Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study
We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensi...
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| Veröffentlicht in: | Blood advances 2020-08, Vol.4 (15), p.3754-3766 |
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| creator | Bergsten, Elisabet Horne, AnnaCarin Hed Myrberg, Ida Aricó, Maurizio Astigarraga, Itziar Ishii, Eiichi Janka, Gritta Ladisch, Stephan Lehmberg, Kai McClain, Kenneth L. Minkov, Milen Nanduri, Vasanta Rosso, Diego A. Sieni, Elena Winiarski, Jacek Henter, Jan-Inge |
| description | We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged |
| doi_str_mv | 10.1182/bloodadvances.2020002101 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_469022</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S2473952920316049</els_id><sourcerecordid>2433240706</sourcerecordid><originalsourceid>FETCH-LOGICAL-c572t-d5e600d86ff9e9659d38ec597af77100e11847f171cc975f9d5802296e9b7f973</originalsourceid><addsrcrecordid>eNqFkUFv1DAQhS0EolXpX0A-ckmxnTiOOSBBBSzSSj20PVtee9wYkjjYzlb77_Fql4U9cfLI872Z0XsIYUpuKO3Y-80QgtV2qycD6YYRRghhlNAX6JI1oq4kr8XLU83kBbpO6UeBqGhrLtlrdFEz0ZGu4Zco3GcYsYFhwDnqKc2DnrLOPkzYhYhN7wcbYcLPPve4hzHMvX4KZpe9wcNunPvQ-1Tw8hOSTx9whLQMOWEXw4hzD3i1XlXlxAanvNjdG_TK6SHB9fG9Qo9fvzzcrqr13bfvt5_WleGC5cpyaAmxXeucBNlyaesODJdCOyEoIVCcaISjghojBXfS8o4wJluQG-GkqK9QdZibnmFeNmqOftRxp4L26vj1s1SgmlYWYeE_HvjSGcEamIodw5nsvDP5Xj2FrRINY7TeD3h3HBDDrwVSVqNPe1_1BGFJijV1zRoiSFvQ7oCaGFKK4E5rKFH7iNVZxOpvxEX69t8zT8I_gRbg8wGAYu7WQ1TJeChjrI9gsrLB_3_Lb3i2wBQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2433240706</pqid></control><display><type>article</type><title>Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>SWEPUB Freely available online</source><creator>Bergsten, Elisabet ; Horne, AnnaCarin ; Hed Myrberg, Ida ; Aricó, Maurizio ; Astigarraga, Itziar ; Ishii, Eiichi ; Janka, Gritta ; Ladisch, Stephan ; Lehmberg, Kai ; McClain, Kenneth L. ; Minkov, Milen ; Nanduri, Vasanta ; Rosso, Diego A. ; Sieni, Elena ; Winiarski, Jacek ; Henter, Jan-Inge</creator><creatorcontrib>Bergsten, Elisabet ; Horne, AnnaCarin ; Hed Myrberg, Ida ; Aricó, Maurizio ; Astigarraga, Itziar ; Ishii, Eiichi ; Janka, Gritta ; Ladisch, Stephan ; Lehmberg, Kai ; McClain, Kenneth L. ; Minkov, Milen ; Nanduri, Vasanta ; Rosso, Diego A. ; Sieni, Elena ; Winiarski, Jacek ; Henter, Jan-Inge</creatorcontrib><description>We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged <18 years fulfilling the study inclusion criteria (5 of 8 diagnostic criteria, affected sibling, or molecular diagnosis in FHL-causative genes) underwent 209 transplants (2004-2012), defined as indicated in patients with familial/genetic, relapsing, or severe/persistent disease. Five-year overall survival (OS) post-HSCT was 66% (95% confidence interval [CI], 59-72); event-free survival (EFS) was 60% (95% CI, 52-67). Five-year OS was 81% (95% CI, 65-90) for children with a complete response and 59% (95% CI, 48-69) for those with a partial response (hazard ratio [HR], 2.12; 95% CI, 1.06-4.27; P = .035). For children with verified FHL (family history/genetically verified, n = 134), 5-year OS was 71% (95% CI, 62-78) and EFS was 62% (95% CI, 54-70); 5-year OS for children without verified FHL (n = 53) was significantly lower (52%; 95% CI, 38-65) (P = .040; HR, 1.69; 95% CI, 1.03-2.77); they were also significantly older. Notably, 20 (38%) of 53 patients without verified FHL had natural killer cell activity reported as normal at diagnosis, after 2 months, or at HSCT, suggestive of secondary HLH; and in addition 14 (26%) of these 53 children had no evidence of biallelic mutations despite having 3 or 4 FHL genes analyzed (natural killer cell activity not analyzed after 2 months or at HSCT). We conclude that post-HSCT survival in FHL remains suboptimal, and that the FHL diagnosis should be carefully investigated before HSCT. Pretransplant complete remission is beneficial but not mandatory to achieve post-HSCT survival. This trial was registered at www.clinicaltrials.gov as #NCT00426101.
