orso
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - A De Matteo
- Oncology Hematology and Cell Therapies Department, AORN Santobono-Pausilipon, Naples, Italy
| | - G Giagnuolo
- Oncology Hematology and Cell Therapies Department, AORN Santobono-Pausilipon, Naples, Italy
| | - A P Iori
- Hematology and HSCT Unit, University La Sapienza, Rome, Italy
| | - S Ladogana
- Pediatric Onco-Hematology Unit, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - A Lucarelli
- Pediatric Emergency Department, Giovanni XXIII Pediatric Hospital, University of Bari, Bari, Italy
| | - M Lupia
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - B Martire
- Pediatrics and Neonatology Unit, Maternal-Infant Department, "Monsignor A.R. Dimiccoli" Hospital, Barletta, Italy
| | - E Mastrodicasa
- Hematology and Bone Marrow Transplantation Unit, Hospital of Perugia, Perugia, Italy
| | - E Massaccesi
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - L Arcuri
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - M C Giarratana
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - G Menna
- Oncology Hematology and Cell Therapies Department, AORN Santobono-Pausilipon, Naples, Italy
| | - M Miano
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - L D Notarangelo
- Medical Direction, Children's Hospital, ASST-Spedali Civili, Brescia, Italy
| | - G Palazzi
- Department of Mother and Child, University Hospital of Modena, Modena, Italy
| | - E Palmisani
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - S Pestarino
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - F Pierri
- HSCT Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - M Pillon
- Maternal and Child Health Department Pediatric Hematology, Oncology and Stem Cell Transplant Center, University of Padua, Padua, Italy
| | - U Ramenghi
- Hematology Unit, "Regina Margherita" Children's Hospital, Turin, Italy
| | - G Russo
- Division of Pediatric Hematology/Oncology, University of Catania, Catania, Italy
| | - F Saettini
- Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - F Timeus
- Pediatrics Department, Chivasso Hospital, Turin, Italy
| | - F Verzegnassi
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - M Zecca
- Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - F Fioredda
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy
| | - C Dufour
- Hematology Unit, IRCCS Giannina Gaslini Children Hospital, Genoa, Italy.
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10
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Babushok DV, DeZern AE, de Castro CM, Rogers ZR, Beenhouwer D, Broder MS, Fanning SR, Gibbs SN, Hanna R, Maciejewski JP, Scott BL, Tantravahi SK, Wlodarski MW, Yermilov I, Patel BJ. Modified Delphi panel consensus recommendations for management of severe aplastic anemia. Blood Adv 2024; 8:3946-3960. [PMID: 38669341 PMCID: PMC11331724 DOI: 10.1182/bloodadvances.2023011642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 03/28/2024] [Accepted: 04/21/2024] [Indexed: 04/28/2024] Open
Abstract
ABSTRACT Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 experts on adult and pediatric aplastic anemia was assembled and, using the RAND/University of California, Los Angeles modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here, we present the panel's recommendations to rule out inherited bone marrow failure syndromes, on supportive care before and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant vs medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.
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Affiliation(s)
- Daria V. Babushok
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Amy E. DeZern
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | - Carlos M. de Castro
- Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute, Durham, NC
| | - Zora R. Rogers
- Division of Pediatric Hematology-Oncology, University of Texas, Southwestern Medical Center, Dallas, TX
| | | | | | - Suzanne R. Fanning
- Prisma Health Cancer Institute, University of South Carolina, Greenville, SC
| | - Sarah N. Gibbs
- Partnership for Health Analytic Research, Beverly Hills, CA
| | - Rabi Hanna
- Department of Pediatric Hematology Oncology and Bone Marrow Transplantation, Cleveland Clinic, Cleveland, OH
| | | | - Bart L. Scott
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Srinivas K. Tantravahi
- Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Marcin W. Wlodarski
- Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Irina Yermilov
- Partnership for Health Analytic Research, Beverly Hills, CA
| | - Bhumika J. Patel
- Prisma Health Cancer Institute, University of South Carolina, Greenville, SC
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11
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Sharathkumar A, Carr J, Claassen D, Syrbu S, Bhagavathi S, Al-Huniti A, Modi A, Bates M, Mott SL. Romiplostim for Treatment of Children and Young Adults With Severe Aplastic Anemia and Myelodysplastic Syndrome. J Pediatr Hematol Oncol 2024; 46:252-261. [PMID: 38787686 DOI: 10.1097/mph.0000000000002891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024]
Abstract
Thrombopoietin receptor agonists (TPO-RAs) induce trilineage hematopoiesis under conditions with acquired hematopoietic failure. We evaluated safety, tolerability, and preliminary efficacy of a TPO-RA, romiplostim (Nplate), with or without standard-of-care immunosuppressive therapy (±IST) for children (ages < 21 y) with newly diagnosed and relapsed/refractory severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS). Data were collected from an observational study and a single arm interventional pilot study. The safety outcome was treatment-related adverse events (AEs). Efficacy was evaluated by complete hematopoietic response (CHR) at week 24. Romiplostim was commenced at 5 µg/kg/week, with dose escalation of 2.5 µg/kg/week (maximum, 20 µg/kg/dose) based on platelet response. Romiplostim was continued until CHR was observed. Ten subjects (SAA, 9 [IST, 4; without IST, 5]; MDS, 1) completed the study (median age: 9.2 y). Median romiplostim dose was 10 µg/kg/week (range: 5 to 17.5 µg/kg/week). The cumulative incidence of CHR was 70.4% (95% CI, 20.2%-92.6%). Among 21 AEs (Grade 1 to 3), 3 were attributed to romiplostim. At a median posttherapy follow-up of 10.9 months (range: 0.7 to 77.5), no clonal evolution, bone marrow fibrosis or mortality was reported. This proof-of-concept study provides data about short-term safety, tolerability, and preliminary efficacy of romiplostim (±IST) for treatment of pediatric SAA/MDS.
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Affiliation(s)
- Anjali Sharathkumar
- Stead Family Department of Pediatrics, Carver College of Medicine
- Holden Comprehensive Cancer Center
| | - Jamie Carr
- Institute for Clinical and Translational Science
| | - David Claassen
- Stead Family Department of Pediatrics, Carver College of Medicine
| | - Sergei Syrbu
- Department of Pathology, University of Iowa, Iowa City, IA
| | | | - Ahmad Al-Huniti
- Department of Pediatrics, Mayo Clinic, Hematology, Rochester, MN
| | - Arunkumar Modi
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Melissa Bates
- Holden Comprehensive Cancer Center
- Department of Health and Human Physiology
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
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12
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Goel C, Kumar N, Tripathi A, Tiwari S, Shrivastava A. Assessment of Malondialdehyde and Organochlorine Pesticides in Aplastic Anemia Severity Groups: Insights Into Oxidative Stress and Exposure. Cureus 2024; 16:e59698. [PMID: 38841016 PMCID: PMC11150336 DOI: 10.7759/cureus.59698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2024] [Indexed: 06/07/2024] Open
Abstract
Background There is little evidence that pesticide exposure is the primary cause of acquired aplastic anemia (AAA), even though the prevalence of aplastic anemia (AA) is substantially higher in underdeveloped countries than in affluent countries. AA caused by pesticides has not yet been fully understood. This study aimed to examine the potential link between plasma levels of malondialdehyde (MDA) and organochlorine pesticides (OCPs) as risk factors for developing AAA in the North Indian population. Methods This case-control study was conducted at a tertiary care hospital in North India. A total of 99 participants were chosen for the study, of whom 45 were cases of AA. These cases attended the Clinical Hematology department over a period of 1.5 years (May 2018 to November 2019). Forty-five controls were age and sex-matched, apparently healthy subjects. Written informed consent was obtained from each subject before performing the study. Exclusion criteria included patients unwilling to give consent, those using medication to treat AA, those genetically predisposed to AA, those with characteristics including granuloma and dysplasia of bone marrow, any other systemic illness, and subjects with a history of smoking, drinking, or using tobacco in any form. Gas chromatography-tandem mass spectrometry (GC-MS/MS) was used to evaluate the plasma levels of organochlorines. The estimation of plasma MDA, i.e., the lipid peroxide content, was measured. Results The severity of AA is significantly associated with plasma levels of α-Hexachlorocyclohexane (p = 0.040), Heptachlor (p = 0.006), Aldrin (p < 0.001), p,p'-Dichlorodiphenyldichloroethane (p = 0.004), Endosulfan sulfate (p = 0.010), and Methoxychlor (p = 0.001). There was a statistically non-significant difference in MDA levels between cases and controls (p = 0.145); however, a statistically significant linear increase in MDA levels (p < 0.001) was observed according to the severity of AA. Conclusion Our study suggests that oxidative stress may be linked to the severity of AA. Pesticide exposure (plasma organochlorine levels) could act as a stressor, potentially initiating an alarmin response of oxidative stress in the form of lipid peroxidation (MDA) from damaged tissue, which could then lead to suppression of hematopoiesis and be a possible factor in the development of AA.
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Affiliation(s)
- Charu Goel
- Physiology, King George's Medical University, Lucknow, IND
- Physiology, Kalyan Singh Government Medical College, Bulandshahr, IND
| | - Nidhish Kumar
- Pathology, Autonomous State Medical College, Shahjahanpur, IND
| | - Anil Tripathi
- Clinical Hematology, King George's Medical University, Lucknow, IND
- Hematology, Hind Institute of Medical Sciences, Barabanki, IND
| | - Sunita Tiwari
- Physiology, King George's Medical University, Lucknow, IND
- Physiology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, IND
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13
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Perolla A, Cela B, Semanaj V, Dedej-Kurti T, Caja T. Aplastic Anaemia in Pregnancy: A Case-Based Comprehensive Review of the Literature. Cureus 2024; 16:e58365. [PMID: 38628381 PMCID: PMC11019473 DOI: 10.7759/cureus.58365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/16/2024] [Indexed: 04/19/2024] Open
Abstract
Aplastic anaemia (AA) is a rare and life-threatening haematologic disorder characterised by pancytopenia and bone marrow failure. Its occurrence during pregnancy is exceedingly rare, posing significant risks and management challenges for both the mother and the foetus. We present here the case of a 23-year-old female, six months pregnant, diagnosed with severe aplastic anaemia (AA), aiming to highlight the diagnostic challenges and management considerations of AA in pregnancy. Our case underscores the critical nature of considering aplastic anaemia in differential diagnosis for pregnant patients presenting with unexplained pancytopenia. Based on that, we performed a comprehensive literature review of the past 20 years of papers published in the English language identified through searches in PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase and the Cochrane Library, to provide an in-depth analysis of the current understanding of AA in pregnancy. We emphasise the necessity for cautious yet thorough investigation in such cases to avoid complications in both maternal and foetal health, focusing attention on the need for further research into safe and effective treatment protocols for managing AA in pregnancy, given the complexities introduced by the condition and its treatment on pregnancy outcomes.
