Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1

doi:10.1016/j.jaci.2018.04.032

Clinical Trial

. 2019 Jan;143(1):266-275.

doi: 10.1016/j.jaci.2018.04.032. Epub 2018 May 18.

Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1

Tsubasa Okano¹, Kohsuke Imai², Yuki Tsujita³, Noriko Mitsuiki¹, Kenichi Yoshida⁴, Chikako Kamae³, Kenichi Honma³, Kanako Mitsui-Sekinaka³, Yujin Sekinaka³, Tamaki Kato³, Katsuyuki Hanabusa¹, Eri Endo¹, Takehiro Takashima¹, Haruka Hiroki¹, Tzu-Wen Yeh¹, Keisuke Tanaka¹, Masakazu Nagahori⁵, Ikuya Tsuge⁶, Yuki Bando⁷, Fuminori Iwasaki⁸, Yoshiaki Shikama⁹, Masami Inoue¹⁰, Tomiko Kimoto¹⁰, Naohiko Moriguchi¹¹, Yuki Yuza¹², Takashi Kaneko¹², Kyoko Suzuki¹³, Tomoyo Matsubara¹³, Yoshihiro Maruo¹⁴, Tomoaki Kunitsu¹⁴, Tomoko Waragai¹⁵, Hideki Sano¹⁶, Yuko Hashimoto¹⁷, Kazuhiro Tasaki¹⁷, Osamu Suzuki¹⁷, Toshihiko Shirakawa¹⁸, Motohiro Kato¹⁹, Toru Uchiyama²⁰, Masataka Ishimura²¹, Tetsuzo Tauchi²², Hiroshi Yagasaki²³, Shiann-Tarng Jou²⁴, Hsin-Hui Yu²⁴, Hirokazu Kanegane¹, Sven Kracker²⁵, Anne Durandy²⁵, Daiei Kojima²⁶, Hideki Muramatsu²⁶, Taizo Wada²⁷, Yuzaburo Inoue²⁸, Hidetoshi Takada²⁹, Seiji Kojima²⁶, Seishi Ogawa⁴, Osamu Ohara³⁰, Shigeaki Nonoyama³, Tomohiro Morio¹

Affiliations

¹ Department of Pediatrics, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
² Department of Pediatrics, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address: kimai.ped@tmd.ac.jp.
³ Department of Pediatrics, National Defense Medical College, Saitama, Japan.
⁴ Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁵ Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
⁶ Department of Pediatrics, School of Medicine, Fujita Health University, Toyoake, Japan.
⁷ Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Japan.
⁸ Division of Hemato-Oncology Regenerative Medicine, Yokohama, Japan.
⁹ Division of Infectious Disease and Immunology, Kanagawa Children's Medical Center, Yokohama, Japan.
¹⁰ Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.
¹¹ Department of Pediatrics, Kindai University Sakai Hospital, Sakai, Japan.
¹² Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
¹³ Department of Pediatrics, Juntendo University, Urayasu Hospital, Chiba, Japan.
¹⁴ Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan.
¹⁵ Department of Pediatrics, Fukushima Medical University, Fukushima, Japan.
¹⁶ Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan.
¹⁷ Department of Diagnostic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
¹⁸ Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.
¹⁹ Division of Transplantation and Cell Therapy, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
²⁰ Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
²¹ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
²² Department of Hematology, Tokyo Medical University, Tokyo, Japan.
²³ Department of Pediatrics, Nihon University Itabashi Hospital, Tokyo, Japan.
²⁴ Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
²⁵ Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, INSERM UMR 1163, Human Lymphohematopoiesis Laboratory, Paris, France.
²⁶ Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²⁷ Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
²⁸ Department of Pediatrics, Eastern Chiba Medical Center, Togane, Chiba, Japan.
²⁹ Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³⁰ Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan.

PMID: 29778502
DOI: 10.1016/j.jaci.2018.04.032

Clinical Trial

Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1

Tsubasa Okano et al. J Allergy Clin Immunol. 2019 Jan.

. 2019 Jan;143(1):266-275.

doi: 10.1016/j.jaci.2018.04.032. Epub 2018 May 18.

Authors

Affiliations

¹ Department of Pediatrics, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
² Department of Pediatrics, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address: kimai.ped@tmd.ac.jp.
³ Department of Pediatrics, National Defense Medical College, Saitama, Japan.
⁴ Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁵ Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
⁶ Department of Pediatrics, School of Medicine, Fujita Health University, Toyoake, Japan.
⁷ Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Japan.
⁸ Division of Hemato-Oncology Regenerative Medicine, Yokohama, Japan.
⁹ Division of Infectious Disease and Immunology, Kanagawa Children's Medical Center, Yokohama, Japan.
¹⁰ Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.
¹¹ Department of Pediatrics, Kindai University Sakai Hospital, Sakai, Japan.
¹² Department of Hematology/Oncology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
¹³ Department of Pediatrics, Juntendo University, Urayasu Hospital, Chiba, Japan.
¹⁴ Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan.
¹⁵ Department of Pediatrics, Fukushima Medical University, Fukushima, Japan.
¹⁶ Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan.
¹⁷ Department of Diagnostic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
¹⁸ Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.
¹⁹ Division of Transplantation and Cell Therapy, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
²⁰ Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
²¹ Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
²² Department of Hematology, Tokyo Medical University, Tokyo, Japan.
²³ Department of Pediatrics, Nihon University Itabashi Hospital, Tokyo, Japan.
²⁴ Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
²⁵ Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute, INSERM UMR 1163, Human Lymphohematopoiesis Laboratory, Paris, France.
²⁶ Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²⁷ Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
²⁸ Department of Pediatrics, Eastern Chiba Medical Center, Togane, Chiba, Japan.
²⁹ Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³⁰ Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan.

PMID: 29778502
DOI: 10.1016/j.jaci.2018.04.032

Abstract

Background: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined.

Objective: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT.

Methods: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities.

Results: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT.

Conclusion: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.

Keywords: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1; IgG(2); PIK3CD; T-cell receptor excision circle; combined immunodeficiency; hematopoietic stem cell transplantation; kappa-deleting recombination excision circle.

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Comment in

Hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: Who, when, and how?
Notarangelo LD. Notarangelo LD. J Allergy Clin Immunol. 2019 Jan;143(1):91-93. doi: 10.1016/j.jaci.2018.08.039. Epub 2018 Sep 12. J Allergy Clin Immunol. 2019. PMID: 30218677 Free PMC article. No abstract available.

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Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1

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Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1

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