•In 187 children with a transplant, 5-year OS post-HSCT was 66% in the entire cohort and 71% in children with FHL.•To spare children from unnecessary HSCT, pretransplant analyses, including possible confirmation of FHL, are recommended.
[Display omitted]</description><identifier>ISSN: 2473-9529</identifier><identifier>EISSN: 2473-9537</identifier><identifier>DOI: 10.1182/bloodadvances.2020002101</identifier><identifier>PMID: 32780845</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Child ; Clinical Trials and Observations ; COVID-19 ; Hematopoietic Stem Cell Transplantation ; Humans ; Lymphohistiocytosis, Hemophagocytic - diagnosis ; Lymphohistiocytosis, Hemophagocytic - genetics ; Lymphohistiocytosis, Hemophagocytic - therapy ; Prospective Studies ; SARS-CoV-2 ; Systemic Inflammatory Response Syndrome</subject><ispartof>Blood advances, 2020-08, Vol.4 (15), p.3754-3766</ispartof><rights>2020 American Society of Hematology</rights><rights>2020 by The American Society of Hematology.</rights><rights>2020 by The American Society of Hematology 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c572t-d5e600d86ff9e9659d38ec597af77100e11847f171cc975f9d5802296e9b7f973</citedby><cites>FETCH-LOGICAL-c572t-d5e600d86ff9e9659d38ec597af77100e11847f171cc975f9d5802296e9b7f973</cites><orcidid>0000-0002-6192-9812 ; 0000-0002-0629-2126 ; 0000-0003-0725-6263</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422132/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422132/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,550,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32780845$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:144455971$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Bergsten, Elisabet</creatorcontrib><creatorcontrib>Horne, AnnaCarin</creatorcontrib><creatorcontrib>Hed Myrberg, Ida</creatorcontrib><creatorcontrib>Aricó, Maurizio</creatorcontrib><creatorcontrib>Astigarraga, Itziar</creatorcontrib><creatorcontrib>Ishii, Eiichi</creatorcontrib><creatorcontrib>Janka, Gritta</creatorcontrib><creatorcontrib>Ladisch, Stephan</creatorcontrib><creatorcontrib>Lehmberg, Kai</creatorcontrib><creatorcontrib>McClain, Kenneth L.</creatorcontrib><creatorcontrib>Minkov, Milen</creatorcontrib><creatorcontrib>Nanduri, Vasanta</creatorcontrib><creatorcontrib>Rosso, Diego A.</creatorcontrib><creatorcontrib>Sieni, Elena</creatorcontrib><creatorcontrib>Winiarski, Jacek</creatorcontrib><creatorcontrib>Henter, Jan-Inge</creatorcontrib><title>Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study</title><title>Blood advances</title><addtitle>Blood Adv</addtitle><description>We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged <18 years fulfilling the study inclusion criteria (5 of 8 diagnostic criteria, affected sibling, or molecular diagnosis in FHL-causative genes) underwent 209 transplants (2004-2012), defined as indicated in patients with familial/genetic, relapsing, or severe/persistent disease. Five-year overall survival (OS) post-HSCT was 66% (95% confidence interval [CI], 59-72); event-free survival (EFS) was 60% (95% CI, 52-67). Five-year OS was 81% (95% CI, 65-90) for children with a complete response and 59% (95% CI, 48-69) for those with a partial response (hazard ratio [HR], 2.12; 95% CI, 1.06-4.27; P = .035). For children with verified FHL (family history/genetically verified, n = 134), 5-year OS was 71% (95% CI, 62-78) and EFS was 62% (95% CI, 54-70); 5-year OS for children without verified FHL (n = 53) was significantly lower (52%; 95% CI, 38-65) (P = .040; HR, 1.69; 95% CI, 1.03-2.77); they were also significantly older. Notably, 20 (38%) of 53 patients without verified FHL had natural killer cell activity reported as normal at diagnosis, after 2 months, or at HSCT, suggestive of secondary HLH; and in addition 14 (26%) of these 53 children had no evidence of biallelic mutations despite having 3 or 4 FHL genes analyzed (natural killer cell activity not analyzed after 2 months or at HSCT). We conclude that post-HSCT survival in FHL remains suboptimal, and that the FHL diagnosis should be carefully investigated before HSCT. Pretransplant complete remission is beneficial but not mandatory to achieve post-HSCT survival. This trial was registered at www.clinicaltrials.gov as #NCT00426101.
