Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study
Summary Background Procedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back gene...
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| Veröffentlicht in: | The lancet oncology 2009-05, Vol.10 (5), p.489-500 |
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| creator | Ciceri, Fabio, MD Bonini, Chiara, MD Stanghellini, Maria Teresa Lupo, MD Bondanza, Attilio, MD Traversari, Catia, BSc Salomoni, Monica, BSc Turchetto, Lucia, PhD Colombi, Scialini, BSc Bernardi, Massimo, MD Peccatori, Jacopo, MD Pescarollo, Alessandra, MD Servida, Paolo, MD Magnani, Zulma, BSc Perna, Serena K, MD Valtolina, Veronica, MSc Crippa, Fulvio, MD Callegaro, Luciano, RN Spoldi, Elena, PhD Crocchiolo, Roberto, MD Fleischhauer, Katharina, MD Ponzoni, Maurilio, MD Vago, Luca, MD Rossini, Silvano, MD Santoro, Armando, MD Todisco, Elisabetta, MD Apperley, Jane, Prof Olavarria, Eduardo, MD Slavin, Shimon, Prof Weissinger, Eva M, MD Ganser, Arnold, Prof Stadler, Michael, MD Yannaki, Evangelia, MD Fassas, Athanasios, MD Anagnostopoulos, Achilles, MD Bregni, Marco, MD Stampino, Corrado Gallo, MD Bruzzi, Paolo, MD Bordignon, Claudio, Prof |
| description | Summary Background Procedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality. Methods In a phase I–II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per μL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00423124. Findings From Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17–66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34–127) from transplantation and 23 days (13–42) from infusion. Ten patients developed acute GVHD (grade I–IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25–73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure. Interpretation Infusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation. Funding MolMed SpA, Italian Association for Cancer Research. |
| doi_str_mv | 10.1016/S1470-2045(09)70074-9 |
| format | Article |
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We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality. Methods In a phase I–II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per μL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00423124. Findings From Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17–66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34–127) from transplantation and 23 days (13–42) from infusion. Ten patients developed acute GVHD (grade I–IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25–73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure. Interpretation Infusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation. Funding MolMed SpA, Italian Association for Cancer Research.</description><identifier>ISSN: 1470-2045</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(09)70074-9</identifier><identifier>PMID: 19345145</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; Aged ; Female ; Gene Transfer Techniques ; Genes, Transgenic, Suicide ; Graft vs Host Disease - prevention & control ; Graft vs Host Disease - therapy ; Haplotypes ; Hematology, Oncology and Palliative Medicine ; Hematopoietic Stem Cell Transplantation - adverse effects ; Histocompatibility - immunology ; HLA Antigens - immunology ; Humans ; Lymphocyte Transfusion ; Male ; Middle Aged ; Simplexvirus - enzymology ; Thymidine Kinase - genetics ; Transplantation Conditioning ; Young Adult</subject><ispartof>The lancet oncology, 2009-05, Vol.10 (5), p.489-500</ispartof><rights>Elsevier Ltd</rights><rights>2009 Elsevier Ltd</rights><rights>Copyright Elsevier Limited May 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c528t-f12e58df51a6123883a29566e09be37cd79b40319148135c9485c901075fed33</citedby><cites>FETCH-LOGICAL-c528t-f12e58df51a6123883a29566e09be37cd79b40319148135c9485c901075fed33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1470204509700749$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19345145$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ciceri, Fabio, MD</creatorcontrib><creatorcontrib>Bonini, Chiara, MD</creatorcontrib><creatorcontrib>Stanghellini, Maria Teresa