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Affiliation(s)
- Adela Perolla
- Internal Medicine/Haematology, University of Medicine, Tirana, ALB
- Internal Medicine/Haematology, University Hospital Center "Mother Teresa", Tirana, ALB
| | - Blerina Cela
- Pathology and Laboratory Medicine, University Hospital Center "Mother Teresa", Tirana, ALB
| | - Valentina Semanaj
- Laboratory Medicine, University Hospital Center "Mother Teresa", Tirana, ALB
| | - Teuta Dedej-Kurti
- Laboratory Medicine, University Hospital Center "Mother Teresa", Tirana, ALB
| | - Tatjana Caja
- Internal Medicine/Haematology, University Hospital Center "Mother Teresa", Tirana, ALB
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14
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Vallejo C, Rosell A, Xicoy B, García C, Albo C, Polo M, Jarque I, Esteban B, Codesido ML. A multicentre ambispective observational study into the incidence and clinical management of aplastic anaemia in Spain (IMAS study). Ann Hematol 2024; 103:705-713. [PMID: 38175253 DOI: 10.1007/s00277-023-05602-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 12/21/2023] [Indexed: 01/05/2024]
Abstract
Aplastic anemia (AA) is a rare, life-threatening hematological disease, with a poorly defined incidence. As the data available on AA varies substantially worldwide, a multicenter, ambispective, observational study was carried out between 2010 and 2019 to assess the incidence, clinical management and survival of AA at seven Spanish hospitals. The incidence of AA was 2.83 per million inhabitants per year, consistent with that reported previously in Europe, with a median age at diagnosis of 61 years-old (range 12-86), and a similar number of males and females. The initial diagnosis was severe or very severe AA in 55.8% of cases and 93.7% required transfusion. The most frequent first line therapy was anti-thymocyte globulin (ATG) plus cyclosporin A (CsA, 44.2%), followed by other CsA-based regimes (46.3%), with hematopoietic stem cell transplantation an infrequent 1st line therapy. The 6-month response rate was 68.2%, which then increased over a median follow-up of 3.9 years. The 5-year overall survival (5OS) was 73.6%, similar in severe (78.6%) and very severe AA patients (74.6%) but lower in moderate AA (MAA) patients (68.4%). The 5OS was 100% in 0-25 year-old patients but dropping to 58.3% in patients ≥ 60 years-old. At the last contact, 75.8% of the patients were alive. In conclusion, the incidence, characteristics and management of AA in our study are consistent with that reported previously. In terms of survival, although the global long-term OS rate was good, there is room for improvement, particularly in older patients. Finally, what appears to be a worse long-term survival of MAA patients, as reported previously, reinforces the importance of not underestimating this condition when diagnosed as MAA.
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Affiliation(s)
- Carlos Vallejo
- Complejo Asistencial Universitario de Salamanca, Salamanca, Spain.
- Hospital Universitario Donostia, San Sebastián, Spain.
- PETHEMA Cooperative Group, Madrid, Spain.
- Instituto de Investigación Sanitaria Biodonostia, Donostia-San Sebastián, Spain.
| | - Ana Rosell
- Hospital Universitario Virgen de La Victoria, Málaga, Spain
| | - Blanca Xicoy
- Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Carmen García
- Hospital General Universitario de Alicante, Alicante, Spain
| | - Carmen Albo
- Hospital Universitario Álvaro Cunqueiro, Vigo, Spain
| | - Marta Polo
- Hospital Clínico Universitario San Carlos, Madrid, Spain
| | | | - Brígida Esteban
- Instituto de Investigación Sanitaria Biodonostia, Donostia-San Sebastián, Spain
| | - M Lorena Codesido
- Instituto de Investigación Sanitaria Biodonostia, Donostia-San Sebastián, Spain
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15
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Chang H, He G, Fu R, Li F, Han B, Li T, Liu L, Mittal H, Jin H, Zhang F. Efficacy and safety of eltrombopag in Chinese patients with refractory or relapsed severe aplastic anemia. Sci Rep 2023; 13:18955. [PMID: 37919313 PMCID: PMC10622422 DOI: 10.1038/s41598-023-45607-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/21/2023] [Indexed: 11/04/2023] Open
Abstract
For patients with severe aplastic anemia (SAA) in China who have had an insufficient response to the first-line treatment with hematopoietic stem cell transplantation or immunosuppressive therapy, there is no established standard of care other than transfusion support and treatment of infections. This non-randomized, open-label, Phase II multicenter trial investigated the efficacy and safety of eltrombopag in 20 adult Chinese patients with refractory or relapsed (r/r) SAA. The primary endpoint of hematologic response rate at Week 26, defined as the proportion of patients who met any of the International Working Group criteria, was observed in 70% (14/20) of patients, with more than 50% of these having at least bi-lineage response. Reduced red blood cell and platelet transfusion at Week 26 were observed in 57% (8/14) and 80% (8/10) of patients, respectively. Safety findings were consistent with the established safety profile of eltrombopag and no new safety signals were reported. None of the patients discontinued eltrombopag because of safety concerns. Although the sample size was small, this is the first prospective study to show that eltrombopag is efficacious and has a favorable safety profile in a Chinese patient population with r/r SAA.Trial registration: This trial is registered on ClinicalTrials.gov (NCT03988608); registered 17 June 2019.
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Affiliation(s)
- Hong Chang
- West China Hospital of Sichuan University, Chengdu, China
| | - Guangsheng He
- The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, China
| | - Rong Fu
- Tianjin Medical University General Hospital, Tianjin, China
| | - Fei Li
- The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Bing Han
- Peking Union Medical College Hospital, Beijing, China
| | - Tao Li
- Novartis Pharma Co., Ltd., Beijing, China
| | - Lei Liu
- Novartis Pharma Co., Ltd., Beijing, China
| | - Hemant Mittal
- Novartis Healthcare Private Limited, Hyderabad, India
| | - Hantao Jin
- Novartis Pharma Co., Ltd., Beijing, China
| | - Fengkui Zhang
- Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
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16
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Li J, Bledsoe JR. Inherited bone marrow failure syndromes and germline predisposition to myeloid neoplasia: A practical approach for the pathologist. Semin Diagn Pathol 2023; 40:429-442. [PMID: 37507252 DOI: 10.1053/j.semdp.2023.06.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023]
Abstract
The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between clinical findings, laboratory and genetic studies, and bone marrow histopathology. The rarity of these disorders and the overlap of clinical and pathologic features between primary and secondary causes of bone marrow failure, acquired aplastic anemia, and myelodysplastic syndrome may result in diagnostic uncertainty. With an emphasis on the pathologist's perspective, we review diagnostically useful features of germline disorders including Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L diseases, Diamond-Blackfan anemia, and acquired aplastic anemia. We discuss the distinction between baseline morphologic and genetic findings of these disorders and features that raise concern for the development of myelodysplastic syndrome.
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Affiliation(s)
- Jingwei Li
- Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, United States
| | - Jacob R Bledsoe
- Department of Pathology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, United States.
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17
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Ye M, Liu G, Yang Y, Yang H, Ren J, Chen W, Gao Z. Network pharmacology and experimental verification of the potential mechanism of Er-Xian decoction in aplastic anemia. Sci Rep 2023; 13:17385. [PMID: 37833363 PMCID: PMC10575897 DOI: 10.1038/s41598-023-44672-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 10/11/2023] [Indexed: 10/15/2023] Open
Abstract
To investigate the potential mechanism of Er-Xian decoction (EXD) in treating aplastic anemia (AA), the active components of EXD were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the targets of the components were predicted by the Swiss Target Prediction database. AA targets were collected from the GeneCards, OMIM, DisGeNET, PharmGKB, DrugBank, and TTD databases, the intersection of AA targets and EXD targets was calculated, and an herb-component-target network was constructed by Cytoscape 3.7.2 software. The STRING database was used for protein‒protein interaction (PPI) analysis, and Cytoscape 3.7.2 software was used to construct a PPI network and perform topology analysis. The core targets were imported into the DAVID database for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The molecular docking software AutoDock was used to measure the affinity between active components and key targets. Finally, we established a mouse model of AA and verified the key targets and signaling pathways of EXD by RT‒PCR, ELISA and Western blot analysis. A total of 53 active components were screened from EXD, 2516 AA-related targets were collected, and 195 common targets were obtained. An herb-component-target network and a PPI network were successfully constructed, and 36 core targets were selected from the PPI network. The main active components of EXD include luteolin, kaempferol, berberine, etc., and key targets include PIK3CA, AKT1, STAT3, etc. GO functional enrichment analysis showed that cell components, molecular functions and biological processes with significant correlations were macromolecular complexes, protein serine/threonine/tyrosine kinase activity and protein phosphorylation, respectively. KEGG pathway analysis showed that the pathways with significant correlations included the PI3K-Akt signaling pathway and JAK-STAT signaling pathway. Molecular docking results showed that the tested key targets had good affinity for the corresponding active components. In AA mice, we found that EXD significantly increased white blood cell count, red blood cell count, platelet count and hemoglobin levels, increased mRNA levels of PIK3CA, PIK3CD, AKT1, JAK2, STAT3 and MAPK1, and promoted phosphorylation of PI3K, AKT, ERK1/2 and STAT3. In summary, EXD acts on PI3K, AKT, STAT3 and other targets through berberine, luteolin, quercetin and other components to regulate the PI3K-Akt pathway, JAK-STAT pathway and other pathways, thus exerting its therapeutic effect on AA. This study explained the Chinese medicine theory of treating AA with EXD by tonifying kidney-yang and provides a scientific basis for the use of EXD in treating AA.
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Affiliation(s)
- Mei Ye
- Department of Hematology, The Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Guangxian Liu
- Department of Pharmacy, The Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Yujun Yang
- School of Basic Medicine, Panzhihua University, Panzhihua, China
| | - Hongyu Yang
- Department of Clinical Laboratory, The Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Juan Ren
- Department of Clinical Laboratory, The Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Wenfei Chen
- Department of Pharmacy, The Affiliated Hospital of Panzhihua University, Panzhihua, China
| | - Zeli Gao
- Department of Hematology, The Affiliated Hospital of Panzhihua University, Panzhihua, China.
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Alsultan A, Abujoub R, Alsudairy R, Memon S, Jarrar MS, Alafghani S, Aldaama S, Ballourah W, Almanjomi F, Essa MF. Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia. Br J Haematol 2023; 203:255-263. [PMID: 37491781 DOI: 10.1111/bjh.19004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/17/2023] [Accepted: 07/10/2023] [Indexed: 07/27/2023]
Abstract
When human leucocyte antigen-matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA) represents the standard of care. Cyclophosphamide (Cy) 200 mg/kg and anti-thymocyte globulin (ATG) are frequently administered, but to-date, no standard conditioning regimen exists. In this study, we investigated the efficacy of a unified HSCT conditioning protocol consisting of low-dose Cy 80 mg/kg, fludarabine and ATG. Data were reviewed from children aged ≤14 years with either acquired SAA or non-Fanconi anaemia inherited bone marrow failure syndrome (IBMFS) between 2011 and 2022 at various Saudi institutions. Graft-versus-host disease (GVHD) prophylaxis included mycophenolate mofetil and calcineurin inhibitors. HSCT was performed in 32 children (17 females and 15 males). Nine patients had deleterious mutations (two ERCC6L2, two ANKRD26, two TINF2, one LZTFL1, one RTEL1 and one DNAJC21). Four patients had short telomeres. All 32 patients engrafted successfully. At 3 years post-transplant, the event-free survival was 93% and overall survival was 95%. Two patients experienced secondary graft failure or myelodysplastic syndrome. A low probability of GVHD was observed (one acute GVHD II and one mild chronic GVHD). These data highlight how HSCT using low-dose Cy as part of a fludarabine-based regimen is safe and effective in SAA/non-Fanconi anaemia IBMFS.
