Early and Effective Immune-Recovery by Gene-Engineered Lymphocytes after Haploidentical Transplantation for Leukemia Abate Late Transplant Mortality

• Published in: Blood 2008-11, Vol.112 (11), p.353-353
• Main Authors: Stanghellini, Maria Teresa Lupo, Ciceri, Fabio, Bonini, Chiara, Bondanza, Attilio, Traversari, Catia, Salomoni, Monica, Turchetto, Lucia, Colombi, Scialini, Bernardi, Massimo, Peccatori, Jacopo, Pescarollo, Alessandra, Servida, Paolo, Magnani, Zulma, Perna, Serena Kimi, Valtolina, Veronica, Crippa, Fulvio, Callegaro, Luciano, Spoldi, Elena, Crocchiolo, Roberto, Fleischhauer, Katharina, Ponzoni, Maurilio, Vago, Luca, Santoro, Armando, Todisco, Elisabetta, Apperley, Jane, Olavarria, Eduardo, Slavin, Shimon, Weissinger, Eva Maria, Hertenstein, Bernd, Stadler, Michael, Yannaki, Evangelia, Fassas, Athanasios, Anagnostopoulos, Achilles, Stampino, Corrado Gallo, Bregni, Marco, Bruzzi, Paolo, Bordignon, Claudio
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V112.11.353.353

Background. Haploidentical family donors represent the ideal solution to offer to every patient with high risk leukemia the potential cure of hematopoietic stem cell transplantation. Extensive application of haploidentical transplantation (haplo-SCT) has been limited by high rate of late transplant related mortality (TRM) and relapse associated with the delayed immune reconstitution (IR) secondary to the procedures of profound T-cell depletion required for severe graft-vs-host-disease (GvHD) prevention. Methods. In a haplo-SCT phase I-II multicenter, open, non-randomized trial sponsored by MolMed SpA, we infused donor lymphocytes genetically engineered to express the suicide gene herpes simplex thymidine kinase (TK-DLI) to induce early IR, while selectively controlling GvHD. We enrolled 54 patients (pts) -median age 51- with high-risk hematologic malignancies. Thirty-two patients were in remission at transplantation. Results. After myeloablative conditioning regimen, 50 pts received a median 11×10^6/ kg CD34+ and 1.1×10^4/kg CD3+ after Clinimacs CD34+ selection. Median time to engraftment of neutrophils > 1.0 ×10^9/L and platelets > 50 ×10^9/L was 14 days. TK cells could always be prepared in the appropriate timeframe, and no drop out secondary to inadequate cell manipulation occurred. Twenty-eight pts received TK-DLI at a dose of CD3+ cells of 0.9–40 ×10^6/kg: 22 pts obtained prompt IR with CD3+>100/mcl at day +75 (median) from haplo-SCT and day +23 from TK-DLI. Eleven pts developed GvHD (10 acute GvHD grade I-IV and 1 chronic GvHD) that was always abrogated by the suicide gene induction; no progression from acute GvHD to chronic GvHD and no GvHD-related death or long-term complication occurred. No acute or chronic adverse event related to the gene transfer procedure was observed during extended follow-up. With a median follow-up of 178 days (range 2–1821), the 3-year TRM in intention to-treat (ITT) analysis was 40% with last mortality event at d+166. Significantly, the cumulative infectious mortality was 10% in TK-treated immune-reconstituted patients. Immune reconstitution obtained with TK-cells infusion correlated with rapid development of a wide T-cell repertoire and detection of high frequencies of T-cells specific for opportunistic pathogens. Initially, TK-cells represented the predominant T cell component in reconstituting patients and showed a effector memory phenotype, an oligoclonal repertoire and a persistent ganciclovir sensitivity. At later t