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Successful management of acute graft-versus-host disease with ibrutinib during cord blood transplantation for germline DDX41-mutated acute myeloid leukemia

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Title: Successful management of acute graft-versus-host disease with ibrutinib during cord blood transplantation for germline DDX41-mutated acute myeloid leukemia
Authors: Ayana Uchimura, Hajime Yasuda, Hiroko Onagi, Tadaaki Inano, Shuichi Shirane, Midori Ishii, Yoko Azusawa, Yasuharu Hamano, Hidetaka Eguchi, Masami Arai, Jun Ando, Miki Ando
Source: Heliyon, Vol 10, Iss 2, Pp e24801- (2024)
Publisher Information: Elsevier, 2024.
Publication Year: 2024
Collection: LCC:Science (General)
LCC:Social sciences (General)
Subject Terms: Allogeneic hematopoietic stem cell transplantation (allo-HSCT, allo-SCT), DEAD-Box RNA helicase 41 (DDX41), Myeloid neoplasms with germline predisposition, Hereditary hematologic malignancies (HHM), Familial myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML), Severe gastrointestinal graft-versus-host-disease (GVHD), Science (General), Q1-390, Social sciences (General), H1-99
More Details: Background: Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with significant morbidity and mortality, and efficacy of currently available therapeutics are limited. Acute and chronic GVHD are similar in that both are initiated by antigen presenting cells and activation of alloreactive B-cells and T-cells, subsequently leading to inflammation, tissue damage, and organ failure. One difference is that acute GVHD is mostly attributed to T-cell activation and cytokine release, whereas B-cells are the key players in chronic GVHD. Ibrutinib is an irreversible inhibitor of the Bruton's tyrosine kinase (BTK), which is part of B-cell receptor signaling. Ibrutinib is currently used for treating chronic GVHD, but its efficacy towards acute GVHD is unknown. Besides BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK), which is predominantly expressed in T-cells and a crucial enzyme for activating the downstream pathway of TCR signaling. ITK activates PLCγ2 and facilitates signaling through NF-κB, NFAT, and MAPK, leading to activation and proliferation of T-cells and enhanced cytokine production. Therefore, the TCR signaling pathway is indispensable for development of acute GVHD, and ITK inhibition by ibrutinib would be a rational therapeutic approach. Case presentation: A 56-year-old male acute myeloid leukemia patient with Myeloid neoplasms with germline DEAD-box RNA helicase 41 (DDX41) mutation underwent cord blood transplantation and developed severe gastrointestinal (GI) acute GVHD which was refractory to steroids and mesenchymal stem cell therapy. While acute GVHD accommodated by multiple life-threatening GI bleeding events persisted, chronic cutaneous GVHD developed, and ibrutinib 420 mg/day was initiated from day 147 of transplant. Although ibrutinib was commenced targeting the chronic GVHD, unexpected and abrupt remission of acute GVHD along with remission of chronic GVHD was observed. Conclusion: Ibrutinib is a promising therapeutic for treating acute GVHD, and further studies are warranted.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2405-8440
Relation: http://www.sciencedirect.com/science/article/pii/S2405844024008326; https://doaj.org/toc/2405-8440
DOI: 10.1016/j.heliyon.2024.e24801
Access URL: https://doaj.org/article/2568fad0772844d3aee047e5688cdf1f
Accession Number: edsdoj.2568fad0772844d3aee047e5688cdf1f
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  Data: Successful management of acute graft-versus-host disease with ibrutinib during cord blood transplantation for germline DDX41-mutated acute myeloid leukemia
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  Data: <searchLink fieldCode="AR" term="%22Ayana+Uchimura%22">Ayana Uchimura</searchLink><br /><searchLink fieldCode="AR" term="%22Hajime+Yasuda%22">Hajime Yasuda</searchLink><br /><searchLink fieldCode="AR" term="%22Hiroko+Onagi%22">Hiroko Onagi</searchLink><br /><searchLink fieldCode="AR" term="%22Tadaaki+Inano%22">Tadaaki Inano</searchLink><br /><searchLink fieldCode="AR" term="%22Shuichi+Shirane%22">Shuichi Shirane</searchLink><br /><searchLink fieldCode="AR" term="%22Midori+Ishii%22">Midori Ishii</searchLink><br /><searchLink fieldCode="AR" term="%22Yoko+Azusawa%22">Yoko Azusawa</searchLink><br /><searchLink fieldCode="AR" term="%22Yasuharu+Hamano%22">Yasuharu Hamano</searchLink><br /><searchLink fieldCode="AR" term="%22Hidetaka+Eguchi%22">Hidetaka Eguchi</searchLink><br /><searchLink fieldCode="AR" term="%22Masami+Arai%22">Masami Arai</searchLink><br /><searchLink fieldCode="AR" term="%22Jun+Ando%22">Jun Ando</searchLink><br /><searchLink fieldCode="AR" term="%22Miki+Ando%22">Miki Ando</searchLink>