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Affiliation(s)
- Abdulrahman Alsultan
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Oncology Center, King Saud University Medical City, Riyadh, Saudi Arabia
- Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Rodaina Abujoub
- Department of Nursing, King Abdullah Specialist Children's Hospital, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Reem Alsudairy
- Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Shahbaz Memon
- Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Mohammad S Jarrar
- Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada
- Windsor Regional Hospital and Cancer Center, Windsor, Ontario, Canada
| | - Sameera Alafghani
- Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Saad Aldaama
- Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Walid Ballourah
- Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Fahd Almanjomi
- Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mohammed F Essa
- Department of Pediatric Hematology/Oncology, King Abdullah Specialist Children's Hospital, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
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Wang T, Qi J, Wang M, Xu H, Wu J, Shang L, Chen L, Li Y. Correlation between human leukocyte antigen ligands and killer cell immunoglobulin-like receptors in aplastic anemia patients from Shaanxi Han. Immunogenetics 2023; 75:445-454. [PMID: 37592108 DOI: 10.1007/s00251-023-01316-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 07/15/2023] [Indexed: 08/19/2023]
Abstract
Regulating natural killer (NK) cell responses in hematological malignancies largely depend on molecular interactions between killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA) class I ligands. The goal of the current study was to examine the key functions of KIR genes, gene combinations of KIR-HLA, and KIR genotypes in genetic predisposition to aplastic anemia (AA). Herein, the genotyping of 16 KIR genes and HLA-A, -B, and -C ligands were performed in 72 AA patients and 150 healthy controls using PCR evaluations with sequence-specific primers using standard assays. According to the obtained results, AA patients had an increased incidence of activating KIR and KIR2DS4 (P = 0.465 × 10-4, Pc = 0.837 × 10-3, OR = 20.81, 95% CI = 2.786-155.5) compared to controls. KIR/HLA class I ligand profile KIR2DS4/C1 (P = 0.350 × 10-4, Pc = 0.630 × 10-3, OR = 8.944, 95% CI = 2.667-29.993) was significantly elevated in AA patients compared to healthy controls. Genotype AA1 (P = 0.003, OR = 2.351, 95% CI = 1.325-4.172) were increased, and AA195 (P = 0.006, OR = 0.060, 95% CI = 0.004-1.023) was decreased among AA cases compared to controls. Our findings indicated that KIR2DS4 may play a role in the pathogenesis of AA. This study revealed the contribution of KIR genes in the etiology of AA cases.
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Affiliation(s)
- Tianju Wang
- HLA Typing Laboratory, Blood Center of the Shaanxi Province, Institute of Xi'an Blood Bank, Xi'an, Shaanxi, 710061, China
| | - Jun Qi
- HLA Typing Laboratory, Blood Center of the Shaanxi Province, Institute of Xi'an Blood Bank, Xi'an, Shaanxi, 710061, China.
| | - Manni Wang
- HLA Typing Laboratory, Blood Center of the Shaanxi Province, Institute of Xi'an Blood Bank, Xi'an, Shaanxi, 710061, China
| | - Hua Xu
- HLA Typing Laboratory, Blood Center of the Shaanxi Province, Institute of Xi'an Blood Bank, Xi'an, Shaanxi, 710061, China
| | - Junhua Wu
- HLA Typing Laboratory, Blood Center of the Shaanxi Province, Institute of Xi'an Blood Bank, Xi'an, Shaanxi, 710061, China
| | - Lixia Shang
- HLA Typing Laboratory, Blood Center of the Shaanxi Province, Institute of Xi'an Blood Bank, Xi'an, Shaanxi, 710061, China
| | - Le Chen
- HLA Typing Laboratory, Blood Center of the Shaanxi Province, Institute of Xi'an Blood Bank, Xi'an, Shaanxi, 710061, China
| | - Yuhui Li
- HLA Typing Laboratory, Blood Center of the Shaanxi Province, Institute of Xi'an Blood Bank, Xi'an, Shaanxi, 710061, China
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Goel C, Kumar N, Tripathi AK, Tiwari S, Shrivastava A, Shukla S, Mishra A, Srivastava A. Plasma Levels of Organochlorine Pesticides and Tumor Necrosis Factor-Alpha: A Potential Risk Factor for Developing Acquired Aplastic Anemia in the North Indian Population. Cureus 2023; 15:e46122. [PMID: 37900403 PMCID: PMC10612378 DOI: 10.7759/cureus.46122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 09/28/2023] [Indexed: 10/31/2023] Open
Abstract
Background Pesticide exposure might have a contributory role in the development of acquired aplastic anemia (AA). However, the precise mechanisms of pesticide-induced AA remain unknown. In this case-control study, we conducted a comparative analysis of plasma levels of organochlorine pesticides (OCP) and tumor necrosis factor-alpha (TNF-alpha) between Indian patients diagnosed with AA and an age- and sex-matched control group. Methods This is an observational case-control study conducted at a tertiary care hospital in North India. In this study, 90 subjects were included, out of which 45 were diagnosed with AA according to the criteria of the International Agranulocytosis and Aplastic Anemia Study. Cases were compared with 45 controls. A trained interviewer gave all study subjects a questionnaire to collect data regarding demographic details, exposure to pesticides, and clinical history. Physical examination and routine laboratory investigations of each subject were performed. Both cases and controls were tested for their plasma levels of organochlorines as per established protocol by gas chromatography-mass spectrometry. TNF-alpha level was measured by enzyme-linked immunosorbent assay in each subject. Results There was a significant increase in plasma levels of delta hexachlorocyclohexane (delta HCH) (p = 0.02) and heptachlor (p = 0.00) in patients with AA as compared to controls. We observed nonsignificant trends towards higher levels of beta HCH (p = 0.643), aldrin (p = 0.399), and p,p'-Dichlorodiphenyltrichloroethane (p,p'-DDT) (p = 0.453) in patients with AA when compared to the controls. There were significantly higher TNF-alpha levels (p = 0.024) in cases as compared to the controls. Conclusion Our study concludes that patients with AA exhibited higher levels of delta-HCH, heptachlor, and TNF-alpha in comparison to the control group. There is a significant positive correlation of TNF alpha with OCPs (alpha HCH, lindane, delta HCH, heptachlor, aldrin, p,p'- DDD, and methoxychlor pesticides). These organochlorines may have accumulated in the fatty tissue of bone marrow because of their lipophilic nature. This suggests that they might have served as a neoantigen to trigger an increase in TNF-alpha production, which may have led to disrupted bone marrow function through cell-mediated immunity, leading to AA.
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Affiliation(s)
- Charu Goel
- Physiology, Muzaffarnagar Medical College & Hospital, Muzaffarnagar, IND
- Physiology, King George's Medical University, Lucknow, IND
| | - Nidhish Kumar
- Pathology, Autonomous State Medical College, Shahjahanpur, IND
| | - Anil K Tripathi
- Clinical Hematology, King George's Medical University, Lucknow, IND
| | - Sunita Tiwari
- Physiology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, IND
| | | | - Saurabh Shukla
- Clinical Hematology, King George's Medical University, Lucknow, IND
| | - Alok Mishra
- Centre for Advanced Research, King George's Medical University, Lucknow, IND
| | - Anshuman Srivastava
- Centre for Advanced Research, King George's Medical University, Lucknow, IND
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Dolai TK, Jain M, Mahapatra M. Idiopathic Aplastic anemia: Indian Perspective. Indian J Hematol Blood Transfus 2023; 39:357-370. [PMID: 37304471 PMCID: PMC10247658 DOI: 10.1007/s12288-022-01592-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 09/26/2022] [Indexed: 06/13/2023] Open
Abstract
Aplastic anemia (AA) is a rare immunologically mediated bone marrow failure syndrome, characterized by progressive loss of hematopoietic stem cells resulting in peripheral pancytopenia. Elaborative investigation including molecular tests is required to exclude inherited bone marrow failure syndrome (IMBFS) as the treatment and prognosis vary dramatically between them. Haematopoietic stem cell transplant with a fully matched sibling donor (MSD-HSCT) is still the only curative treatment. Management of AA is a real-time challenge in India, because of the delay in the diagnosis, lack of proper supportive care, limited availability of the expertise centre, and the patient's affordability. Recently, results with intensified immunosuppressive therapy that includes anti-thymocyte globulin with cyclosporine-A (CsA) and eltrombopag, are enough encouraging to consider it as treatment of choice in patients lacking MSD or who are not fit for HSCT. However, limitations in resource constraints settings including the cost of therapy limit its full utilization. Relapse of the disease or evolution to myelodysplasia or paroxysmal nocturnal haemoglobinuria (PNH) in a proportion of patients is another challenge with immunosuppressants. The majority of the AA patients still receive CsA with or without androgens in India, mostly because of increased cost and limited availability of HSCT and ATG. The use of the unrelated or alternative donor is still upcoming in India, with unavailable data in terms of response and survival. Therefore, there is an utmost need for novel agents for the better management of AA having a balanced efficacy and toxicity profile to improve the survival and quality of life.
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Affiliation(s)
- Tuphan Kanti Dolai
- Department of Haematology, Nil Ratan Sircar Medical College and Hospital, Kolkata, India
| | - Manisha Jain
- Department of Medical oncology and Haematology, Medanta Medcity, India
| | - Manoranjan Mahapatra
- Department of Haematology, All India Institute of Medical science, New Delhi, India
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22
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Wang S, You Y, Ge M, Shao Y, Huo J, Ren X, Li X, Huang J, Zhang J, Wang M, Nie N, Jin P, Zheng Y. Interleukin-10 promoter variability is associated with the susceptibility, severity, and clinical outcomes of aplasitc anemia in Han-Chinese population. Int J Lab Hematol 2023; 45:204-212. [PMID: 36397188 DOI: 10.1111/ijlh.13993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 10/11/2022] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Acquired aplastic anemia (AA), a heterogeneous bone marrow (BM) failure disease, is mainly mediated by the immune destruction of hematopoietic stem cells (HSCs). Given the predominant role of immunosuppressive therapy (IST) in AA, it is sensible to theorize that variants of cytokine genes might affect the outcome of IST. METHODS In this study, we analyzed three single nucleotide polymorphisms (SNPs) of interleukin (IL)-10 gene in promoter region to clarify their relationship with susceptibility, clinical efficacy and prognosis of AA. RESULTS We observed that CT genotype of IL-10 rs1800896 was associated with a decreased risk of AA (adjusted OR = 0.541 [95% CI 0.295-0.993], p = .047). Besides, the disease severity differed considerably by IL-10 gene promoter genotypes and alleles. Furthermore, IL-10 SNPs influenced efficacy of IST, with unfavorable response exhibited by rs1800871 and rs1800872 in dominant models (GG + AG vs. AA, adjusted OR = 0.409 [95% CI 0.178-0.943, p = .036] for rs1800871 and GG + GT vs. TT, adjusted OR = 0.396 [95% CI 0.173-0.909, p = .028] for rs1800872, respectively). CONCLUSION The polymorphisms of IL-10 promoter region were informatively genetic risk factors which might be conducive to the insights into the mechanisms of AA and the design of individual regimens.
