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

Fabio Ciceri, Chiara Bonini, Maria Teresa Lupo Stanghellini, Attilio Bondanza, Catia Traversari, Monica Salomoni, Lucia Turchetto, Scialini Colombi, Massimo Bernardi, Jacopo Peccatori, Alessandra Pescarollo, Paolo Servida, Zulma Magnani, Serena K. Perna, Veronica Valtolina, Fulvio Crippa, Luciano Callegaro, Elena Spoldi, Roberto Crocchiolo, Katharina FleischhauerMaurilio Ponzoni, Luca Vago, Silvano Rossini, Armando Santoro, Elisabetta Todisco, Jane Apperley, Eduardo Olavarria, Shimon Slavin, Eva M. Weissinger, Arnold Ganser, Michael Stadler, Evangelia Yannaki, Athanasios Fassas, Achilles Anagnostopoulos, Marco Bregni, Corrado Gallo Stampino, Paolo Bruzzi, Claudio Bordignon

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)489-500
Number of pages12
JournalThe Lancet Oncology
Volume10
Issue number5
DOIs
Publication statusPublished - May 2009

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Stem Cell Transplantation
Suicide
Leukemia
Tissue Donors
Graft vs Host Disease
Lymphocytes
Genes
Mortality
Stem Cells
Transplantation
Transplants
Herpes Simplex
Intention to Treat Analysis
Thymidine Kinase
Cell Transplantation
Cell Count
Survival
Infection
Research
Neoplasms

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Ciceri, Fabio; Bonini, Chiara; Stanghellini, Maria Teresa Lupo; Bondanza, Attilio; Traversari, Catia; Salomoni, Monica; Turchetto, Lucia; Colombi, Scialini; Bernardi, Massimo; Peccatori, Jacopo; Pescarollo, Alessandra; Servida, Paolo; Magnani, Zulma; Perna, Serena K.; Valtolina, Veronica; Crippa, Fulvio; Callegaro, Luciano; Spoldi, Elena; Crocchiolo, Roberto; Fleischhauer, Katharina; Ponzoni, Maurilio; Vago, Luca; Rossini, Silvano; Santoro, Armando; Todisco, Elisabetta; Apperley, Jane; Olavarria, Eduardo; Slavin, Shimon; Weissinger, Eva M.; Ganser, Arnold; Stadler, Michael; Yannaki, Evangelia; Fassas, Athanasios; Anagnostopoulos, Achilles; Bregni, Marco; Stampino, Corrado Gallo; Bruzzi, Paolo; Bordignon, Claudio.

In: The Lancet Oncology, Vol. 10, No. 5, 05.2009, p. 489-500.

Research output: Contribution to journalArticle

Ciceri, F, Bonini, C, Stanghellini, MTL, Bondanza, A, Traversari, C, Salomoni, M, Turchetto, L, Colombi, S, Bernardi, M, Peccatori, J, Pescarollo, A, Servida, P, Magnani, Z, Perna, SK, Valtolina, V, Crippa, F, Callegaro, L, Spoldi, E, Crocchiolo, R, Fleischhauer, K, Ponzoni, M, Vago, L, Rossini, S, Santoro, A, Todisco, E, Apperley, J, Olavarria, E, Slavin, S, Weissinger, EM, Ganser, A, Stadler, M, Yannaki, E, Fassas, A, Anagnostopoulos, A, Bregni, M, Stampino, CG, Bruzzi, P & Bordignon, C 2009, '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', The Lancet Oncology, vol. 10, no. 5, pp. 489-500. https://doi.org/10.1016/S1470-2045(09)70074-9
Ciceri, Fabio ; Bonini, Chiara ; Stanghellini, Maria Teresa Lupo ; Bondanza, Attilio ; Traversari, Catia ; Salomoni, Monica ; Turchetto, Lucia ; Colombi, Scialini ; Bernardi, Massimo ; Peccatori, Jacopo ; Pescarollo, Alessandra ; Servida, Paolo ; Magnani, Zulma ; Perna, Serena K. ; Valtolina, Veronica ; Crippa, Fulvio ; Callegaro, Luciano ; Spoldi, Elena ; Crocchiolo, Roberto ; Fleischhauer, Katharina ; Ponzoni, Maurilio ; Vago, Luca ; Rossini, Silvano ; Santoro, Armando ; Todisco, Elisabetta ; Apperley, Jane ; Olavarria, Eduardo ; Slavin, Shimon ; Weissinger, Eva M. ; Ganser, Arnold ; Stadler, Michael ; Yannaki, Evangelia ; Fassas, Athanasios ; Anagnostopoulos, Achilles ; Bregni, Marco ; Stampino, Corrado Gallo ; Bruzzi, Paolo ; Bordignon, Claudio. / 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. In: The Lancet Oncology. 2009 ; Vol. 10, No. 5. pp. 489-500.
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abstract = "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.",
author = "Fabio Ciceri and Chiara Bonini and Stanghellini, {Maria Teresa Lupo} and Attilio Bondanza and Catia Traversari and Monica Salomoni and Lucia Turchetto and Scialini Colombi and Massimo Bernardi and Jacopo Peccatori and Alessandra Pescarollo and Paolo Servida and Zulma Magnani and Perna, {Serena K.} and Veronica Valtolina and Fulvio Crippa and Luciano Callegaro and Elena Spoldi and Roberto Crocchiolo and Katharina Fleischhauer and Maurilio Ponzoni and Luca Vago and Silvano Rossini and Armando Santoro and Elisabetta Todisco and Jane Apperley and Eduardo Olavarria and Shimon Slavin and Weissinger, {Eva M.} and Arnold Ganser and Michael Stadler and Evangelia Yannaki and Athanasios Fassas and Achilles Anagnostopoulos and Marco Bregni and Stampino, {Corrado Gallo} and Paolo Bruzzi and Claudio Bordignon",
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TY - JOUR

T1 - Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial)

T2 - a non-randomised phase I-II study

AU - Ciceri, Fabio

AU - Bonini, Chiara

AU - Stanghellini, Maria Teresa Lupo

AU - Bondanza, Attilio

AU - Traversari, Catia

AU - Salomoni, Monica

AU - Turchetto, Lucia

AU - Colombi, Scialini

AU - Bernardi, Massimo

AU - Peccatori, Jacopo

AU - Pescarollo, Alessandra

AU - Servida, Paolo

AU - Magnani, Zulma

AU - Perna, Serena K.

AU - Valtolina, Veronica

AU - Crippa, Fulvio

AU - Callegaro, Luciano

AU - Spoldi, Elena

AU - Crocchiolo, Roberto

AU - Fleischhauer, Katharina

AU - Ponzoni, Maurilio

AU - Vago, Luca

AU - Rossini, Silvano

AU - Santoro, Armando

AU - Todisco, Elisabetta

AU - Apperley, Jane

AU - Olavarria, Eduardo

AU - Slavin, Shimon

AU - Weissinger, Eva M.

AU - Ganser, Arnold

AU - Stadler, Michael

AU - Yannaki, Evangelia

AU - Fassas, Athanasios

AU - Anagnostopoulos, Achilles

AU - Bregni, Marco

AU - Stampino, Corrado Gallo

AU - Bruzzi, Paolo

AU - Bordignon, Claudio

PY - 2009/5

Y1 - 2009/5

N2 - 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.

AB - 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.

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