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Franciszek K Glowka - One of the best experts on this subject based on the ideXlab platform.
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kinetics of in vitro guanine n7 alkylation in calf thymus dna by 2s 3s 1 2 epoxybutane 3 4 diol 4 methanesulfonate and 2s 3s 1 2 3 4 diepoxybutane revision of the mechanism of dna cross linking by the prodrug Treosulfan
Molecular Pharmaceutics, 2019Co-Authors: Michal Romanski, Alicja Pogorzelska, Franciszek K GlowkaAbstract:Prodrug Treosulfan, originally registered for treatment of ovarian cancer, has gained a use in conditioning prior to hematopoietic stem cell transplantation. Treosulfan converts nonenzymatically to...
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Treosulfan pharmacokinetics and its variability in pediatric and adult patients undergoing conditioning prior to hematopoietic stem cell transplantation current state of the art in depth analysis and perspectives
Clinical Pharmacokinectics, 2018Co-Authors: Michal Romanski, Jacek Wachowiak, Franciszek K GlowkaAbstract:Treosulfan is a prodrug that undergoes a highly pH- and temperature-dependent nonenzymatic conversion to the monoepoxide {(2S,3S)-1,2-epoxy-3,4-butanediol 4-methanesulfonate [S,S-EBDM]} and diepoxide {(2S,3S)-1,2:3,4-diepoxybutane [S,S-DEB]}. Currently, Treosulfan is tested in clinical trials as an alternative to busulfan in conditioning prior to hematopoietic stem cell transplantation (HSCT). Of note, the optimal dosing of the prodrug is still unresolved, especially in infants. In this paper, the pharmacokinetics of Treosulfan, together with its biologically active epoxides, is comprehensively reviewed for the first time, with the focus on conditioning prior to HSCT. Most of the insightful data presented in this review comes from studies that have been conducted in the last 3 years. The article widely discusses the volume of distribution and total clearance of Treosulfan. In particular, the interindividual variability of these key parameters in infants, children above 1 year of age, and adults is analyzed, including possible covariates. A clinically important aspect of the formation rate-limited elimination of S,S-EBDM and S,S-DEB is described, including the correlation between the exposure of the prodrug and S,S-EBDM in children. The significance of the elimination half-life of Treosulfan and its epoxides for successful conditioning prior to HSCT is also raised. Furthermore, the organ disposition of Treosulfan and S,S-EBDM in rats is discussed in the context of the clinical toxicity and myeloablative activity of Treosulfan versus busulfan. Moreover, perspectives for future therapeutic drug monitoring of Treosulfan are presented. The review is intended to be helpful to pharmacists and doctors in the comprehension of the clinical pharmacokinetics of Treosulfan.
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determination of Treosulfan in plasma and urine by hplc with refractometric detection pharmacokinetic studies in children undergoing myeloablative treatment prior to haematopoietic stem cell transplantation
Journal of Chromatography B, 2007Co-Authors: Franciszek K Glowka, Marta Karaźniewicz łada, Grzegorz Grund, Jacek WachowiakAbstract:Abstract A direct and selective HPLC method with refractometric detection was worked out for determination of Treosulfan in plasma and urine of children. Before injection onto reverse phase column plasma samples with Treosulfan and barbital (I.S.) were clarified using filtration. The mobile phase was composed of phosphate buffer, pH 5 and acetonitrile. The linear range of the standard curve of Treosulfan spanned concentrations of 10.0–2000.0 μg/ml and 50.0–10000.0 μg/ml in plasma and urine, respectively, and covered the levels found in biological fluids after infusion of the drug. The limit of detection amounted to 5 μg/ml for plasma and 25 μg/ml for urine. Intra- and inter-day precision and accuracy of the measurement fulfilled analytical criteria accepted in pharmacokinetic studies. Recovery of Treosulfan as well as stability in biological fluids was also calculated. The validated method was successfully applied in pharmacokinetic studies of Treosulfan administered to children prior to haematopoietic stem cell transplantation. Differences between pharmacokinetics of Treosulfan in children and adults were also studied.