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Affiliation(s)
- Shichong Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yahong You
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Meili Ge
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yingqi Shao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jiali Huo
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Xiang Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Xingxin Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jinbo Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jing Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Min Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Neng Nie
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Peng Jin
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yizhou Zheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
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23
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Kharya G, Jaiswal SR, Bhat S, Raj R, Yadav SP, Dua V, Sen S, Bakane A, Badiger S, Uppuluri R, Rastogi N, Sachdev M, Sharma B, Saifullah A, Chakrabarti S. Impact of Conditioning Regimen and Graft-versus-Host Disease Prophylaxis on The Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation for High-Risk Severe Aplastic Anemia in Children and Young Adults: A Report from the Pediatric Severe Aplastic Anemia Consortium of India. Transplant Cell Ther 2023; 29:199.e1-199.e10. [PMID: 36572385 DOI: 10.1016/j.jtct.2022.12.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/16/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022]
Abstract
Allogenic hematopoietic cell transplantation (HCT) is the best curative approach for patients with severe aplastic anemia (SAA). The outcomes of HCT from haploidentical family donors (HFDs) have improved, making it a feasible option for patients lacking an HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In this multicenter retrospective study, we evaluated the outcomes of 79 patients undergoing HFD-HCT for SAA. All the patients were heavily pretransfused, the median time to HCT was >12 months, and 67% had failed previous therapies. Conditioning was based on fludarabine (Flu)-cyclophosphamide (Cy)-antithymocyte globulin (ATG)/total body irradiation (TBI) with or without thiotepa/melphalan (TT/Mel). Post-transplantation Cy (PTCy) and calcineurin inhibitors (CNIs)/sirolimus were used as graft-versus-host disease (GVHD) prophylaxis with or without abatacept. The rate of primary graft failure (PGF) was 16.43% overall, lower in patients conditioned with TT/Mel. The incidences of acute and chronic GVHD were 26.4% and 18.9%, respectively. At a median follow-up of 48 months, the overall survival (OS) and event-free survival (EFS) were 61.6% and 58.1%, respectively. Both OS and EFS were better in the TT/Mel recipients and with abatacept as GVHD prophylaxis. On multivariate analysis, the use of abatacept was found to favorably impact the outcome variables, including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, in whom optimization of conditioning and GVHD prophylaxis might further improve outcomes.
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Affiliation(s)
- Gaurav Kharya
- Centre For Bone Marrow Transplant & Cellular Therapy, Indrprastha Apollo Hospital, New Delhi, India.
| | - Sarita R Jaiswal
- Department of Hematology and Bone Marrow Transplant, Dharamshilla Narayana Superspeciality Hospital, New Delhi, India
| | - Sunil Bhat
- Department of Pediatric Hematology Oncology & Bone Marrow Transplant, Narayana Health City, Bangalore, Karnataka, India
| | - Revathi Raj
- Apollo Cancer Centre, Chennai, Tamil Nadu, India
| | - Satya P Yadav
- Department of Pediatric Hematology Oncology and Bone Marrow Transplant, Medanta-The Medicity, Gurugram, Harayana, India
| | - Vikas Dua
- Department of Pediatric Hematology Oncology and Bone Marrow Transplant, Fortis Memorial Research Hospital, Gurugram, Haryana, India
| | - Santanu Sen
- Department of Pediatric Hematology Oncology and Bone Marow Transplant, Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute, Mumbai, India
| | - Atish Bakane
- Centre For Bone Marrow Transplant & Cellular Therapy, Indrprastha Apollo Hospital, New Delhi, India
| | - Shobha Badiger
- Department of Pediatric Hematology Oncology & Bone Marrow Transplant, Narayana Health City, Bangalore, Karnataka, India
| | | | - Neha Rastogi
- Department of Pediatric Hematology Oncology and Bone Marrow Transplant, Medanta-The Medicity, Gurugram, Harayana, India
| | - Mansi Sachdev
- Department of Pediatric Hematology Oncology and Bone Marrow Transplant, Fortis Memorial Research Hospital, Gurugram, Haryana, India
| | - Bharti Sharma
- Centre For Bone Marrow Transplant & Cellular Therapy, Indrprastha Apollo Hospital, New Delhi, India
| | - Ashraf Saifullah
- Department of Hematology and Bone Marrow Transplant, Dharamshilla Narayana Superspeciality Hospital, New Delhi, India
| | - Suparno Chakrabarti
- Department of Hematology and Bone Marrow Transplant, Dharamshilla Narayana Superspeciality Hospital, New Delhi, India
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Mesenchymal Stem Cells in Acquired Aplastic Anemia: The Spectrum from Basic to Clinical Utility. Int J Mol Sci 2023; 24:ijms24054464. [PMID: 36901900 PMCID: PMC10003043 DOI: 10.3390/ijms24054464] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/17/2023] [Accepted: 02/21/2023] [Indexed: 03/12/2023] Open
Abstract
Aplastic anemia (AA), a rare but potentially life-threatening disease, is a paradigm of bone marrow failure syndromes characterized by pancytopenia in the peripheral blood and hypocellularity in the bone marrow. The pathophysiology of acquired idiopathic AA is quite complex. Mesenchymal stem cells (MSCs), an important component of the bone marrow, are crucial in providing the specialized microenvironment for hematopoiesis. MSC dysfunction may result in an insufficient bone marrow and may be associated with the development of AA. In this comprehensive review, we summarized the current understanding about the involvement of MSCs in the pathogenesis of acquired idiopathic AA, along with the clinical application of MSCs for patients with the disease. The pathophysiology of AA, the major properties of MSCs, and results of MSC therapy in preclinical animal models of AA are also described. Several important issues regarding the clinical use of MSCs are discussed finally. With evolving knowledge from basic studies and clinical applications, we anticipate that more patients with the disease can benefit from the therapeutic effects of MSCs in the near future.
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Ni R, Fan L, Zhang L, Song Y, Wang H, Wang A, Liu B. A mouse model of irradiation and spleen-thymus lymphocyte infusion induced aplastic anemia. HEMATOLOGY (AMSTERDAM, NETHERLANDS) 2022; 27:932-945. [PMID: 36004514 DOI: 10.1080/16078454.2022.2113356] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES The immune-induced aplastic anemia (AA) mouse model has been used for the study of AA. However, there were no uniform conditions for establishing a model and no assessment of immunological homeostasis. Our study aimed to identify the conditions of establishing a model and assess the AA model in immunology and pathology. METHODS We induced an AA mouse model by the combination between sublethal irradiation and spleen-thymus lymphocyte infusion. The success of establishing the AA model was identified by blood routine tests and pathology of bone marrow. The frequency of Th17 and Treg cells was measured by flow cytometry. The frequency of CD34+ and CD41+ cells was detected by immunohistochemical technique.IL-6, IL-8, IL-17, TNF-α and IFN-γ were evaluated by ELISA. RESULTS The 137Cs sublethal irradiation (5 Gy) and spleen-thymus lymphocyte infusion (5 × 106) induced the AA mouse model successfully. The AA mice had a long lifetime and manifested pancytopenia and bone marrow failure. The percentage of Th17 cells increased and the percentage of Treg cells decreased distinctly in AA mice. The area of hematopoietic tissues and count of CD34+ cells and CD41+ cells were significantly reduced in AA mice.The level of cytokines, IL-6, IL-8, IL-17, TNF-α and IFN-γ, was increased significantly in peripheral blood and bone marrow. CONCLUSION Our data suggest that the improved AA mouse model conforms to the diagnosis standard of AA and simulates the immune internal environment of human AA. The AA mouse model has a longer lifetime and unbalances of Th17/Treg cells caused the destruction of CD34+ cells and CD41+ cells, which was immune-mediated pathogenesis to adapt to long-term research.
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Affiliation(s)
- Runfeng Ni
- Department of traditional Chinese medicine, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Leiwei Fan
- Department of traditional Chinese medicine, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Le Zhang
- Department of traditional Chinese medicine, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Yanqi Song
- Department of traditional Chinese medicine, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Haijin Wang
- Department of traditional Chinese medicine, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Aidi Wang
- Department of traditional Chinese medicine, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Baoshan Liu
- Department of traditional Chinese medicine, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
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Hu J, Zhang L, Zhao X, Liu X, Jing L, Zhou K, Li Y, Li Y, Li J, Ye L, Peng G, Fan H, Yang W, Yang Y, Xiong Y, Song L, Zhang F. First-line immunosuppressive therapy with rATG and CsA for severe aplastic anemia: 15 years' experience. Ann Hematol 2022; 101:2405-2412. [PMID: 36151352 DOI: 10.1007/s00277-022-04952-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 07/31/2022] [Indexed: 11/24/2022]
Abstract
Rabbit antithymocyte globulin (rATG) instead of horse ATG has been used for severe aplastic anemia (SAA) patients in China. This study aimed to investigate the hematologic responses and long-term overall survival (OS) outcomes in SAA patients who received rATG and cyclosporine as first-line immunosuppressive therapy. We analyzed data of 542 SAA patients treated with this therapy between 2005 and 2019. The median age was 20 (range, 2-80) years, and the median follow-up time was 45.5 (range, 0.1-191.4) months. The early mortality rate was 3.9%. The overall response rates (ORRs) were 40.2%, 56.1%, and 62.4% at 3, 6, and 12 months, respectively. The 6- and 12-month ORR of patients treated with 3 mg/kg/d of rATG in 2015-2019 seemed higher than that of patients treated with 3.5-3.75 mg/kg/day in 2005-2014 (60.2% vs. 54.9%, P = 0.30 and 69.9% vs. 60.1%, P = 0.049, respectively). The 10-year cumulative incidences of relapse and clonal evolution were 10.6 ± 2.9% and 7.5 ± 1.5%, respectively. The 10-year OS rate and event-free survival rate were 80.1 ± 2.1% and 75.6 ± 3.7%, respectively. Age, disease severity, treatment periods, and the interval from diagnosis to IST were independent predictors of OS. In conclusion, 3 mg/kg/day rATG is effective as first-line treatment for SAA.
