Allogeneic Stem Cell Transplantation After Conditioning With

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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 relapse and graft failures were competing risks. Patients alive with no history of relapse were censored at the time of last Patients aged 18–60 were eligible for the study if they had acute fi clinical examination of the disease status. Patients alive without relapse or lymphoblastic leukemia in rst or subsequent CR and indication for AHSC persisting disease were censored at last contact. According to study according to the German Acute Lymphoblastic Leukemia Study Group. protocol and the definition of relapse according to GALL protocol, the Furthermore, patients had to have an HLA-identical sibling or an HLA-A, criteria to define CR were bone marrow showing o5% blasts (M0 or M1), -B, -C, -DRB1 and DQB1 compatible unrelated donor, allowing one no blasts in peripheral blood and no organ involvement. Ag-mismatch. Patients had to be not eligible for TBI owing to either prior Overall survival was defined as the P of survival irrespective of disease 4 4 radiation of the spine 30 Gy, prior radiation of the mediastinum 30 Gy, status at any point in time. Patients alive at their last follow-up were severe encephalopathy during induction chemotherapy, decreased censored. pulmonary function with diffusing capacity of lung for carbon monoxide DFS was measured from time of start of stem cell transplantation o ’ 50%, or patient s wish to avoid TBI as conditioning regimen. Major ( = day 0) to time of event. Events were defined as relapse of disease, graft exclusion criteria were absence of CR at registration, severe irreversible failure or death (whatever occurred first). Patients without relapse or renal, hepatic, pulmonary or cardiac disease, and progressive invasive persisting disease are censored at the last time without indication of fungal infection at time of registration. The conditioning regimen consisted relapse or persisting disease. 2 – of treosulfan (12 g/m ) given intravenously on three consecutive days ( 7, Chimerism studies by bone marrow and blood samples were performed – – 6 and 5) plus etoposide (30 mg/kg body weight) given intravenously on prior to transplantation, following engraftment at day 28, day 100, at – day 4, and cyclophosphamide (60 mg/kg body weight) given intrave- 6 months, and at 1 year after transplantation. Chimerism tests were – – nously on day 3 and 2. GvHD prophylaxis consisted of ATG-Fresenius performed either with variable number of tandem repeat regions, in sex- fi – – (Fresenius Biotech, Gräfel ng, Germany), 20 mg/kg given on day 3, 2 and mismatch-patients with FISH. –1 for unrelated donors, and optional for matched related donors. All patients received cyclosporine A and a short course of methotrexate. Cyclosporine A was to be started at a dose of 3 mg/kg body weight per day RESULTS as continuous infusion, starting on day –1, according to the local standard policy, subsequently adjusted to blood level, which should be between Between 06 July 2007 and 18 August 2010, 50 patients with a 200 and 300 μg/L (monoclonal). Cyclosporine A was to be switched to oral median age of 46.5 years (range: 18–64) were enrolled to this trial application, 3 mg/kg b.i.d. when tolerating oral medications, in the absence by 10 sites. Last patient last visit was conducted on 16 October of GvHD. When Cyclosporine A was switched orally the dose was to be 2012. Median follow-up was 24.2 months. maintained to target achieve a serum level of 200–300 mg. Cyclosporine A was tapered around day 120 in the case of no acute GvHD and was further tapered (25% every 2 weeks) to be discontinued at day 180, provided that Toxicity and GvHD there was no evidence of GvHD. Further dose reduction or withdrawal due Within 28 days after SCT, all patients suffered from at least one to toxicity was to be performed according to the local policy. Methotrexate adverse event. In total, 2%, 2%, 66%, 28% and 2% of patients