•In 187 children with a transplant, 5-year OS post-HSCT was 66% in the entire cohort and 71% in children with FHL.•To spare children from unnecessary HSCT, pretransplant analyses, including possible confirmation of FHL, are recommended.
[Display omitted]</description><subject>Adolescent</subject><subject>Child</subject><subject>Clinical Trials and Observations</subject><subject>COVID-19</subject><subject>Hematopoietic Stem Cell Transplantation</subject><subject>Humans</subject><subject>Lymphohistiocytosis, Hemophagocytic - diagnosis</subject><subject>Lymphohistiocytosis, Hemophagocytic - genetics</subject><subject>Lymphohistiocytosis, Hemophagocytic - therapy</subject><subject>Prospective Studies</subject><subject>SARS-CoV-2</subject><subject>Systemic Inflammatory Response Syndrome</subject><issn>2473-9529</issn><issn>2473-9537</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqFkUFv1DAQhS0EolXpX0A-ckmxnTiOOSBBBSzSSj20PVtee9wYkjjYzlb77_Fql4U9cfLI872Z0XsIYUpuKO3Y-80QgtV2qycD6YYRRghhlNAX6JI1oq4kr8XLU83kBbpO6UeBqGhrLtlrdFEz0ZGu4Zco3GcYsYFhwDnqKc2DnrLOPkzYhYhN7wcbYcLPPve4hzHMvX4KZpe9wcNunPvQ-1Tw8hOSTx9whLQMOWEXw4hzD3i1XlXlxAanvNjdG_TK6SHB9fG9Qo9fvzzcrqr13bfvt5_WleGC5cpyaAmxXeucBNlyaesODJdCOyEoIVCcaISjghojBXfS8o4wJluQG-GkqK9QdZibnmFeNmqOftRxp4L26vj1s1SgmlYWYeE_HvjSGcEamIodw5nsvDP5Xj2FrRINY7TeD3h3HBDDrwVSVqNPe1_1BGFJijV1zRoiSFvQ7oCaGFKK4E5rKFH7iNVZxOpvxEX69t8zT8I_gRbg8wGAYu7WQ1TJeChjrI9gsrLB_3_Lb3i2wBQ</recordid><startdate>20200811</startdate><enddate>20200811</enddate><creator>Bergsten, Elisabet</creator><creator>Horne, AnnaCarin</creator><creator>Hed Myrberg, Ida</creator><creator>Aricó, Maurizio</creator><creator>Astigarraga, Itziar</creator><creator>Ishii, Eiichi</creator><creator>Janka, Gritta</creator><creator>Ladisch, Stephan</creator><creator>Lehmberg, Kai</creator><creator>McClain, Kenneth L.</creator><creator>Minkov, Milen</creator><creator>Nanduri, Vasanta</creator><creator>Rosso, Diego A.</creator><creator>Sieni, Elena</creator><creator>Winiarski, Jacek</creator><creator>Henter, Jan-Inge</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0002-6192-9812</orcidid><orcidid>https://orcid.org/0000-0002-0629-2126</orcidid><orcidid>https://orcid.org/0000-0003-0725-6263</orcidid></search><sort><creationdate>20200811</creationdate><title>Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study</title><author>Bergsten, Elisabet ; Horne, AnnaCarin ; Hed Myrberg, Ida ; Aricó, Maurizio ; Astigarraga, Itziar ; Ishii, Eiichi ; Janka, Gritta ; Ladisch, Stephan ; Lehmberg, Kai ; McClain, Kenneth L. ; Minkov, Milen ; Nanduri, Vasanta ; Rosso, Diego A. ; Sieni, Elena ; Winiarski, Jacek ; Henter, Jan-Inge</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c572t-d5e600d86ff9e9659d38ec597af77100e11847f171cc975f9d5802296e9b7f973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adolescent</topic><topic>Child</topic><topic>Clinical Trials and Observations</topic><topic>COVID-19</topic><topic>Hematopoietic Stem Cell Transplantation</topic><topic>Humans</topic><topic>Lymphohistiocytosis, Hemophagocytic - diagnosis</topic><topic>Lymphohistiocytosis, Hemophagocytic - genetics</topic><topic>Lymphohistiocytosis, Hemophagocytic - therapy</topic><topic>Prospective Studies</topic><topic>SARS-CoV-2</topic><topic>Systemic Inflammatory Response Syndrome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bergsten, Elisabet</creatorcontrib><creatorcontrib>Horne, AnnaCarin</creatorcontrib><creatorcontrib>Hed Myrberg, Ida</creatorcontrib><creatorcontrib>Aricó, Maurizio</creatorcontrib><creatorcontrib>Astigarraga, Itziar</creatorcontrib><creatorcontrib>Ishii, Eiichi</creatorcontrib><creatorcontrib>Janka, Gritta</creatorcontrib><creatorcontrib>Ladisch, Stephan</creatorcontrib><creatorcontrib>Lehmberg, Kai</creatorcontrib><creatorcontrib>McClain, Kenneth L.</creatorcontrib><creatorcontrib>Minkov, Milen</creatorcontrib><creatorcontrib>Nanduri, Vasanta</creatorcontrib><creatorcontrib>Rosso, Diego A.