Lupo, MD</creatorcontrib><creatorcontrib>Bondanza, Attilio, MD</creatorcontrib><creatorcontrib>Traversari, Catia, BSc</creatorcontrib><creatorcontrib>Salomoni, Monica, BSc</creatorcontrib><creatorcontrib>Turchetto, Lucia, PhD</creatorcontrib><creatorcontrib>Colombi, Scialini, BSc</creatorcontrib><creatorcontrib>Bernardi, Massimo, MD</creatorcontrib><creatorcontrib>Peccatori, Jacopo, MD</creatorcontrib><creatorcontrib>Pescarollo, Alessandra, MD</creatorcontrib><creatorcontrib>Servida, Paolo, MD</creatorcontrib><creatorcontrib>Magnani, Zulma, BSc</creatorcontrib><creatorcontrib>Perna, Serena K, MD</creatorcontrib><creatorcontrib>Valtolina, Veronica, MSc</creatorcontrib><creatorcontrib>Crippa, Fulvio, MD</creatorcontrib><creatorcontrib>Callegaro, Luciano, RN</creatorcontrib><creatorcontrib>Spoldi, Elena, PhD</creatorcontrib><creatorcontrib>Crocchiolo, Roberto, MD</creatorcontrib><creatorcontrib>Fleischhauer, Katharina, MD</creatorcontrib><creatorcontrib>Ponzoni, Maurilio, MD</creatorcontrib><creatorcontrib>Vago, Luca, MD</creatorcontrib><creatorcontrib>Rossini, Silvano, MD</creatorcontrib><creatorcontrib>Santoro, Armando, MD</creatorcontrib><creatorcontrib>Todisco, Elisabetta, MD</creatorcontrib><creatorcontrib>Apperley, Jane, Prof</creatorcontrib><creatorcontrib>Olavarria, Eduardo, MD</creatorcontrib><creatorcontrib>Slavin, Shimon, Prof</creatorcontrib><creatorcontrib>Weissinger, Eva M, MD</creatorcontrib><creatorcontrib>Ganser, Arnold, Prof</creatorcontrib><creatorcontrib>Stadler, Michael, MD</creatorcontrib><creatorcontrib>Yannaki, Evangelia, MD</creatorcontrib><creatorcontrib>Fassas, Athanasios, MD</creatorcontrib><creatorcontrib>Anagnostopoulos, Achilles, MD</creatorcontrib><creatorcontrib>Bregni, Marco, MD</creatorcontrib><creatorcontrib>Stampino, Corrado Gallo, MD</creatorcontrib><creatorcontrib>Bruzzi, Paolo, MD</creatorcontrib><creatorcontrib>Bordignon, Claudio, Prof</creatorcontrib><title>Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>Summary Background Procedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality. Methods In a phase I–II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per μL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00423124. Findings From Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17–66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34–127) from transplantation and 23 days (13–42) from infusion. Ten patients developed acute GVHD (grade I–IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25–73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure. Interpretation Infusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation. Funding MolMed SpA, Italian Association for Cancer Research.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Female</subject><subject>Gene Transfer Techniques</subject><subject>Genes, Transgenic, Suicide</subject><subject>Graft vs Host Disease - prevention & control</subject><subject>Graft vs Host Disease - therapy</subject><subject>Haplotypes</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Hematopoietic Stem Cell Transplantation - adverse effects</subject><subject>Histocompatibility - immunology</subject><subject>HLA Antigens - immunology</subject><subject>Humans</subject><subject>Lymphocyte Transfusion</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Simplexvirus - enzymology</subject><subject>Thymidine Kinase - genetics</subject><subject>Transplantation Conditioning</subject><subject>Young 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haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study</title><author>Ciceri, Fabio, MD ; Bonini, Chiara, MD ; Stanghellini, Maria Teresa Lupo, MD ; Bondanza, Attilio, MD ; Traversari, Catia, BSc ; Salomoni, Monica, BSc ; Turchetto, Lucia, PhD ; Colombi, Scialini, BSc ; Bernardi, Massimo, MD ; Peccatori, Jacopo, MD ; Pescarollo, Alessandra, MD ; Servida, Paolo, MD ; Magnani, Zulma, BSc ; Perna, Serena K, MD ; Valtolina, Veronica, MSc ; Crippa, Fulvio, MD ; Callegaro, Luciano, RN ; Spoldi, Elena, PhD ; Crocchiolo, Roberto, MD ; Fleischhauer, Katharina, MD ; Ponzoni, Maurilio, MD ; Vago, Luca, MD ; Rossini, Silvano, MD ; Santoro, Armando, MD ; Todisco, Elisabetta, MD ; Apperley, Jane, Prof ; Olavarria, Eduardo, MD ; Slavin, Shimon, Prof ; Weissinger, Eva M, MD ; Ganser, Arnold, Prof ; Stadler, Michael, MD ; Yannaki, Evangelia, MD ; Fassas, Athanasios, MD ; Anagnostopoulos, Achilles, MD ; Bregni, Marco, MD ; Stampino, Corrado Gallo, MD ; 