Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.,Journal of Clinical Immunology

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Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.
Journal of Clinical Immunology ( IF 7.2 ) Pub Date : 2021-07-29 , DOI: 10.1007/s10875-021-01098-0
Hasan Hashem ₁ , Giorgia Bucciol _{2,

3} , Seza Ozen _{4,

5} , Sule Unal ₆ , Ikbal Ok Bozkaya ₇ , Nurten Akarsu ₈ , Mervi Taskinen ₉ , Minna Koskenvuo ₁₀ , Janna Saarela _{11,

12} , Dimana Dimitrova ₁₃ , Dennis D Hickstein ₁₄ , Amy P Hsu ₁₅ , Steven M Holland ₁₅ , Robert Krance ₁₆ , Ghadir Sasa ₁₆ , Ashish R Kumar _{17,

18} , Ingo Müller ₁₉ , Monica Abreu de Sousa ₁₉ , Selket Delafontaine _{2,

3} , Leen Moens ₃ , Florian Babor ₂₀ , Federica Barzaghi ₂₁ , Maria Pia Cicalese ₂₂ , Robbert Bredius ₂₃ , Joris van Montfrans ₂₄ , Valentina Baretta ₂₅ , Simone Cesaro ₂₅ , Polina Stepensky ₂₆ , Neven Benedicte ₂₇ , Despina Moshous ₂₇ , Guillaume Le Guenno ₂₈ , David Boutboul ₂₉ , Jignesh Dalal ₃₀ , Joel P Brooks ₃₁ , Elif Dokmeci ₃₂ , Jasmeen Dara ₃₃ , Carrie L Lucas ₃₁ , Sophie Hambleton ₃₄ , Keith Wilson ₃₅ , Stephen Jolles ₃₆ , Yener Koc ₃₇ , Tayfun Güngör ₃₈ , Caroline Schnider ₃₉ , Fabio Candotti ₄₀ , Sandra Steinmann ₄₁ , Ansgar Schulz ₄₁ , Chip Chambers ₄₂ , Michael Hershfield ₄₃ , Amanda Ombrello ₄₄ , Jennifer A Kanakry ₁₃ , Isabelle Meyts _{2,

3}

Affiliation

Department of Pediatrics, Division of Pediatric Hematology and Oncology, Bone Marrow Transplant Unit, King Hussein Cancer Center (KHCC), P.O Box 1269, Amman, 11941, Jordan.
Department of Pediatrics, ERN RITA Core Center, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
Hacettepe University Vasculitis Research Center, Ankara, Turkey.
Department of Pediatric Hematology, Research Center for Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara, Turkey.
Division of Pediatric Hematology and Oncology, Bone Marrow Transplant Unit, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.
Department of Medical Genetics, Hacettepe University, Sihhiye, 06100, Ankara, Turkey.
Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland.
Pediatric Hematology, Oncology and Stem Cell Transplantation, Children and Adolescents, Helsinki University Hospital, Helsinki, Finland.
Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland.
Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway.
Experimental Transplantation and Immunotherapy Branch, National Cancer Institute of the National Institutes of Health, Bethesda, MD, USA.
Immune Deficiency Cellular Therapy Program, CCR, NCI, MD, Bethesda, USA.
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
San Raffaele Telethon Institute for Gene Therapy (TIGET), Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute Milan, Milan, Italy.
Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands.
Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, Netherlands.
Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Center, Jerusalem, Israel.
Pediatric Immunology, Hematology and Rheumatology Unit, Hôpital Necker-Enfants Malades, APHP, Paris, France.
Department of Internal Medicine, University Hospital Estaing, CHU Clermont-Ferrand, Clermont-Ferrand, France.
Clinical Immunology Department, Hospital Saint Louis, Université de Paris, Paris, France.
Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH, USA.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Department of Pediatrics, University of New Mexico, Albuquerque, NM, USA.
Department of Pediatrics, Division of Allergy, Immunology, Blood and Marrow Transplantation, University of California San Francisco, San Francisco, CA, USA.
Newcastle University Translational and Clinical Research Institute and Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, , Newcastle Upon Tyne, UK.
Department of Hematology, University Hospital of Wales, Cardiff, UK.
Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, UK.
Stem Cell Transplant Unit, Medicana International, Istanbul, Turkey.
Division of Hematology/Oncology/Immunology, Gene Therapy, and Stem Cell Transplantation, University Children's Hospital Zurich - Eleonore Foundation & Children's Research Center (CRC), Steinwiesstrasse 75, CH-8032, Zurich, Switzerland.
Pediatric Immuno-Rheumatology of Western Switzerland, Department Women-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland.
Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine and Biochemistry, Duke University Medical Center, Durham, NC, USA.
Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute (NHGRI), Bethesda, MD, USA.

PURPOSE Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. METHODS We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). RESULTS Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. CONCLUSION HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. CLINICAL IMPLICATIONS HCT is a definitive cure for DADA2 with > 95% survival.

中文翻译：

造血细胞移植治愈腺苷脱氨酶 2 缺乏症：30 名患者的报告。

目的腺苷脱氨酶 2 (DADA2) 缺乏是一种遗传性先天性免疫缺陷，其特征为自身炎症（反复发热）、血管病变（葡萄状青斑、结节性多动脉炎、腔隙性缺血性中风和颅内出血）、免疫缺陷、淋巴细胞增殖、免疫性血细胞减少和骨髓衰竭（BMF）。肿瘤坏死因子 (TNF-α) 阻断是血管病变的首选治疗方法，但通常无法逆转难治性血细胞减少症。我们的目的是研究 DADA2 患者的造血细胞移植 (HCT) 的结果。方法我们对 DADA2 患者的 HCT 结果进行了回顾性研究。主要结局是总生存期（OS）。结果来自 12 个国家的 30 名 DADA2 患者总共接受了 38 次 HCT。 HCT 的适应症是 BMF、免疫性血细胞减少、恶性肿瘤或免疫缺陷。 HCT 的中位年龄为 9 岁（范围：2-28 岁）。最终移植的预处理方案为清髓性（n = 20）、降低强度（n = 8）或非清髓性（n = 2）。供体为 HLA 匹配相关 (n = 4)、HLA 匹配无关 (n = 16)、HLA 单倍体相合 (n = 2) 或 HLA 不匹配无关 (n = 8)。中位随访 2 年（范围：0.5-16 年）后，2 年 OS 为 97%，2 年无 GvHD 无复发生存率为 73%。血液学和免疫学表型得到解决，并且没有新的血管事件。 16/17 名测试患者的血浆 ADA2 酶活性恢复正常。六名患者需要不止一次 HCT。结论 HCT 是 DADA2 的有效治疗方法，成功逆转了难治性血细胞减少症以及血管病变和免疫缺陷。临床意义 HCT 是 DADA2 的最终治愈方法，存活率 > 95%。

更新日期：2021-07-29

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