</creatorcontrib><creatorcontrib>Sieni, Elena</creatorcontrib><creatorcontrib>Winiarski, Jacek</creatorcontrib><creatorcontrib>Henter, Jan-Inge</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Blood advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bergsten, Elisabet</au><au>Horne, AnnaCarin</au><au>Hed Myrberg, Ida</au><au>Aricó, Maurizio</au><au>Astigarraga, Itziar</au><au>Ishii, Eiichi</au><au>Janka, Gritta</au><au>Ladisch, Stephan</au><au>Lehmberg, Kai</au><au>McClain, Kenneth L.</au><au>Minkov, Milen</au><au>Nanduri, Vasanta</au><au>Rosso, Diego A.</au><au>Sieni, Elena</au><au>Winiarski, Jacek</au><au>Henter, Jan-Inge</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study</atitle><jtitle>Blood advances</jtitle><addtitle>Blood Adv</addtitle><date>2020-08-11</date><risdate>2020</risdate><volume>4</volume><issue>15</issue><spage>3754</spage><epage>3766</epage><pages>3754-3766</pages><issn>2473-9529</issn><eissn>2473-9537</eissn><abstract>We report the largest prospective study thus far on hematopoietic stem cell transplantation (HSCT) in hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. Although all patients with HLH typically need intensive anti-inflammatory therapy, patients with FHL also need HSCT to be cured. In the international HLH-2004 study, 187 children aged <18 years fulfilling the study inclusion criteria (5 of 8 diagnostic criteria, affected sibling, or molecular diagnosis in FHL-causative genes) underwent 209 transplants (2004-2012), defined as indicated in patients with familial/genetic, relapsing, or severe/persistent disease. Five-year overall survival (OS) post-HSCT was 66% (95% confidence interval [CI], 59-72); event-free survival (EFS) was 60% (95% CI, 52-67). Five-year OS was 81% (95% CI, 65-90) for children with a complete response and 59% (95% CI, 48-69) for those with a partial response (hazard ratio [HR], 2.12; 95% CI, 1.06-4.27; P = .035). For children with verified FHL (family history/genetically verified, n = 134), 5-year OS was 71% (95% CI, 62-78) and EFS was 62% (95% CI, 54-70); 5-year OS for children without verified FHL (n = 53) was significantly lower (52%; 95% CI, 38-65) (P = .040; HR, 1.69; 95% CI, 1.03-2.77); they were also significantly older. Notably, 20 (38%) of 53 patients without verified FHL had natural killer cell activity reported as normal at diagnosis, after 2 months, or at HSCT, suggestive of secondary HLH; and in addition 14 (26%) of these 53 children had no evidence of biallelic mutations despite having 3 or 4 FHL genes analyzed (natural killer cell activity not analyzed after 2 months or at HSCT). We conclude that post-HSCT survival in FHL remains suboptimal, and that the FHL diagnosis should be carefully investigated before HSCT. Pretransplant complete remission is beneficial but not mandatory to achieve post-HSCT survival. This trial was registered at www.clinicaltrials.gov as #NCT00426101.
•In 187 children with a transplant, 5-year OS post-HSCT was 66% in the entire cohort and 71% in children with FHL.•To spare children from unnecessary HSCT, pretransplant analyses, including possible confirmation of FHL, are recommended.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32780845</pmid><doi>10.1182/bloodadvances.2020002101</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-6192-9812</orcidid><orcidid>https://orcid.org/0000-0002-0629-2126</orcidid><orcidid>https://orcid.org/0000-0003-0725-6263</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adolescent Child Clinical Trials and Observations COVID-19 Hematopoietic Stem Cell Transplantation Humans Lymphohistiocytosis, Hemophagocytic - diagnosis Lymphohistiocytosis, Hemophagocytic - genetics Lymphohistiocytosis, Hemophagocytic - therapy Prospective Studies SARS-CoV-2 Systemic Inflammatory Response Syndrome |
| title | Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study |
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