Rudolf Trenschel - One of the best experts on this subject based on the ideXlab platform.
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Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome mc fludt 14 l a randomised non inferiority phase 3 trial
The Lancet Haematology, 2020Co-Authors: Dietrich W Beelen, Matthias Stelljes, Peter Remenyi, Evamaria Wagnerdrouet, Peter Dreger, Rudolf Trenschel, Christoph Groth, Tamas Masszi, Beate Hauptrock, Thomas LuftAbstract:Summary Background Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with Treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts Findings Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the Treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8–23·6) for patients treated with Treosulfan and 17·4 months (6·3–23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0–70·9) in the Treosulfan group and 50·4% (42·8–57·5) in the busulfan group (HR 0·65 [95% CI 0·47–0·90]; p Interpretation Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the Treosulfan–fludarabine regimen suggest its potential to become a standard preparative regimen in this population. Funding medac GmbH.
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Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial
'Elsevier BV', 2020Co-Authors: Dietrich W Beelen, Matthias Stelljes, Peter Remenyi, Peter Dreger, Rudolf Trenschel, Christoph Groth, Tamas Masszi, Beate Hauptrock, E.-. Wagner-drouet, Thomas LuftAbstract:Background: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with Treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 Treosulfan daily applied as a 2-h infusion for 3 days (days –4 to –2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days –4 and –3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days –6 to –2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008–002356–18) and ClinicalTrials.gov (NCT00822393). Findings: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the Treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8–23·6) for patients treated with Treosulfan and 17·4 months (6·3–23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0–70·9) in the Treosulfan group and 50·4% (42·8–57·5) in the busulfan group (HR 0·65 [95% CI 0·47–0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the Treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the Treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. Interpretation: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the Treosulfan–fludarabine regimen suggest its potential to become a standard preparative regimen in this population. Funding: medac GmbH
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final results of a prospective randomized multicenter phase iii trial comparing Treosulfan fludarabine to reduced intensity conditioning with busulfan fludarabine prior to allogeneic hematopoietic stem cell transplantation in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndrome
Blood, 2017Co-Authors: Dietrich W Beelen, Matthias Stelljes, Peter Remenyi, Evamaria Wagnerdrouet, Peter Dreger, Wolfgang Bethge, Fabio Ciceri, Rudolf Trenschel, Tamas Masszi, Friedrich StoelzelAbstract:Background Allogeneic hematopoietic stem cell transplantation (aHSCT) is a potentially curative treatment option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). A significant challenge in the management of elderly and comorbid patients with AML or MDS is the high transplantation-related mortality (TRM) associated with standard myeloablative preparative regimens preceding aHSCT. Reduced intensity conditioning (RIC) regimens are less toxic, but have often been associated with a higher relapse risk. Hence, there is a high unmet medical need for preparative regimens that reduce the risk of TRM without increasing the incidence of relapse. Patients and Methods In this prospective, randomized (1:1), group-sequential, open-label, multicenter, phase III trial, we enrolled patients with AML in complete remission (i.e. blast counts 2). The trial was designed to demonstrate at least non-inferiority in event-free survival (EFS) of intravenous (i.v.) Treosulfan (10 g/m²/day [d-4 to d-2]) to i.v. busulfan (3.2 mg/kg/day [d-4 to d-3]), both in combination with i.v. fludarabine (30 mg/m²/day [d-6 to d-2]), within 24 months after aHSCT. Events of EFS were defined as relapse of disease, graft failure, or death, whichever occurred first. Secondary objectives included overall survival (OS), cumulative incidence of relapse/progression, and transplant-related mortality (TRM). Engraftment as well as d+28 and d+100 incidence of complete donor-type