Table 2. Adverse events a 1.0000

Patients with AE n = 50 (100%) 0.9000 = Infectious complication n 36 (72%) 0.8000 Gastrointestinal n = 29 (58%) Cardiac n = 12 (24%) 0.7000 = Metabolic n 13 (26%) 0.6000 Pulmonary n = 10 (20%) Skin n = 6 (12%) 0.5000 Median [m] 23.6 = Range [m] 2.4-23.6 Neurological n 5 (10%) 0.4000 6m rate 0.88 Bleeding n = 4 (8%) 90%-C.I. (0.81, 0.95) Renal n = 6 (12%) 0.3000 12m rate 0.74 Kaplan-meier-estimate 90%-C.I. (0.64, 0.84) = Allergy n 3 (6) % 0.2000 18m rate 0.55 Hepatobiliary n = 1 (2) % 90%-C.I. (0.43, 0.67) 24m rate 0.48 0.1000 90%-C.I. (0.35, 0.61) Abbreviation: AE ¼ adverse event. 0.0000 0 6 12 18 24 30 Patients at risk Time [months] 50 44 37 26 15 0 1.0000 Median [m] n.a. Range [m] 2.4-15.5 b 0.9000 6m rate 0.06 1.0000 90%-C.I. (0.01, 0.12) 0.8000 12m rate 0.08 0.9000 90%-C.I. (0.02, 0.15) 18m rate 0.16 0.7000 0.8000 90%-C.I. (0.07, 0.25) 0.6000 24m rate 0.16 90%-C.I. (0.07, 0.25) 0.7000 0.5000 0.6000

0.4000 1. CR > 1. CR 0.5000 Median [m] n.a. 16

Cumulative incidence 0.3000 0.4000 Range [m] 3.3-23.6 2.4-17.5 0.2000 6m rate 0.89 0.85 90%-C.I. (0.81, 0.97) (0.69, 1.00)

Kaplan-meier-estimate 0.3000 0.1000 12m rate 0.76 0.69 90%-C.I. (0.64, 0.87) (0.49, 0.90) 0.2000 0.0000 18m rate 0.61 0.38 90%-C.I. (0.47, 0.75) (0.14, 0.63) 0 612182430 0.1000 24m rate 0.51 0.38 Patients at risk Time [months] 90%-C.I. (0.36, 0.66) (0.14, 0.63) 0.0000 48 35 24 15 7 0 0 6 12 18 24 30

Figure 1. Cumulative incidence of non-relapse mortality. Patients at risk Time [months] 37 33 28 21 11 0 13 11 9540 Figure 3. (a) Overall survival for the entire study population and 1.0000 (b) according to 1. or 2. CR. 0.9000

0.8000 suffered from maximum common toxicity criteria (CTC) grades I, II, III, IV and V, respectively. Focusing on those adverse events that 0.7000 were judged to be at least possibly related to the conditioning 0.6000 regimen, the respective worst grades were 6, 10, 64, 20 and 0%, 0.5000 respectively. The most frequent adverse events were of CTC category 0.4000 ‘gastrointestinal’ (98%), followed by ‘infection’ (80%), ‘metabolic/ 0.3000 ’ ‘ ’ ‘ ’ ‘ Cumulative incidence laboratory (52%), cardiac general (50%), pain (48%), dermatol- ’ ‘ ’ 0.2000 ogy/skin (46%) and pulmonary/upper respiratory (40%). All other CTC categories were documented in o40% of study patients. 0.1000 Among the gastrointestinal adverse events, mucositis/stomatitis 0.0000 occurred most often (82%), followed by diarrhea in 44% of 0306121824 patients and nausea in 26% of patients. Among the category Time [months] Patients at risk ‘infection’, infections with grade III–IV neutropenia were most 35 26 19 13 7 0 frequent (34%), whereas hyperbilirubinemia was most often 1383200documented in the CTC category ‘metabolic/laboratory’ (28%). 1. CR > 1. CR Focusing on grade III/IV/V adverse events, 96% of patients Median [m] 25.7 10.5 experienced at least one event. In the CTC categories ‘gastro- Range [m] 1.2–25.7 1–21.5 ’ ‘ ’ 6m rate 0.17 0.31 intestinal (72%), followed by CTC category infection (62%), the 90%-C.I. (0.07, 0.28) (0.10, 0.51) leading events were mucositis/stomatitis (58%), and ‘infection 12m rate 0.23 0.69 90%-C.I. (0.11, 0.35) (0.44, 0.95) with grade III–IV neutrophils’ (34%), respectively. Veno-occlusive 18m rate 0.34 0.77 90%-C.I. (0.20, 0.48) (0.51, 1.00) disease was seen in four patients. Veno-occlusive disease was 24m rate 0.34 0.92 classiﬁed as mild (n = 3) and severe (n =1) 90%-C.I. (0.20, 0.48) (0.66, 1.00) The cumulative incidence of acute GvHD after transplantation Figure 2. Cumulative incidence of relapse according to 1. vs 2. CR. was 53%. The cumulative incidence of grades III–IV acute GvHD