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Affiliation(s)
- Jing Hu
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Li Zhang
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xin Zhao
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xu Liu
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Liping Jing
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Kang Zhou
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yuan Li
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yang Li
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Jianping Li
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Lei Ye
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Guangxin Peng
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Huihui Fan
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Wenrui Yang
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yang Yang
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Youzhen Xiong
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Lin Song
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Fengkui Zhang
- Anemia Therapeutic Centre, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
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Zaidi U, Fatima M, Samad SA, Shafique K, Waseem HF, Farzana T, Shamsi TS. Fludarabine/Cyclophosphamide Conditioning Regimen in Aplastic Anemia Patients Receiving Matched-Sibling Donor Transplant Is Non-inferior to ATG/Cyclophosphamide: A Single-Center Experience from Pakistan. Stem Cells Int 2022; 2022:1442613. [PMID: 36117722 PMCID: PMC9481407 DOI: 10.1155/2022/1442613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
The successful outcome of allogeneic hematopoietic stem cell transplant (HSCT) in aplastic anemia patients is driven by suitable donor selection, appropriate conditioning regimen, early intervention, and optimal supportive care after transplant. Pakistan, being a developing country, faces grave economic challenges due to meager health care budget; therefore, cost constraints remain the foremost impediment in optimizing transplant facilities for socioeconomically deprived patients. We conducted a single-center retrospective analysis of aplastic anemia patients (N = 130), who received matched sibling donor transplants from 2011 to 2019, treated with either fludarabine/cyclophosphamide (Flu/Cy) or antithymocyte globulin/cyclophosphamide (ATG/CY) conditioning regimen. Median age was 16 years (IQR, 11-20), and it ranged from 3 to 48 years. The median time from diagnosis to transplant was 3 months (IQR, 2 to 4), and it ranged from 1 to 8 months. The estimated overall survival (OS), relapse-free survival (RFS), and GvHD-free survival (GFS) were found to be 69.0%, 66.7%, and 64.3% in the ATG/Cy group while 76.1%, 72.7%, and 62.5% in the Flu/Cy group, respectively, after a median follow-up of 30 months (IQR, 8 to 55), and it ranged from 0 to 98 months for the study groups. The Flu/Cy regimen was well tolerated and was not associated with increased risk of GvHD. Hence, it may be an appropriate alternative conditioning regimen for developing countries with limited health care resources.
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Affiliation(s)
- Uzma Zaidi
- Department of Clinical Hematology, National Institute of Blood Diseases & Bone Marrow Transplantation, Karachi, Pakistan
| | - Mushkbar Fatima
- Department of Research and Development, National Institute of Blood Diseases & Bone Marrow Transplantation, Karachi, Pakistan
| | - Shafaq Abdul Samad
- Department of Clinical Hematology, National Institute of Blood Diseases & Bone Marrow Transplantation, Karachi, Pakistan
| | - Kashif Shafique
- School of Public Health, Dow University of Health Sciences, Karachi, Pakistan
| | - Hira Fatima Waseem
- School of Public Health, Dow University of Health Sciences, Karachi, Pakistan
| | - Tasneem Farzana
- Department of Clinical Hematology, National Institute of Blood Diseases & Bone Marrow Transplantation, Karachi, Pakistan
| | - Tahir Sultan Shamsi
- Department of Clinical Hematology, National Institute of Blood Diseases & Bone Marrow Transplantation, Karachi, Pakistan
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Zhang L, Ni R, Li J, Fan L, Song Y, Wang H, Wang A, Liu B. Dioscin Regulating Bone Marrow Apoptosis in Aplastic Anemia. Drug Des Devel Ther 2022; 16:3041-3053. [PMID: 36105320 PMCID: PMC9467696 DOI: 10.2147/dddt.s370506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 09/01/2022] [Indexed: 11/23/2022] Open
Abstract
Background Aplastic anemia (AA), a disease of bone marrow failure, is caused by CD8+T mediated apoptosis of hematopoietic cells. However, traditional immunosuppressive therapy (IST) has severe liver and kidney toxicity and even cannot achieve the expected therapeutic effect in some patients. Purpose Our study is aimed to investigate the effect and mechanism of dioscin (DNS) for treating AA. Methods Briefly, we established and evaluated the AA mouse model, DNS and positive control drugs were used for intervention treatment. After 14 days of intervention, femoral bone marrow pathology, bone marrow mononuclear cells (BMMCs) apoptosis rate, bone marrow CD34+ cell surface Fas (CD95) expression and Fas signaling pathway key proteins were detected. Results After the establishment of the AA mouse model, the number of peripheral blood cells including granulocytes, erythrocytes, hemoglobin, platelets and reticulocytes in the AA group model was significantly decreased compared with the group control (P < 0.01). The degree of bone marrow hyperplasia in the sternum and femur is extremely low. After different drug interventions, compared with the group model, the number of peripheral blood cells in the AA mice rebounded significantly in group DNS (P < 0.01). Not only that the apoptosis rate of BM-MCs decreased (P < 0.01), meanwhile, the CD95 molecule expressed on the CD34+ bone marrow cells had a significant decline (P < 0.01), and the expression level of the key proteins of Fas signaling pathway was also significantly decreased (P < 0.01). Conclusion DNS recovered the peripheral pancytopenia and bone marrow failure in AA mice. DNS reduced the key protein of Fas signaling pathway level to inhibit apoptosis of bone marrow cells to treat AA.
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Affiliation(s)
- Le Zhang
- Department of Traditional Chinese Medicine, General Hospital of Tianjin Medical University, Tianjin, 300052, People’s Republic of China
| | - Runfeng Ni
- Department of Traditional Chinese Medicine, General Hospital of Tianjin Medical University, Tianjin, 300052, People’s Republic of China
| | - Jiani Li
- Department of Gynecology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, 100091, People’s Republic of China
| | - Liwei Fan
- Department of Traditional Chinese Medicine, General Hospital of Tianjin Medical University, Tianjin, 300052, People’s Republic of China
| | - Yanqi Song
- Department of Traditional Chinese Medicine, General Hospital of Tianjin Medical University, Tianjin, 300052, People’s Republic of China
| | - Haijin Wang
- Department of Traditional Chinese Medicine, General Hospital of Tianjin Medical University, Tianjin, 300052, People’s Republic of China
| | - Aidi Wang
- Department of Traditional Chinese Medicine, General Hospital of Tianjin Medical University, Tianjin, 300052, People’s Republic of China
| | - Baoshan Liu
- Department of Traditional Chinese Medicine, General Hospital of Tianjin Medical University, Tianjin, 300052, People’s Republic of China
- Correspondence: Baoshan Liu; Aidi Wang, Department of traditional Chinese medicine, General Hospital of Tianjin Medical University, Tianjin, 300052, People’s Republic of China, Email ;
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Gao X, Bian ZL, Qiao XH, Qian XW, Li J, Shen GM, Miao H, Yu Y, Meng JH, Zhu XH, Jiang JY, Le J, Yu L, Wang HS, Zhai XW. Population Pharmacokinetics of Cyclosporine in Chinese Pediatric Patients With Acquired Aplastic Anemia. Front Pharmacol 2022; 13:933739. [PMID: 35979231 PMCID: PMC9377374 DOI: 10.3389/fphar.2022.933739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Cyclosporine (CsA) is a component of the first-line treatment for acquired aplastic anemia (acquired AA) in pediatric patients. This study aimed to develop a population pharmacokinetic (PK) model of CsA in Chinese pediatric patients with acquired AA to inform individual dosage regimens. A total of 681 CsA whole blood concentrations and laboratory data of 157 pediatric patients with acquired AA were retrospectively collected from two hospitals in Shanghai. A nonlinear mixed-effect model approach was used to build the population PK model. Potential covariate effects of age, body weight, and biochemical measurements (renal and liver functions) on CsA PK disposition were evaluated. Model fit was assessed using the basic goodness of fit and a visual predictive check. The CsA concentration data were accurately described using a two-compartment disposition model with first-order absorption and elimination. Body weight value was implemented as a fixed allometric function on all clearance and volume of distribution parameters. Total bilirubin level was identified as a significant covariate on apparent clearance (CL/F), with a 1.07% reduction per 1 nmol/L rise in total bilirubin level. The final estimates for CL/F and central volume (Vc/F) were 29.1 L/h and 325 L, respectively, for a typical 28 kg child. Other covariates (e.g., gender, age, albumin, hemoglobin, hematocrit, serum creatinine, and concomitant medication) did not significantly affect the PK properties of CsA. This population PK model, along with a maximum a posteriori Bayesian approach, could estimate individual PK parameters in pediatric patients with acquired AA to conduct individual CsA therapy.
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Affiliation(s)
- Xuan Gao
- Outpatient and Emergency Management Office, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Zhu-Li Bian
- Department of Pediatrics, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiao-Hong Qiao
- Department of Pediatrics, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiao-Wen Qian
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Jun Li
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Guo-Mei Shen
- Outpatient and Emergency Management Office, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Hui Miao
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Yi Yu
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Jian-Hua Meng
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Xiao-Hua Zhu
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Jun-Ye Jiang
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Jun Le
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Ling Yu
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Hong-Sheng Wang
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
- *Correspondence: Xiao-Wen Zhai, ; Hong-Sheng Wang,
| | - Xiao-Wen Zhai
- Department of Hematology and Oncology, National Children’s Medical Center, Children’s Hospital of Fudan University, Shanghai, China
- *Correspondence: Xiao-Wen Zhai, ; Hong-Sheng Wang,
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SARS-CoV-2 Infection Associated with Aplastic Anemia and Pure Red Cell Aplasia. Blood Adv 2022; 6:3840-3843. [PMID: 35452511 PMCID: PMC9040401 DOI: 10.1182/bloodadvances.2022007174] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
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HLA class I and II alleles profile in Indian patients with aplastic anemia. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Patel BA, Townsley DM, Scheinberg P. Immunosuppressive therapy in severe aplastic anemia. Semin Hematol 2022; 59:21-29. [DOI: 10.1053/j.seminhematol.2022.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/10/2022] [Accepted: 01/11/2022] [Indexed: 11/11/2022]
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Dan H, Haichao Z, Ziyang Y, Di Z, Shuihan Z. Protective effects of Fufang Ejiao Jiang against aplastic anemia assessed by network pharmacology and metabolomics strategy. DIGITAL CHINESE MEDICINE 2021. [DOI: 10.1016/j.dcmed.2021.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Hu H, Chen T, Liu W, Shen Y, Li Q, Zhou Y, Ye B, Wu D. Differentiation of Yin, Yang and Stasis Syndromes in Severe Aplastic Anemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation and Their Correlation with Iron Metabolism, cAMP/cGMP, 17-OH-CS and Thyroxine. J Blood Med 2021; 12:975-989. [PMID: 34803418 PMCID: PMC8598128 DOI: 10.2147/jbm.s332171] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/03/2021] [Indexed: 12/13/2022] Open
Abstract
Objective To better understanding and differentiation of traditional Chinese medicine (TCM) syndromes in severe aplastic anemia (SAA) patients undergoing hematopoietic stem cell transplantation (Allo-HSCT) and their correlation with iron metabolism, cAMP/cGMP, 17-OH-CS and thyroxine. Methods Eighteen patients with SAA who underwent HSCT were enrolled. The syndrome was evaluated before conditioning and days after stem cell reinfusion (−10d, −1d, +7d, +30d, +60d, and +90d). The correlation of TCM syndrome (Yin, Yang, and stasis) to cyclic nucleotides, 17-OH-CS, thyroxine, and iron metabolism were analyzed and compared to data from normal subjects. Results More “Yin deficiency” (n=11, 11/18) syndrome was observed before HSCT, and nearly 61% was complicated with “blood stasis”. After conditioning, the proportion of “kidney Yin and Yang deficiency” increased to 61.6%. Fourteen days after HSCT, the syndrome developed into “Spleen-Kidney Yang Deficiency,” and the stasis score decreased. On +90day, majority patients were diagnosed with “Kidney Yang Deficiency” (35.7%) or “Spleen-Kidney Yang Deficiency” (28.6%), and 88.9% were diagnosed without stasis. The correlation analysis showed that cGMP might represent “Deficient Yang” as well as low total triiodothyronine (T3) and free T3 (FT3). There was also a positive relation between labile plasma iron (LPI), hepcidin, soluble transferrin receptor (sTfR), and “Yin deficiency”, and the last two factors, along with marrow nitric oxide synthase were also positively related to “Stasis” syndrome. Conclusion During HSCT, the syndrome evolved from “kidney Yin and Yang deficiency” to “kidney Yang deficiency” or “spleen–kidney Yang deficiency”, and the “stasis” along with “Yin deficiency” syndromes were quickly relieved within 90 days. The changes of cyclic nucleotides, 17-OH-CS, thyroxine, and iron metabolism indexes can be applied for better differentiation of TCM syndrome.
