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.
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 muL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00423124.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
MolMed SpA, Italian Association for Cancer Research.
Ciceri
Fabio
F
Haematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy.
Bonini
Chiara
C
Stanghellini
Maria Teresa Lupo
MT
Bondanza
Attilio
A
Traversari
Catia
C
Salomoni
Monica
M
Turchetto
Lucia
L
Colombi
Scialini
S
Bernardi
Massimo
M
Peccatori
Jacopo
J
Pescarollo
Alessandra
A
Servida
Paolo
P
Magnani
Zulma
Z
Perna
Serena K
SK
Valtolina
Veronica
V
Crippa
Fulvio
F
Callegaro
Luciano
L
Spoldi
Elena
E
Crocchiolo
Roberto
R
Fleischhauer
Katharina
K
Ponzoni
Maurilio
M
Vago
Luca
L
Rossini
Silvano
S
Santoro
Armando
A
Todisco
Elisabetta
E
Apperley
Jane
J
Olavarria
Eduardo
E
Slavin
Shimon
S
Weissinger
Eva M
EM
Ganser
Arnold
A
Stadler
Michael
M
Yannaki
Evangelia
E
Fassas
Athanasios
A
Anagnostopoulos
Achilles
A
Bregni
Marco
M
Stampino
Corrado Gallo
CG
Bruzzi
Paolo
P
Bordignon
Claudio
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D006086:Graft vs Host Disease / Q000517:prevention & control* / Q000628:therapy; D006680:HLA Antigens / Q000276:immunology*; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006648:Histocompatibility / Q000276:immunology; D006801:Humans; D017710:Lymphocyte Transfusion; D008297:Male; D008875:Middle Aged; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D019172:Transplantation Conditioning; D055815:Young Adult
D006680:HLA Antigens; D013937:Thymidine Kinase