© 2015 Macmillan Publishers Limited Bone Marrow Transplantation (2015) 1503 – 1507 Treosulfan-based conditioning for ALL N Kröger et al 1506 after transplantation was 14%. The cumulative incidence of TBI in comparison with busulfan-conditioning regimen for patients chronic GvHD at 24 months after transplantation was 41%. with acute lymphoblastic leukemia who underwent AHSC. The Focusing on extensive cGvHD only, revealed cumulative incidence International Bone Marrow Transplant Registry reported a 3-year of 14% at 24 months. survival of 55% for TBI-, and 40% for busulfan-containing In total, 26 severe adverse events were reported in 12 patients regimens.13 A German study, which included 264 patients with as listed in Table 2. Within 28 days after SCT, 22% of patients were ALL also reported a superior DFS for patients who received TBI affected; 4% of patients suffered from grade III-severe adverse instead of busulfan as conditioning regimen prior to AHSC (30% vs advent, and 18% patients from grade III-severe adverse advent. 17%, P = 0.04).9 Considering these retrospective data and realizing No unexpected severe adverse advent occurred. Haematological the medical need of a non-TBI conditioning regimen for patients severe adverse events were excluded within the first 28 days after with acute lymphoblastic leukemia, we investigated a treosulfan- transplantation. based regimen (NCT00682305). We observed engraftment at day 28 in 88% of the patients, and Engraftment and chimerism three patients experienced graft-failure. The toxicity profile was The engraftment rates at day 28 were 88% for leukocytes, and modest, resulting in low NRM at 1 and 2 years of 8% and 16%, 63% for platelets. On day 56 leukocyte engraftment was 96% and respectively. Major cause of treatment failure was relapse in 36% for platelets 84%. Three primary graft failures were observed, at 1 year and 51% at 2 years, resulting in an overall survival at 2 years of 48%. The incidence of relapse at 2 years was higher in and one patient died due to graft failure. Overall, complete donor- fi type chimerism could be achieved in 83% of patients at day 100. patients beyond rst CR (92% vs 34%), which resulted in a 2-year overall survival of 51% for patients transplanted in first CR, and 38% for those beyond first CR. These results with respect to Non-relapse mortality relapse and survival seem to be comparable to those reported NRM at day 100 was 2% (90% confidence interval: 0–5%). from larger studies, which mainly used TBI-based conditioning One-year NRM rate was 8% (90% confidence interval: 2–15%) regimens with relapse rates between 24% and 61, and 5-year (see Figure 1). As the upper limit of the confidence interval is survival between 38 and 54%.20–23 The TBI-containing myeloa- statistically significant below 35% (one-sided Po0.05), which was blative regimen developed at Stanford is considered the standard considered to be the benchmark for concluding that treosulfan conditioning regimen for acute lymphoblastic leukemia; however, might be promising in this indication at the design stage of this no randomized trials are available so far. Apart from acute toxicity, trial, at the end of follow-up (two years), the cumulative incidence major concerns regarding TBI are long-term effects, such as of NRM increased to 16%. Infections were the major cause of secondary malignancies, which occurs more frequently after death, one patient died to EBV-related lymphoma. TBI-based regimens than after chemotherapy-based regimens.24 To lower toxicity especially for older patients, reduced-intensity DFS and overall survival conditioning regimens have been developed. Several groups and The median DFS was 13.6 months, the 12- and 