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MSc</creatorcontrib><creatorcontrib>Crippa, Fulvio, MD</creatorcontrib><creatorcontrib>Callegaro, Luciano, RN</creatorcontrib><creatorcontrib>Spoldi, Elena, PhD</creatorcontrib><creatorcontrib>Crocchiolo, Roberto, MD</creatorcontrib><creatorcontrib>Fleischhauer, Katharina, MD</creatorcontrib><creatorcontrib>Ponzoni, Maurilio, MD</creatorcontrib><creatorcontrib>Vago, Luca, MD</creatorcontrib><creatorcontrib>Rossini, Silvano, MD</creatorcontrib><creatorcontrib>Santoro, Armando, MD</creatorcontrib><creatorcontrib>Todisco, Elisabetta, MD</creatorcontrib><creatorcontrib>Apperley, Jane, Prof</creatorcontrib><creatorcontrib>Olavarria, Eduardo, MD</creatorcontrib><creatorcontrib>Slavin, Shimon, Prof</creatorcontrib><creatorcontrib>Weissinger, Eva M, MD</creatorcontrib><creatorcontrib>Ganser, Arnold, Prof</creatorcontrib><creatorcontrib>Stadler, Michael, MD</creatorcontrib><creatorcontrib>Yannaki, Evangelia, MD</creatorcontrib><creatorcontrib>Fassas, Athanasios, MD</creatorcontrib><creatorcontrib>Anagnostopoulos, Achilles, MD</creatorcontrib><creatorcontrib>Bregni, Marco, MD</creatorcontrib><creatorcontrib>Stampino, Corrado Gallo, MD</creatorcontrib><creatorcontrib>Bruzzi, Paolo, MD</creatorcontrib><creatorcontrib>Bordignon, Claudio, Prof</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ciceri, Fabio, MD</au><au>Bonini, Chiara, MD</au><au>Stanghellini, Maria Teresa Lupo, MD</au><au>Bondanza, Attilio, MD</au><au>Traversari, Catia, BSc</au><au>Salomoni, Monica, BSc</au><au>Turchetto, Lucia, PhD</au><au>Colombi, Scialini, BSc</au><au>Bernardi, Massimo, MD</au><au>Peccatori, Jacopo, MD</au><au>Pescarollo, Alessandra, MD</au><au>Servida, Paolo, MD</au><au>Magnani, Zulma, BSc</au><au>Perna, Serena K, MD</au><au>Valtolina, Veronica, MSc</au><au>Crippa, Fulvio, MD</au><au>Callegaro, Luciano, RN</au><au>Spoldi, Elena, PhD</au><au>Crocchiolo, Roberto, MD</au><au>Fleischhauer, Katharina, MD</au><au>Ponzoni, Maurilio, MD</au><au>Vago, Luca, MD</au><au>Rossini, Silvano, MD</au><au>Santoro, Armando, MD</au><au>Todisco, Elisabetta, MD</au><au>Apperley, Jane, Prof</au><au>Olavarria, Eduardo, MD</au><au>Slavin, Shimon, Prof</au><au>Weissinger, Eva M, MD</au><au>Ganser, Arnold, Prof</au><au>Stadler, Michael, MD</au><au>Yannaki, Evangelia, MD</au><au>Fassas, Athanasios, MD</au><au>Anagnostopoulos, Achilles, MD</au><au>Bregni, Marco, MD</au><au>Stampino, Corrado Gallo, MD</au><au>Bruzzi, Paolo, MD</au><au>Bordignon, Claudio, Prof</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2009-05-01</date><risdate>2009</risdate><volume>10</volume><issue>5</issue><spage>489</spage><epage>500</epage><pages>489-500</pages><issn>1470-2045</issn><eissn>1474-5488</eissn><coden>LANCAO</coden><abstract>Summary Background Procedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality. Methods In a phase I–II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per μL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00423124. Findings From Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17–66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34–127) from transplantation and 23 days (13–42) from infusion. Ten patients developed acute GVHD (grade I–IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25–73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure. Interpretation Infusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation. Funding MolMed SpA, Italian Association for Cancer Research.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>19345145</pmid><doi>10.1016/S1470-2045(09)70074-9</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-2045 |
| ispartof | The lancet oncology, 2009-05, Vol.10 (5), p.489-500 |
| issn | 1470-2045 1474-5488 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67190775 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adolescent Adult Aged Female Gene Transfer Techniques Genes, Transgenic, Suicide Graft vs Host Disease - prevention & control Graft vs Host Disease - therapy Haplotypes Hematology, Oncology and Palliative Medicine Hematopoietic Stem Cell Transplantation - adverse effects Histocompatibility - immunology HLA Antigens - immunology Humans Lymphocyte Transfusion Male Middle Aged Simplexvirus - enzymology Thymidine Kinase - genetics Transplantation Conditioning Young Adult |
| title | Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study |
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