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  Data: Heliyon, Vol 10, Iss 2, Pp e24801- (2024)
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  Data: <searchLink fieldCode="DE" term="%22Allogeneic+hematopoietic+stem+cell+transplantation+%28allo-HSCT%2C+allo-SCT%29%22">Allogeneic hematopoietic stem cell transplantation (allo-HSCT, allo-SCT)</searchLink><br /><searchLink fieldCode="DE" term="%22DEAD-Box+RNA+helicase+41+%28DDX41%29%22">DEAD-Box RNA helicase 41 (DDX41)</searchLink><br /><searchLink fieldCode="DE" term="%22Myeloid+neoplasms+with+germline+predisposition%22">Myeloid neoplasms with germline predisposition</searchLink><br /><searchLink fieldCode="DE" term="%22Hereditary+hematologic+malignancies+%28HHM%29%22">Hereditary hematologic malignancies (HHM)</searchLink><br /><searchLink fieldCode="DE" term="%22Familial+myelodysplastic+syndrome+%28MDS%29+%2F+acute+myeloid+leukemia+%28AML%29%22">Familial myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML)</searchLink><br /><searchLink fieldCode="DE" term="%22Severe+gastrointestinal+graft-versus-host-disease+%28GVHD%29%22">Severe gastrointestinal graft-versus-host-disease (GVHD)</searchLink><br /><searchLink fieldCode="DE" term="%22Science+%28General%29%22">Science (General)</searchLink><br /><searchLink fieldCode="DE" term="%22Q1-390%22">Q1-390</searchLink><br /><searchLink fieldCode="DE" term="%22Social+sciences+%28General%29%22">Social sciences (General)</searchLink><br /><searchLink fieldCode="DE" term="%22H1-99%22">H1-99</searchLink>
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  Label: Description
  Group: Ab
  Data: Background: Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with significant morbidity and mortality, and efficacy of currently available therapeutics are limited. Acute and chronic GVHD are similar in that both are initiated by antigen presenting cells and activation of alloreactive B-cells and T-cells, subsequently leading to inflammation, tissue damage, and organ failure. One difference is that acute GVHD is mostly attributed to T-cell activation and cytokine release, whereas B-cells are the key players in chronic GVHD. Ibrutinib is an irreversible inhibitor of the Bruton's tyrosine kinase (BTK), which is part of B-cell receptor signaling. Ibrutinib is currently used for treating chronic GVHD, but its efficacy towards acute GVHD is unknown. Besides BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK), which is predominantly expressed in T-cells and a crucial enzyme for activating the downstream pathway of TCR signaling. ITK activates PLCγ2 and facilitates signaling through NF-κB, NFAT, and MAPK, leading to activation and proliferation of T-cells and enhanced cytokine production. Therefore, the TCR signaling pathway is indispensable for development of acute GVHD, and ITK inhibition by ibrutinib would be a rational therapeutic approach. Case presentation: A 56-year-old male acute myeloid leukemia patient with Myeloid neoplasms with germline DEAD-box RNA helicase 41 (DDX41) mutation underwent cord blood transplantation and developed severe gastrointestinal (GI) acute GVHD which was refractory to steroids and mesenchymal stem cell therapy. While acute GVHD accommodated by multiple life-threatening GI bleeding events persisted, chronic cutaneous GVHD developed, and ibrutinib 420 mg/day was initiated from day 147 of transplant. Although ibrutinib was commenced targeting the chronic GVHD, unexpected and abrupt remission of acute GVHD along with remission of chronic GVHD was observed. Conclusion: Ibrutinib is a promising therapeutic for treating acute GVHD, and further studies are warranted.
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      – SubjectFull: DEAD-Box RNA helicase 41 (DDX41)
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