24-month rates international registries reported encouraging results of using were 56% and 36%, respectively. Patients in first CR experienced a reduced-intensity conditioning regimens for acute lymphoblastic leukemia prior to AHSC with comparable results to myeloablative median DFS of 25.7 months versus 8.9 months in patients beyond 25–27 first CR. The 12- and 24-month DFS-rates were 69% and 50%, regimens in a non-randomized comparison. However, despite fi 26,27 respectively, compared with 23% and 0%, respectively. Cumulative the bene t of lower NRM, there was a higher risk of relapse, incidence of relapse was 36% (90% confidence interval: 37–65) suggesting the optimal conditioning regimen should have high fi after 12 months, and 51% (90% confidence interval: 37–65) after intensity with low toxicity pro le. A major prognostic factor for fi outcome after AHSC for ALL is the amount of minimal residual 24 months (see Figure 2). Patients in rst CR showed a 12-month 28,29 relapse rate of 23% compared with 69% in patients beyond first disease at time of transplantation, which was not tested with CR. After 24 months, the respective rates were 34% compared our prospective study. Overall, we conclude that conditioning with 92%. Kaplan–Meier estimates of overall survival were 74% regimen containing treosulfan, etoposide and cyclophosphamide after 12 months declining to 48% after 24 months (see Figure 3). represents a potential alternative for patients with ALL in 1. CR Median survival was 23.6 months. No difference within subgroups who need AHSC but are not eligible for TBI. Patients with was observed. advanced disease might potentially benefit from alternative cytoredeductive strategies before AHSCT and potentially also from maintenance therapy. DISCUSSION Treosulfan (L-threitol-1,4-bis-methanesulphonate) is a bifunctional CONFLICT OF INTEREST alkylating cytotoxic agent that has been approved in Germany for treatment of ovarian cancer. In preclinical models, antineoplastic NK received research funding from Medac/Germany. The remaining authors declare fl activity of treosulfan against other malignancies has been shown no con ict of interest. including activity against acute lymphoblastic leukemia.14 In human ALL-SCID-19 xenografts, antileukemic activity of treosulfan AUTHOR CONTRIBUTIONS was demonstrated.15,16 Because of the limited non-hematological toxicity, treosulfan has been investigated for conditioning NK designed the study, interpreted the data and wrote the manuscript. UP prior allogeneic transplantation. Treosulfan in combination with assisted in the study design, analyzed the data, performed statistics and edited fludarabine or cyclophosphamide as conditioning regimen prior the manuscript. MB, MS, RT, CS, RA, HM, MH, CW, RGM, WB, GK, FA, NG, DH, AZ to AHSC has shown significant activity with a low toxicity profile in and DB assisted with data collection and edited the manuscript. different hematological malignancies such as myelodysplastic – syndromes and AML.17 19 REFERENCES This prospective multicentre phase II-study investigated 1 Rowe JM. Prognostic factors in adult acute lymphoblastic leukaemia. Br J non-TBI-containing conditioning regimen containing treosulfan, Haematol 2010; 150: 389–405. etoposide and cyclophosphamide in patients with acute 2 Ram R, Gafter-Gvili A, Vidal L, Paul M, Ben-Bassat I, Shpilberg O et al. Management lymphoblastic leukemia in first or subsequent CR that were not of adult patients with acute lymphoblastic leukemia in first complete remission: eligible for TBI. Retrospective studies suggested a superiority of systematic review and meta-analysis. Cancer 2010; 116:3447–3457.

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