Bone Marrow Transplantation (2017) 52, 238–244 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/17 www.nature.com/bmt ORIGINAL ARTICLE Safety and efficacy of thiotepa-based conditioning for allogeneic transplantation in AML: a survey from the ALWP of the EBMT S Eder1,2, M Labopin1, J Finke3, D Bunjes4, A Olivieri5, S Santarone6, A Rambaldi7, L Kanz8, G Messina9, M Mohty1,2,11 and A Nagler1,10,11 on behalf of the ALWP of the EBMT This study evaluated the safety and efficacy of thiotepa-based regimens before allogeneic stem cell transplantation in 310 adult patients with AML. Disease status at the time of transplantation was CR1 in 50%, CR2+ in 23.5% and advanced disease in 26.5%. Transplantation was performed from haploidentical (35%), matched sibling (27%), unrelated (20%) or cord blood (18%) donors. As for safety: mucositis occurred in 46.8% of the patients and the cumulative incidence (CI) of sinusoidal obstruction syndrome was 4.0%. With a median follow-up of 37 months, the CI of acute GvHD grade4II was 26.5%, whereas CI of chronic GvHD was 28.1% at 3 years. CI for non-relapse mortality at 3 years was 38.4%, 49.7% and 45.4% for patients in CR1, CR2+ and advanced disease, respectively (P = 0.10). Relapse incidence at 3 years was 20.2, 30.7 and 40.6% in these three respective groups (P = 0.002). CI for 3-year leukemia-free survival and overall survival were 41.4% and 45.6% (CR1), 19.6% and 27.7% (CR2+), and 13.9% and 13.6% (advanced disease), respectively (Po10À4 for both). Our data suggest that thiotepa-based conditioning therapy in AML is feasible, effective and safe, as investigated for sinusoidal obstruction syndrome and mucositis. Bone Marrow Transplantation (2017) 52, 238–244; doi:10.1038/bmt.2016.239; published online 19 September 2016 INTRODUCTION lymphoma, replacing BCNU and thus reducing lung toxicity Allogeneic hematopoietic stem cell transplantation (HSCT) is a (TECAM–thiotepa, etoposide, cytoxan, ARA-C and melphalan) with 10 well-established curative therapy for hematological diseases, very good results. including AML.1 Subsequently, thiotepa was incorporated into pre-allogeneic TBI has traditionally been an integral part of pre-transplantation transplantation conditioning regimens using HLA-matched conditioning. However, it is associated with substantial toxicity donors, both for malignant and non-malignant indications. In 11 and undesirable long-term side effects.2 the 1990s, Bacigalupo et al. reported on the use of thiotepa in Thiotepa (N,N'N'-triethylenethiophosphoramide) is an alkylating patients with advanced leukemia using myeloablative condition- compound with an antineoplastic activity that has been used in ing. Thiotepa was administered at a dose of 15 mg/kg in oncology (for example, neuroblastoma, breast-, ovarian- and combination with cyclophosphamide. The transplant-related bladder cancer) for decades.3,4 Besides its antineoplastic mortality was 29% and the 2-year overall survival (OS) was 57%. activity,5,6 thiotepa has immunosuppressive properties7 and the Rosales and colleagues12 used thiotepa (5 mg/kg × 2 days), in ability to penetrate the blood-brain barrier,8 in conjunction with a addition to the standard busulfan/cyclophosphamide regimen good toxicity profile. Thiotepa is metabolized in the liver by with comparable results and moderate toxicity rates. cytochrome P450 into its metabolite, tepa. Two percent of the Later on, thiotepa was included in reduced-intensity drug is excreted unchanged in the urine. There is a direct conditioning (RIC) regimens, aiming in intensifying the anti correlation between thiotepa/tepa area under the curve and leukemic effect reducing the relapse rates that were toxicity, such as mucositis, hepatitis and brain toxicity.9 higherpostRICincomparisonwiththemyeloablative – On the basis of these favorable charactristics thiotepa has been regimens.13 15 Indeed, Bacigalupo et al.,16 were able to show subsequently incorporated into chemotherapeutic protocols used an impressive outcome of thiotepa-based RIC regimens with for hematological malignancies and HSCT. However, there are few 10-year follow-up. studies focusing on the analysis of the benefit of thiotepa in the In recent years, thiotepa has become an integral part of the TBF pre-allogeneic HSCT conditioning in a specific disease category. (thiotepa, busulfan and fludarabine) protocol, which is being used Early studies reported on the use of thiotepa in the conditioning with increasing frequency for alternative donor transplantations, regimen before autologous HSCT, mainly in patients with including haploidentical and cord blood transplants.17–20 1EBMT Office Paris, Hôpital Saint-Antoine, Paris, France; 2Service d’Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, Paris, France; 3Department of Medicine— Hematology, Oncology, University of Freiburg, Freiburg, Germany; 