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Affiliation(s)
- Huijin Hu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Tao Chen
- Department of Hematology, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Wenbin Liu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Yiping Shen
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Qiushuang Li
- Center of Clinical Evaluation and Analysis, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Yuhong Zhou
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Baodong Ye
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Dijiong Wu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
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Shimano KA, Narla A, Rose MJ, Gloude NJ, Allen SW, Bergstrom K, Broglie L, Carella BA, Castillo P, Jong JLO, Dror Y, Geddis AE, Huang JN, Lau BW, McGuinn C, Nakano TA, Overholt K, Rothman JA, Sharathkumar A, Shereck E, Vlachos A, Olson TS, Bertuch AA, Wlodarski MW, Shimamura A, Boklan J. Diagnostic work-up for severe aplastic anemia in children: Consensus of the North American Pediatric Aplastic Anemia Consortium. Am J Hematol 2021; 96:1491-1504. [PMID: 34342889 DOI: 10.1002/ajh.26310] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/19/2022]
Abstract
The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is a group of pediatric hematologist-oncologists, hematopathologists, and bone marrow transplant physicians from 46 institutions in North America with interest and expertise in aplastic anemia, inherited bone marrow failure syndromes, and myelodysplastic syndromes. The NAPAAC Bone Marrow Failure Diagnosis and Care Guidelines Working Group was established with the charge of harmonizing the approach to the diagnostic workup of aplastic anemia in an effort to standardize best practices in the field. This document outlines the rationale for initial evaluations in pediatric patients presenting with signs and symptoms concerning for severe aplastic anemia.
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Affiliation(s)
- Kristin A. Shimano
- Department of Pediatrics University of California San Francisco Benioff Children's Hospital San Francisco California USA
| | - Anupama Narla
- Department of Pediatrics Stanford University School of Medicine Stanford California USA
| | - Melissa J. Rose
- Division of Hematology, Oncology, and Bone Marrow Transplant Nationwide Children's Hospital, The Ohio State University College of Medicine Columbus Ohio USA
| | - Nicholas J. Gloude
- Department of Pediatrics University of California San Diego, Rady Children's Hospital San Diego California USA
| | - Steven W. Allen
- Pediatric Hematology/Oncology University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA
| | - Katie Bergstrom
- Cancer and Blood Disorders Center Seattle Children's Hospital Seattle Washington USA
| | - Larisa Broglie
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation Medical College of Wisconsin Milwaukee Wisconsin USA
| | - Beth A. Carella
- Department of Pediatrics Kaiser Permanente Washington District of Columbia USA
| | - Paul Castillo
- Division of Pediatric Hematology Oncology UF Health Shands Children's Hospital Gainesville Florida USA
| | - Jill L. O. Jong
- Section of Hematology‐Oncology, Department of Pediatrics University of Chicago Chicago Illinois USA
| | - Yigal Dror
- Marrow Failure and Myelodysplasia Program, Division of Hematology and Oncology, Department of Paediatrics The Hospital for Sick Children Toronto Ontario Canada
| | - Amy E. Geddis
- Cancer and Blood Disorders Center Seattle Children's Hospital Seattle Washington USA
| | - James N. Huang
- Department of Pediatrics University of California San Francisco Benioff Children's Hospital San Francisco California USA
| | - Bonnie W. Lau
- Pediatric Hematology‐Oncology Dartmouth‐Hitchcock Lebanon New Hampshire USA
| | - Catherine McGuinn
- Department of Pediatrics Weill Cornell Medicine New York New York USA
| | - Taizo A. Nakano
- Center for Cancer and Blood Disorders Children's Hospital Colorado Aurora Colorado USA
| | - Kathleen Overholt
- Pediatric Hematology and Oncology Riley Hospital for Children at Indiana University Indianapolis Indiana USA
| | - Jennifer A. Rothman
- Division of Pediatric Hematology and Oncology Duke University Medical Center Durham North Carolina USA
| | - Anjali Sharathkumar
- Stead Family Department of Pediatrics University of Iowa Carver College of Medicine Iowa City Iowa USA
| | - Evan Shereck
- Department of Pediatrics Oregon Health and Science University Portland Oregon USA
| | - Adrianna Vlachos
- Hematology, Oncology and Cellular Therapy Cohen Children's Medical Center New Hyde Park New York USA
| | - Timothy S. Olson
- Cell Therapy and Transplant Section, Division of Oncology and Bone Marrow Failure, Division of Hematology, Department of Pediatrics Children's Hospital of Philadelphia and University of Pennsylvania Philadelphia Pennsylvania USA
| | | | | | - Akiko Shimamura
- Cancer and Blood Disorders Center Boston Children's Hospital and Dana Farber Cancer Institute Boston Massachusetts USA
| | - Jessica Boklan
- Center for Cancer and Blood Disorders Phoenix Children's Hospital Phoenix Arizona USA
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Strategic priorities for hematopoietic stem cell transplantation in the EMRO region. Hematol Oncol Stem Cell Ther 2021; 16:162-169. [PMID: 34688625 DOI: 10.1016/j.hemonc.2021.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/23/2021] [Indexed: 11/22/2022] Open
Abstract
The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region.
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Metabolomics-Based Clinical Efficacy of Compound Shenlu Granule, a Chinese Patent Medicine, in the Supportive Management of Aplastic Anemia Patients: A Randomized Controlled Pilot Trial. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6655848. [PMID: 34630613 PMCID: PMC8497100 DOI: 10.1155/2021/6655848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 08/29/2021] [Accepted: 09/11/2021] [Indexed: 11/24/2022]
Abstract
Objective To explore the clinical efficacy and mechanism of compound Shenlu granule (SLG) treatment in patients with aplastic anemia (AA). Methods A total of 89 AA patients were randomly divided into an SLG supportive group (group A, n = 44) and a control group (group B, n = 45) while continuing Western medical management. After 6 months, hemograms, traditional Chinese medicine (TCM) syndrome scores, and overall clinical efficacy rate were assessed. Serum metabolomics characteristics were observed using ultraperformance liquid chromatography-mass spectrometry after SLG intervention. Results The levels of red blood cell (RBC), hemoglobin (Hb), and platelet (PLT) were increased in both groups after treatment for 6 months (P < 0.05), and in group A, the elevation of PLT became much more significant (P < 0.01). The TCM syndrome score was lower in group A than in group B after treatment (P < 0.05). Metabolomics data showed a significant difference in the patients using SLG after 6 months, and 14 biomarkers were identified. Conclusion SLG supportive treatment showed positive results in patients with AA, and metabolomics data indicated that SLG influenced aminoacyl-tRNA biosynthesis and glycerophospholipid metabolism to gradually return to normal.
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Sharma P, Palta A, Tahlan A, Kaur M, Singh R. Immunoexpression of CD34, CD117, and p53 in Hypocellular Bone Marrow Disorders. J Lab Physicians 2021; 14:139-143. [PMID: 35982883 PMCID: PMC9381312 DOI: 10.1055/s-0041-1732491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives
Hypocellular bone marrow (BM) disorders comprise heterogeneous entities associated with peripheral cytopenias and decreased production of hematopoietic cells in BM. This study was undertaken to analyze immunohistochemical expression of CD34, CD117, and p53 in morphologically diagnosed patients of hypocellular BM (aplastic anemia [AA], hypocellular myelodysplastic syndrome [h-MDS], and hypocellular acute myeloid leukemia [h-AML]).
Materials and Methods
BM specimens were obtained from patients presenting with pancytopenia/bicytopenia. On 30 patients diagnosed as hypocellular BM, immunohistochemistry (IHC) for CD34, CD117, and p53 was performed.
Results
BM cellularity was < 30% in all (100%) patients. Blast count was increased in h-MDS and h-AML. Features of dysplasia were noted in six (20%) patients. Out of these, three patients were diagnosed as h-MDS having bilineage/trilineage dysplasia, and the other three patients were of AA (11.5% patients) displaying only dyserythropoiesis. On IHC, percentage of BM CD34+ cells was increased in h-MDS+ h-AML (3.87 ± 0.86) as compared with AA (0.19 ± 0.15) and controls (0.81 ± 0.21),
p
= 0.01. Percentage of BM p53+ cells was also increased in h-MDS+ h-AML (2.9 ± 2.07) as compared with AA and controls, which did not show any p53+ cells,
p
= 0.0. No statistically significant difference was observed in the expression of CD117 in h-MDS+ h-AML (4.95 ± 3.40) compared with AA (4.49 ± 1.07),
p
= 0.99.
Conclusion
The study demonstrates the usefulness of CD34 and p53 immunoexpression as an important ancillary method in distinguishing various hypocellular BM disorders, especially h-MDS and AA. However, the role of CD117 remains unclear and needs to be evaluated further by larger studies.
