• Fabio Ciceri, Chiara Bonini, StanghelliniMaria Teresa LupoMT, 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 Fleischhauer, Maurilio 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, and Claudio Bordignon.
• Haematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy.
• Lancet Oncol. 2009 May 1; 10 (5): 489-500.

BackgroundProcedures 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.MethodsIn 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.FindingsFrom 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.InterpretationInfusion 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.FundingMolMed SpA, Italian Association for Cancer Research.

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