4Klinik fuer Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany; 5Department of Hematology, Azienda Ospedali Riuniti di Ancona, Ancona-Torrete, Italy; 6Department of Hematology, Ospedale Civile, Pescara, Italy; 7USC Ematologia, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; 8Abteilung II, Universität Tübingen, Tübingen, Germany; 9Centro Trapianti Midollo Osseo, Azienda Ospedaliera ‘BMM’, Reggio Calabria, Italy and 10Chaim Sheba Medical Center, Tel-Hashomer, Israel. Correspondence: Dr S Eder, Service d’Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, Paris 75012, France. E-mail: [email protected] 11The two last authors share senior authorship. Received 20 April 2016; revised 22 July 2016; accepted 27 July 2016; published online 19 September 2016 Safety and efficacy of thiotepa for allo-HSCT in AML S Eder et al 239 The aim of the current analysis was to investigate the potential Disease status at HSCT was CR1 in 50% and CR2+ in 23.5%, impact of thiotepa as part of the conditioning therapy for although 26.5% of the patients had an advanced disease at the AML patients, undergoing allogeneic transplantation from time of transplantation. HLA-matched or alternative donors, with respect to efficacy and Thiotepa was mostly combined with fludarabine (43%), safety. fludarabine+busulfan (32%) or cyclophosphamide (25%; Table 1). The median dose of thiotepa was 10 mg/kg (range, 4–20). Anti-GvHD prophylaxis included cyclosporine A alone or in PATIENTS AND METHODS combination with methotrexate and/or mycophenolate mofetil, Study design and data collection in vitro T-cell depletion or post-transplantation cyclophosphamide This is a retrospective multicenter analysis based on the registry data of the (Table 2). Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) registry. The study was designed and Transplantation outcome 4 approved by the ALWP. The EBMT is a voluntary working group of 600 Engraftment. The median follow-up time was 37 months (range, transplant centers that are required to report all consecutive HSCT 6–169). CI of neutrophil engraftment (defined as ⩾ 0.5 × 109/L) procedures and their follow-up once a year. Audits are routinely performed was 88.7% (95% confidence interval (CI): 84.5–81.8) at day +30 to determine the accuracy of the data. Since 1990, patients provide post HSCT. Median time to engraftment was 16 days (range, 8–38). informed consent authorizing the use of their personal information for fi ⩾ 9 research purposes. CI of platelet engraftment (de ned as 20 × 10 /L) was 86.2% Eligible patients for this analysis were adults (age 418 years) with (95% CI: 81.6-89.7) at day +60 post HSCT. de novo or secondary AML who underwent a first allogeneic (optionally after autologous) HSCT with a thiotepa-based regimen between 1992 Organ toxicity and GvHD. Mucositis (all grades) occurred in 46.8% and 2012 (median year of HSCT 2008). Any donors were included of patients with a median day of onset at day 3 after HSCT. (HLA-matched siblings, unrelated or haploidentical donors and cord blood The CI of SOS was low: 4.0% (95% CI: 2.2–6.6). The median day transplantation). of onset was day 8 post HSCT. It was severe in only in one patient, Variables collected included recipient and donor characteristics in whom it resulted in multiorgan failure and death. (age, gender, CMV and serostatus), disease status at transplant, The incidence of acute GvHD (gradeXII) was 26.5% (95% CI: transplant-related factors, including conditioning regimen, immunosup- 21.6–31.6) at day 100 post HSCT, whereas CI of chronic GvHD was pression (in vivo T-cell depletion vs none), stem cell source, prophylaxis of 28.1% (95% CI: 23.1–33.4) at 3 years (56% of the patients had a GvHD and outcome variables (acute and chronic GvHD, relapse, limited and 44% an extensive disease). non-relapse mortality (NRM), leukemia-free survival (LFS), OS, toxicity (sinusoidal obstruction syndrome (SOS) and mucositis) and causes NRM and cause of death. Overall, the NRM was 19.0% (95% CI: of death. 14.9–23.6) and 43.0% (95% CI: 37.1–48.7) at day 100 and 3 years post HSCT, respectively. Statistical analysis The 3-year NRM was 38.4% (95% CI: 27.4–49.2), 49.7% (95%CI: The primary end points of the study were LFS and OS. Secondary end 38.9–59.6) and 45.4% (95% CI: 34.4–55.7) for patients in CR1, CR2+ points included: disease relapse incidence (RI), NRM, engraftment, and advanced disease, respectively (P = 0.10; Figure 1a). incidence, and severity of acute and chronic GvHD. The starting point Three-year NRM was 32.3% (95% CI: 23.7–41.2), 29.2% for time-to-event analysis was ‘date of transplantation’. OS was defined as (95% CI: 20.9–38.1), 55.7% (95% CI: 47.4–63.1) and 49.3% the time to death from any cause. Surviving patients were censored at the (95% CI: 40.6–57.4) for matched sibling, unrelated, haploidentical fi time of last follow-up.