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Affiliation(s)
- Pooja Sharma
- Department of Pathology, Government Medical College and Hospital, Chandigarh, India
| | - Anshu Palta
- Department of Pathology, Government Medical College and Hospital, Chandigarh, India
| | - Anita Tahlan
- Department of Pathology, Government Medical College and Hospital, Chandigarh, India
| | - Manveen Kaur
- Department of Pathology, Government Medical College and Hospital, Chandigarh, India
| | - Ram Singh
- Department of Medicine, Government Medical College and Hospital, Chandigarh, India
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Lesmana H, Jacobs T, Boals M, Gray N, Lewis S, Ding J, Kang G, Hale M, Weiss M, Reiss U, Wang W, Wlodarski M. Eltrombopag in children with severe aplastic anemia. Pediatr Blood Cancer 2021; 68:e29066. [PMID: 33855784 DOI: 10.1002/pbc.29066] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/04/2021] [Accepted: 03/22/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND Immunosuppressive therapy with horse antithymocyte globulin and cyclosporine currently remains the standard therapy for children with severe aplastic anemia (SAA) who lack human leukocyte antigen (HLA)-identical sibling. The thrombopoietin receptor agonist eltrombopag has been recently approved for SAA patients 2 years and older. However, there are limited data on its safety and efficacy in pediatric cohorts. METHODS We conducted a retrospective study of patients ≤18 years old consecutively diagnosed with SAA between 2000 and 2018. Patients received either standard immunosuppressive therapy (IST-Std) or IST with eltrombopag (IST-Epag). The primary outcome was the objective response (OR), including partial and complete response (CR), at 6 and 12 months after starting therapy. RESULTS We identified 16 patients receiving IST-Std and nine IST-Epag treatment (seven of nine as upfront therapy and two of seven after previously failed IST). The OR at 6 and 12 months in IST-Std arm was 71% and 100%, with CR in 29% and 58%, respectively. Seven patients receiving upfront IST-Epag had OR at 6 and 12 months, with two of seven (29%) achieving CR at 6 and 12 months. Two patients who previously failed standard IST did not respond to eltrombopag. No significant differences were observed in both cohorts with regard to infections. One IST-Epag-treated patient developed transient grade 3 transaminitis. Finally, no changes in paroxysmal nocturnal hemoglobinuria (PNH) clone size and cytogenetic abnormalities were seen in either cohort. CONCLUSION The addition of eltrombopag to standard IST was well tolerated and resulted in satisfactory hematological response at 6 and 12 months in this single-institution experience. A larger cohort with longer follow-up is required to assess response durability.
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Affiliation(s)
- Harry Lesmana
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.,Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Cleveland Clinic, Cleveland, Ohio, USA
| | - Timothy Jacobs
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Michelle Boals
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Nathan Gray
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Sara Lewis
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Juan Ding
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Guolian Kang
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Melvanique Hale
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Mitchell Weiss
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Ulrike Reiss
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Winfred Wang
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Marcin Wlodarski
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Richards SJ, Painter D, Dickinson AJ, Griffin M, Munir T, Arnold L, Payne D, Pike A, Muus P, Hill A, Newton DJ, McKinley C, Jones R, Kelly R, Smith A, Roman E, Hillmen P. The incidence and prevalence of patients with paroxysmal nocturnal haemoglobinuria and aplastic anaemia PNH syndrome: A retrospective analysis of the UK's population-based haematological malignancy research network 2004-2018. Eur J Haematol 2021; 107:211-218. [PMID: 34060690 DOI: 10.1111/ejh.13640] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/26/2021] [Accepted: 04/27/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVES A retrospective population-based study to determine the incidence and prevalence of patients with the rare blood disease paroxysmal nocturnal haemoglobinuria (PNH). METHODS All patients were identified by flow cytometric detection of blood cells deficient in glycosylphosphatidylinositol (GPI) linked proteins at a single diagnostic reference laboratory that serves the Yorkshire based, Haematological Malignancy Research Network (HMRN) with a population of 3.8 million. RESULTS One hundred and ninety-seven patients with detectable PNH clones at a level of >0.01% in at least two lineages of cells (neutrophils, monocytes and/or red cells) were identified over a 15-year period (2004-2018). Of these, 88% had aplastic anaemia (AA), 8% classical PNH and 3% myelodysplastic syndrome. The overall incidence rate was estimated at 0.35 cases per 100 000 people per year. This equates to 220 cases newly diagnosed in the United Kingdom each year. The overall prevalence rate was 3.81 per 100 000, this equates to an estimated 2400 prevalent cases in the UK. The overall and relative 5-year survival rates were 72% and 82.7%, respectively. CONCLUSIONS This study showed that classical haemolytic PNH is a rare disease and represents only a small proportion overall of patients with detectable PNH cells, the majority of which have aplastic anaemia.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Anemia, Aplastic/complications
- Anemia, Aplastic/diagnosis
- Anemia, Aplastic/epidemiology
- Anemia, Aplastic/history
- Biomarkers
- Child
- Child, Preschool
- Female
- Hemoglobinuria, Paroxysmal/complications
- Hemoglobinuria, Paroxysmal/diagnosis
- Hemoglobinuria, Paroxysmal/epidemiology
- Hemoglobinuria, Paroxysmal/history
- History, 21st Century
- Humans
- Immunophenotyping
- Incidence
- Male
- Middle Aged
- Population Surveillance
- Prevalence
- Retrospective Studies
- Syndrome
- United Kingdom/epidemiology
- Young Adult
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Affiliation(s)
- Stephen J Richards
- Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Daniel Painter
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
| | - Anita J Dickinson
- Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals NHS Trust, St. James's University Hospital, Leeds, UK
| | - Morag Griffin
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Talha Munir
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Louise Arnold
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Daniel Payne
- Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals NHS Trust, St. James's University Hospital, Leeds, UK
| | - Alexandra Pike
- Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Petra Muus
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Anita Hill
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
- Alexion Pharmaceuticals Inc., Leeds, UK
| | - Darren J Newton
- Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Claire McKinley
- Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Rachael Jones
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Richard Kelly
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Alex Smith
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
| | - Eve Roman
- Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK
| | - Peter Hillmen
- Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
- Department of Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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Adult aplastic anemia in Thailand: incidence and treatment outcome from a prospective nationwide population-based study. Ann Hematol 2021; 100:2443-2452. [PMID: 34269837 PMCID: PMC8440252 DOI: 10.1007/s00277-021-04566-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 06/04/2021] [Indexed: 11/20/2022]
Abstract
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.
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42
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A Step Toward Comprehensive Transplant Solutions for Aplastic Anemia. Transplantation 2021; 105:955-957. [PMID: 32639404 DOI: 10.1097/tp.0000000000003343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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43
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Iftikhar R, Ahmad P, de Latour R, Dufour C, Risitano A, Chaudhri N, Bazarbachi A, De La Fuente J, Höchsmann B, Osman Ahmed S, Gergis U, Elhaddad A, Halkes C, Albeirouti B, Alotaibi S, Kulasekararaj A, Alzahrani H, Ben Othman T, Cesaro S, Alahmari A, Rihani R, Alshemmari S, Ali Hamidieh A, Bekadja MA, Passweg J, Al-Khabori M, Rasheed W, Bacigalupo A, Chaudhry QUN, Ljungman P, Marsh J, El Fakih R, Aljurf M. Special issues related to the diagnosis and management of acquired aplastic anemia in countries with restricted resources, a report on behalf of the Eastern Mediterranean blood and marrow transplantation (EMBMT) group and severe aplastic anemia working party of the European Society for blood and marrow transplantation (SAAWP of EBMT). Bone Marrow Transplant 2021; 56:2518-2532. [PMID: 34011966 DOI: 10.1038/s41409-021-01332-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 03/30/2021] [Accepted: 04/26/2021] [Indexed: 11/09/2022]
Abstract
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.
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Affiliation(s)
- Raheel Iftikhar
- Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan.
| | - Parvez Ahmad
- Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan
| | | | - Carlo Dufour
- G Gaslini Children Research Hospital, Genova, Italy
| | - Antonio Risitano
- AORN Moscati, Avellino, Italy.,Federico II University, Naples, Italy
| | - Naeem Chaudhri
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Ali Bazarbachi
- American University of Beirut Medical Center, Beirut, Lebanon
| | | | | | - Syed Osman Ahmed
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Usama Gergis
- Sidney Kimmel Cancer Center, Philadelphia, PA, USA
| | - Alaa Elhaddad
- National Cancer Institute, Cairo University, Cairo, Egypt
| | | | - Bassim Albeirouti
- King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
| | | | | | - Hazzaa Alzahrani
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Tarek Ben Othman
- Center National de Greffe de Moelle Osseuse de Tunis, Tunis, Tunisia
| | - Simone Cesaro
- Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Ali Alahmari
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | | | | | - Amir Ali Hamidieh
- Pediatric Cell Therapy Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | | | - Walid Rasheed
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | | | | | - Per Ljungman
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden.,Division of Hematology Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | | | - Riad El Fakih
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Mahmoud Aljurf
- King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
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Postvaccination graft dysfunction/aplastic anemia relapse with massive clonal expansion of autologous CD8+ lymphocytes. Blood Adv 2021; 4:1378-1382. [PMID: 32267929 DOI: 10.1182/bloodadvances.2019000853] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 02/22/2020] [Indexed: 11/20/2022] Open
Abstract
Key Points
Acquired aplastic anemia is a T-cell–mediated autoimmune bone marrow aplasia, without a known etiologic trigger. Clonal expansion of CD8+ effector T lymphocytes can occur following vaccination and accompany graft dysfunction or aplastic anemia relapse.
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45
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Scheinberg P. Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries. Br J Haematol 2021; 194:954-969. [PMID: 33855695 DOI: 10.1111/bjh.17403] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 02/16/2021] [Indexed: 11/28/2022]
Abstract
The progress in aplastic anaemia (AA) management is one of success. Once an obscure entity resulting in death in most affected can now be successfully treated with either haematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). The mechanisms that underly the diminution of haematopoietic stem cells (HSCs) are now better elucidated, and include genetics and immunological alterations. Advances in supportive care with better antimicrobials, safer blood products and iron chelation have greatly impacted AA outcomes. Working somewhat 'mysteriously', anti-thymocyte globulin (ATG) forms the base for both HSCT and IST protocols. Efforts to augment immunosuppression potency have not, unfortunately, led to better outcomes. Stimulating HSCs, an often-sought approach, has not been effective historically. The thrombopoietin receptor agonists (Tpo-RA) have been effective in stimulating early HSCs in AA despite the high endogenous Tpo levels. Dosing, timing and best combinations with Tpo-RAs are being defined to improve HSCs expansion in AA with minimal added toxicity. The more comprehensive access and advances in HSCT and IST protocols are likely to benefit AA patients worldwide. The focus of this review will be on the medical treatment advances in AA.
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Affiliation(s)
- Phillip Scheinberg
- Division of Haematology, Hospital A Beneficência Portuguesa, São Paulo, Brazil
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46
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When Should We Think of Myelodysplasia or Bone Marrow Failure in a Thrombocytopenic Patient? A Practical Approach to Diagnosis. J Clin Med 2021; 10:jcm10051026. [PMID: 33801484 PMCID: PMC7958851 DOI: 10.3390/jcm10051026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/11/2021] [Accepted: 02/17/2021] [Indexed: 12/15/2022] Open
Abstract
Thrombocytopenia can arise from various conditions, including myelodysplastic syndromes (MDS) and bone marrow failure (BMF) syndromes. Meticulous assessment of the peripheral blood smear, identification of accompanying clinical conditions, and characterization of the clinical course are important for initial assessment of unexplained thrombocytopenia. Increased awareness is required to identify patients with suspected MDS or BMF, who are in need of further investigations by a step-wise approach. Bone marrow cytomorphology, histopathology, and cytogenetics are complemented by myeloid next-generation sequencing (NGS) panels. Such panels are helpful to distinguish reactive cytopenia from clonal conditions. MDS are caused by mutations in the hematopoietic stem/progenitor cells, characterized by cytopenia and dysplasia, and an inherent risk of leukemic progression. Aplastic anemia (AA), the most frequent acquired BMF, is immunologically driven and characterized by an empty bone marrow. Diagnosis remains challenging due to overlaps with other hematological disorders. Congenital BMF, certainly rare in adulthood, can present atypically with thrombocytopenia and can be misdiagnosed. Analyses for chromosome fragility, telomere length, and germline gene sequencing are needed. Interdisciplinary expert teams contribute to diagnosis, prognostication, and choice of therapy for patients with suspected MDS and BMF. With this review we aim to increase the awareness and provide practical approaches for diagnosis of these conditions in suspicious cases presenting with thrombocytopenia.
