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Allogeneic Stem Cell Transplantation After Conditioning With Bone Marrow Transplantation (2015) 50, 1503–1507 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt ORIGINAL ARTICLE Allogeneic stem cell transplantation after conditioning with treosulfan, etoposide and cyclophosphamide for patients with ALL: a phase II-study on behalf of the German Cooperative Transplant Study Group and ALL Study Group (GMALL) N Kröger1, M Bornhäuser2, M Stelljes3, U Pichlmeier4, R Trenschel5, C Schmid6, R Arnold7, H Martin8, M Heinzelmann1, C Wolschke1, RG Meyer9, W Bethge10, G Kobbe11, F Ayuk1, N Gökbuget12, D Hölzer12, A Zander1 and D Beelen5 TBI-based preparative regimens are considered as standard conditioning therapy for allogeneic stem cell transplantation (AHSC) in patients with ALL. We investigated toxicity and efficacy of a non-TBI-based regimen consisting of treosulfan, etoposide and cyclophosphamide for ALL within a prospective study. Major inclusion criteria were CR and non-eligibility for TBI. Fifty patients with a median age of 46.5 years (range, 18–64) were included. Donors were HLA-identical sibling (n = 8), matched (n = 42) or mismatched (n = 10) unrelated. The toxicity was moderate, resulting in a cumulative incidence of non-relapse mortality (NRM) at 1 year of 8% (90% confidence interval: 2–15%). Acute GvHD grade II–IV and grade III/IV was noted in 53% and 14%, respectively. Chronic GvHD at one year was seen in 41%. After a median follow-up of 24 months the cumulative incidence of relapse was 36% (90% confidence interval: 24–48) and 51% (90% confidence interval: 37–65) at 1 and 2 years, respectively. The estimated 2-year disease-free and overall survivals were 36 and 48%, respectively. Treosulfan, etoposide and cyclophosphamide followed by AHSC has a favorable toxicity profile with low NRM and therefore represents a potential alternative regimen for ALL in 1. CR (NCT00682305). Bone Marrow Transplantation (2015) 50, 1503–1507; doi:10.1038/bmt.2015.202; published online 14 September 2015 INTRODUCTION The major limiting factor for the application of AHSC for ALL ALL is a hematological malignancy characterized by rapid patients is the relatively high treatment-related mortality, proliferation and subsequent accumulation of immature lympho- which exceeded 30% in most of the studies.9,10 This high cytes. Acute lymphoblastic leukemia accounts for ~ 20% of all treatment-related mortality can be caused in part by intensified acute leukemia seen in adults older than 20 years. Over the past regimen including TBI. The most commonly used regimen for decade, there has been substantial improvement in treatment of transplantation of patients with acute lymphoblastic leukemia is 1–3 adult patients with acute lymphoblastic leukemia. With modern cyclophosphamide in combination with TBI. Some centers intensified chemotherapy, ~ 30% of the adult patients can achieve replaced etoposide for cyclophosphamide or added etoposide a cure of their disease. High-dose chemotherapy or high-chemo- to cyclophosphamide in combination with TBI.11 To reduce radiotherapy followed by allogeneic stem cell transplantation toxicity, investigators at Johns Hopkins University approached (AHSC) has resulted in a long-term disease-free survival (DFS) in the problem by substituting busulfan for TBI to decrease the some patients with advanced or relapsed disease and has been long-term side effects of TBI.12 These non-radiation-dependent successfully utilized in patients with high-risk disease transplanted – regimens showed activity in the treatment of ALL and suggest in first remission.4 6 A benefit for allogeneic transplantation in that TBI is not an absolute requirement for successful treatment of comparison with chemotherapy with autologous transplantation was confirmed.7 In this study, the beneficial effect was more ALL by high-dose chemotherapy. However, in retrospective frequently seen in patients with high-risk acute leukemia with a studies from International Bone Marrow Transplant Registry and DFS of 44% in the allografting group in comparison with 11% in Germany, the TBI-cyclophosphamide regimen was superior to the 10,13 the group with chemotherapy or autologous transplantation. The non-TBI-containing busulfan-based regimen. Hence, these International Bone Marrow Transplant Registry reported a DFS of data demonstrate a strong need to evaluate new drugs with a 42% for those patients who received an allogeneic transplantation lower toxicity as conditioning regimen for patients with acute in second CR.8 Recent data suggest that unrelated transplantation lymphoblastic leukemia. Treosulfan as part of the conditioning resulted in similar outcome in comparison with related donors.9,10 regimen might be an alternative to TBI-based regimens. 1Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Department of Hematology/Oncology, University Hospital Dresden, Dresen, Germany; 3Department of Hematology/Oncology, University Hospital Münster, Münster, Germany; 4CTS—Clinical Trial Solutions, Wedel, Germany; 5Department of Bone Marrow Transplantation, University Hospital, Essen, Germany; 6Department of Hematology/Oncology, Community Hospital, Augsburg, Germany; 7Department of Hematology/Oncology, University Hospital Charité, Berlin, Germany; 8Department of Hematology/Oncology, University Hospital, Frankfurt, Germany; 9Department of Hematology/Oncology, University Medical Center Mainz, Mainz, Germany; 10Department of Hematology/Oncology, University Hospital, Tübingen, Germany; 11Department of Hematology/Oncology, University Hospital, Düsseldorf, Germany and 12Study Office German ALL Study Group (GMALL), Frankfurt, Germany. Correspondence: Professor N Kröger, Department of Stem Cell Transplantation University, Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg D-20246, Germany. E-mail: [email protected] Received 15 January 2015; revised 26 June 2015; accepted 2 July 2015; published online 14 September 2015 Treosulfan-based conditioning for ALL N Kröger et al 1504 was to be given on day +1 at a dose of 15 mg/m2, and at a dose of 10 mg/ Table 1. Patients’ characteristics (n = 50) 2 m on day +3, day +6 and day +11 intravenously. In case of severe mucositis and high bilirubin level, the dose of methotrexate was to be Median age (range) 46.5 years (18–64 years) adjusted according to the local policy. Sex Between July 2007 and August 2010, 50 patients were enrolled from 10 Male 25 (50%) German centers. The patients' characteristics are listed in Table 1. Primary Female 25 (50%) objective of the study was engraftment on day 28, and non-relapse mortality (NRM) at day +100, and at 1 year. Secondary objectives were Risk profile (according to GMALL) incidence of acute and chronic GvHD, DFS and overall survival at 2 years, Standard risk n = 7 (14%) toxicity according NCT-CTCAE v3.0, cumulative incidence of relapse at High risk n = 22 (44%) 2 years. All patients gave written informed consent, and the study was very high risk n = 21 (42%) approved by the Ethics Committee of the German Health Authorities, and registered under NCT00682305, EudraCT: 2006-0035 66-34. Disease status at transplantation 1st CR n = 37 (74%) Infectious prophylaxis and supportive care = 2nd CR n 11 (22%) All patients received antibacterial prophylaxis with ofloxacin or ciproflox- 4 = 2nd CR n 2 (4%) acin until engraftment. Antiviral prophylaxis were given with acyclovir according to local policy, with cotrimoxacole twice weekly or alternatively Donor type monthly, and with inhalation with pentamidine up to 1 year after AHSC. = HLA-identical sibling n 8 (16%) Preemptive CMV-treatment with ganciclovir in case of documented viral = Matched unrelated donor n 42 (84%) reactivation, determined by pp65-test or PCR-technique. CMV-negative = Mismatched unrelated donor n 10 (20%) patients were to be transfused with CMV-negative blood products or with adequately fitting system. All blood products had to be irradiated. Inclusion criteria Antiemetic medication were given according to local practice or Prior radiation n = 9 (18%) = international guidelines. Fluid administration was done according to local Prior encephalopathy n 2 (4%) policy. DCLO o50% n = 15 (30%) Patient’s wish n = 24 (48%) Statistical methods and assessment criteria Abbreviations: DCLO ¼ diffusing capacity of lung for carbon monoxide; Neutrophil engraftment was to be documented as the first of 3 GMALL ¼ German Acute Lymphoblastic Leukemia Study Group. consecutive days with an absolute neutrophilic granulocyte count of 40.5 × 109/L in the peripheral blood. Leukocyte engraftment was to be documented by the first of 3 consecutive days with a total WBC count 41×109/L in the peripheral blood. Platelet engraftment was to be The present study was a multicentre, prospective phase II-study, fi fi documented by the rst of 3 consecutive days with a platelet engraftment investigating safety and ef cacy of the combination of treosulfan, count of 420 × 109/L and 450 × 109/L in the absence of platelet etoposide and cyclophosphamide as conditioning regimen for transfusion. patients with acute lymphoblastic leukemia who are not eligible NRM was defined as the P of dying in the absence of persisting disease for a TBI-containing regimen. or previous occurrence of relapse or graft failures. Persisting disease/ relapse was considered a competing event. Patients alive without relapse or persisting disease were censored at last contact. PATIENTS AND METHODS Patients were considered to be experiencing an event when they had Patient's characteristics relapsed. Death without
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