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47
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Demerdash Y, Kain B, Essers MAG, King KY. Yin and Yang: The dual effects of interferons on hematopoiesis. Exp Hematol 2021; 96:1-12. [PMID: 33571568 DOI: 10.1016/j.exphem.2021.02.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/11/2022]
Abstract
Interferons are an ancient and well-conserved group of inflammatory cytokines most famous for their role in viral immunity. A decade ago, we discovered that interferons also play an important role in the biology of hematopoietic stem cells (HSCs), which are responsible for lifelong blood production. Though we have learned a great deal about the role of interferons on HSC quiescence, differentiation, and self-renewal, there remains some controversy regarding how interferons impact these stem cells, with differing conclusions depending on experimental models and clinical context. Here, we review the contradictory roles of Type 1 and 2 interferons in hematopoiesis. Specifically, we highlight the roles of interferons in embryonic and adult hematopoiesis, along with short-term and long-term adaptive and maladaptive responses to inflammation. We discuss experimental challenges in the study of these powerful yet short-lived cytokines and strategies to address those challenges. We further review the contribution by interferons to disease states including bone marrow failure and aplastic anemia as well as their therapeutic use to treat myeloproliferative neoplasms and viral infections, including SARS-CoV2. Understanding the opposing effects of interferons on hematopoiesis will elucidate immune responses and bone marrow failure syndromes, and future therapeutic approaches for patients undergoing HSC transplantation or fighting infectious diseases and cancer.
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Affiliation(s)
- Yasmin Demerdash
- Division Inflammatory Stress in Stem Cells, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGMBH), Heidelberg, Germany; Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Bailee Kain
- Program in Translational Biology and Molecular Medicine, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX
| | - Marieke A G Essers
- Division Inflammatory Stress in Stem Cells, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGMBH), Heidelberg, Germany; DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Katherine Y King
- Program in Translational Biology and Molecular Medicine, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Section of Infectious Diseases and Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX.
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Li H, Xu X, Wang D, Zhang Y, Chen J, Li B, Su S, Wei L, You H, Fang Y, Wang Y, Liu Y. Hypermethylation-mediated downregulation of long non-coding RNA MEG3 inhibits osteogenic differentiation of bone marrow mesenchymal stem cells and promotes pediatric aplastic anemia. Int Immunopharmacol 2021; 93:107292. [PMID: 33529912 DOI: 10.1016/j.intimp.2020.107292] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/02/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND The reduced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is the typical characteristics of pediatric aplastic anemia (AA) pathogenesis. Long non-coding RNA MEG3 is reported to promote osteogenic differentiation of BMSCs via inducing BMP4 expression. OBJECTIVE This study aims to investigate the mechanism of DNMT1/MEG3/BMP4 pathway in osteogenic differentiation of BMSCs in pediatric AA. METHODS BMSCs were isolated and purified from bone marrows of pediatric AA patients (n = 5) and non-AA patients (n = 5). The expression of DNMT1, MEG3, and BMP4 in isolated BMSCs was detected using quantitative real-time PCR and western blot analysis. Osteogenic differentiation was determined using Alizarin red staining. The methylation of MEG3 promoter and the interaction between DNMT1 and MEG3 promoter were detected using methylation-specific PCR and chromatin immunoprecipitation assay, respectively. RESULTS Lowly expressed MEG3 and BMP4 and highly expressed DNMT1 were observed in BMSCs of pediatric AA patients. The overexpression of MEG3 promoted osteogenic differentiation of BMSCs. Luciferase reporter assay showed that MEG3 overexpression increased transcriptional activity of BMP4. The inhibitor of methylation, 5-azacytidine, suppressed DNMT1 expression and reduced methylation of MEG3 promoter. Overexpression of DNMT1 increased the binding between DNMT1 and MEG3 promoter. The simultaneous overexpression of DNMT1 and MEG3 restored the inhibition of osteogenic differentiation caused by DNMT1 overexpression alone. CONCLUSIONS Our findings indicated that DNMT1 mediated the hypermethylation of MEG3 promoter in BMSCs, and DNMT1/MEG3/BMP4 pathway modulated osteogenic differentiation of BMSCs in pediatric AA.
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Affiliation(s)
- Huanhuan Li
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xueju Xu
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Dao Wang
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yuan Zhang
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jiao Chen
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Bai Li
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Shufang Su
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Linlin Wei
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Hongliang You
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yingqi Fang
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yingchao Wang
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yufeng Liu
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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Adhikari S, Nayek K, Bandyopadhyay A, Mandal P. Implication of therapeutic outcomes associated with molecular characterization of paediatric aplastic anaemia. Biochem Biophys Rep 2021; 25:100899. [PMID: 33490648 PMCID: PMC7809188 DOI: 10.1016/j.bbrep.2020.100899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/22/2020] [Accepted: 12/22/2020] [Indexed: 11/19/2022] Open
Abstract
Objectives Severe aplastic anemia is characterized by a hypocellular bone marrow and peripheral cytopenia. Mesenchymal stem cells (MSCs) play a crucial role in haematopoietic stem cells (HSCs) development and the development of microenvironment suitable for hematopoiesis. Molecular characterization of telomere maintenance pathway and gene expression profiling of MSCs can be important for the therapeutic interventions among paediatric aplastic anaemia patients. Methods The study involved paediatric aplastic anaemia patients (n = 10) and age matched paediatric healthy donors (n = 8). Peripheral blood samples were collected from the individuals. Average leucocyte telomere length and gene expression of the telomere maintenance genes were determined by quantitative real time PCR. Microarray based gene expression profiles (GSE33812) of MSCs for five paediatric aplastic anaemia patients were analyzed compared to five healthy controls and the data was downloaded from the GEO database. Results The telomere length was significantly shorter among paediatric AA patients compared to age matched healthy donors. Interestingly, one subgroup (n = 2) of paediatric AA patients has moderate telomere length comparable to age matched healthy donors. Based on the gene expression analysis of telomere maintenance pathway, TERF2 was significantly downregulated among paediatric patients with shorter telomere length but not among paediatric patients with moderate telomere length. Gene expression profiling of MSCs revealed three differentially expressed genes (GAS2L3, MK167 and TMSB15A) among the patients and was associated with therapeutic outcome. Conclusion Telomere length estimation and gene expression patterns of the MSCs and telomere length maintenance pathway may serve as a potential biomarker and could be associated with therapeutic choice of paediatric aplastic anaemia patients.
One subgroup of paediatric AA patients has moderate telomere length comparable to age matched healthy donors. TERF2 was differentially downregulated among paediatric patients with shorter telomere length. Differential downregulation of GAS2L3, MK167 and TMSB15A genes in MSCs among the patients with immunosuppressive therapy.
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Affiliation(s)
- Sarmistha Adhikari
- Biomedical Genetics Laboratory, Department of Zoology, The University of Burdwan, West Bengal, India
| | - Kaustav Nayek
- Department of Paediatric Medicine, Burdwan Medical College & Hospital, West Bengal, India
| | | | - Paramita Mandal
- Biomedical Genetics Laboratory, Department of Zoology, The University of Burdwan, West Bengal, India
- Corresponding author. Biomedical Genetics Laboratory, Department of Zoology, The University of Burdwan, Burdwan, 713104, West Bengal, India.
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Pulsipher MA, Lehmann LE, Bertuch AA, Sasa G, Olson T, Nakano T, Gilio A, Burroughs LM, Lipton JM, Huang JN, Dickerson KE, Bertaina A, Zhuang C, Malsch M, Fleming M, Weller E, Shimamura A, Williams DA. A study assessing the feasibility of randomization of pediatric and young adult patients between matched unrelated donor bone marrow transplantation and immune-suppressive therapy for newly diagnosed severe aplastic anemia: A joint pilot trial of the North American Pediatric Aplastic Anemia Consortium and the Pediatric Transplantation and Cellular Therapy Consortium. Pediatr Blood Cancer 2020; 67:e28444. [PMID: 32776425 PMCID: PMC9533334 DOI: 10.1002/pbc.28444] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 05/07/2020] [Accepted: 05/13/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Recent data show survival after matched unrelated donor (MUD) bone marrow transplantation (BMT) is similar to matched sibling procedures for young patients with severe aplastic anemia (SAA). Donor delays, risk of transplant-related mortality (TRM), and concern about chronic graft versus host disease raise questions about whether MUD BMT or immune suppression therapy (IST) should be preferred initial therapy for young patients lacking matched sibling donors. PROCEDURE We performed a pilot trial to assess the feasibility of randomizing patients under age 26 with newly diagnosed SAA to receive IST versus MUD BMT. Primary aims assessed the acceptability of randomization and timing of BMT. Secondary aims measured toxicities, response, and survival. RESULTS Sixty-seven patients with possible SAA were screened at nine centers. Of 57 with confirmed SAA, 23 underwent randomization and received therapy with a median follow-up of 18 months. Of 12 randomized to BMT, 10 started BMT as initial therapy at a median of 36 days after randomization. One BMT recipient experienced secondary graft failure, requiring a second procedure. Six of 11 randomized to IST responded, whereas five with refractory disease underwent successful salvage BMT. One patient achieving complete response relapsed after discontinuation of immune suppression and died of infection after salvage BMT. CONCLUSIONS This feasibility study showed that a high percentage of patients underwent randomization and received up-front MUD BMT. Our study lays the groundwork for a larger randomized trial that will define best initial therapy for young patients with SAA who have an available MUD.
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Affiliation(s)
- Michael A. Pulsipher
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California
| | - Leslie E. Lehmann
- Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Alison A. Bertuch
- Baylor College of Medicine, Center for Cell and Gene Therapy and Texas Children’s Hospital, Houston, Texas
| | - Ghadir Sasa
- Baylor College of Medicine, Center for Cell and Gene Therapy and Texas Children’s Hospital, Houston, Texas
| | - Timothy Olson
- Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | | | | | - Lauri M. Burroughs
- Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington
| | - Jeffrey M. Lipton
- Division of Hematology/Oncology and Cellular Therapy, Cohen Children’s Medical Center of New York, New York
| | - James N. Huang
- UCSF Benioff Children’s Hospital and University of California, San Francisco, California
| | | | - Alice Bertaina
- Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, California
| | - Cindy Zhuang
- Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California
| | - Maggie Malsch
- Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mark Fleming
- Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Edie Weller
- Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Akiko Shimamura
- Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - David A. Williams
- Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
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