chimerism (CC) were also evaluated. Further, occurrence of acute and chronic graft-versus-host disease as well as incidence and severity of adverse events between d-6 and d+28 were compared. Pre- and post-transplant immunosuppressive treatment was standardized in both arms and included ciclosporin and short-course methotrexate; anti-thymocyte globuline was used in case of matched unrelated donors (MUD). A confirmatory interim analysis as pre-specified in the protocol was conducted and the results were reviewed by an independent data monitoring committee (DMC) in Nov 2016. The DMC recommended to stop further patient accrual due to statistically proven non-inferiority of the Treosulfan/fludarabine regimen. All data presented here are derived from the 476 patients included in the confirmatory final analysis. Results Median patient age was 60 years with 94 % of patients aged 50 years or older; 64 % had AML and 76 % underwent MUD-aHSCT. HCT-CI scores were well-balanced between treatment regimens. Both regimens were comparable with regard to all safety evaluations between d-6 and d+28. Trilineage engraftment was also similar after both regimens, although the rate of CC at d+28 was significantly higher after Treosulfan. The EFS at 24 months after aHSCT was significantly non-inferior (64.0 % vs. 50.4 %), corresponding to a hazard ratio (HR) of 0.65 in favor of Treosulfan (p=0.0000164). The Kaplan-Meier estimate of OS at 24 months was also significantly superior for patients treated with the Treosulfan as compared to the busulfan regimen (72.5 % vs. 56.4 %; p=0.0082). Estimates of 24-months EFS and OS were consistent within relevant prognostic subgroups. Furthermore, the Treosulfan regimen significantly reduced 24-months TRM (11.3 % vs. 28.2 %; HR 0.54; p=0.0201) in this more vulnerable patient population. Notably, the cumulative incidence of relapse/progression at 24 months was comparable between the two regimens. Conclusions The results of this large randomized, multicenter, phase III trial clearly demonstrate at least non-inferiority of the Treosulfan/fludarabine regimen compared to the RIC busulfan/fludarabine regimen for elderly or comorbid AML and MDS patients undergoing aHSCT. Moreover, the clinical results were consistently in favor of the Treosulfan/fludarabine regimen regarding the most relevant endpoints of aHSCT and thus confirm a major clinical benefit of this regimen as compared to the RIC busulfan/fludarabine regimen in this selected patient population. (Funded by medac GmbH; MC-FludT.14/L, EudraCT no: 2008-002356-18; ClinicalTrials.gov identifier: NCT00822393) Disclosures Masszi: Janssen-Cilag: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. Dreger: medac GmbH, Wedel, Germany: Other: Travel grants. Bethge: medac GmbH, Wedel, Germany: Honoraria, Other: Travel grants. Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Stoelzel: medac: Other: Travel support. Michallet: medac GmbH, Wedel, Germany: Honoraria, Other: Travel grants. Markiewicz: medac GmbH, Wedel, Germany: Other: Travel grants.
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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
Bone Marrow Transplantation, 2015Co-Authors: N Kroger, Uwe Pichlmeier, Martin Bornhauser, Rudolf Trenschel, M Stelljes, Christoph Schmid, Renate Arnold, Hans Martin, Marion Heinzelmann, Christine WolschkeAbstract: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).
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allogeneic hematopoietic sct in patients with aml following Treosulfan fludarabine conditioning
Bone Marrow Transplantation, 2012Co-Authors: Jochen Casper, Rudolf Trenschel, Liisa Volin, Jerzy Holowiecki, Hannes Wandt, Kerstin Schaefereckart, Tapani Ruutu, H Einsele, Gernot Stuhler, Lutz UharekAbstract:An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on Treosulfan and fludarabine, has recently been identified. The safety and efficacy of this new conditioning regimen has been investigated prospectively in patients with AML. A total number of 75 patients with AML in CR were treated with 3 × 14 g/m(2) Treosulfan and 5 × 30 mg/m(2) fludarabine, followed by matched sibling or unrelated SCT. Patients were evaluated for engraftment, adverse events, GVHD, and for non-relapse mortality, relapse incidence, overall and disease-free survival (DFS). All patients showed primary engraftment of neutrophils after a median of 20 days. Non-hematological adverse events grade III-IV in severity included mainly infections (59%) and gastrointestinal symptoms (7%). Acute GVHD grade II-IV occurred in 21% and extensive chronic GVHD occurred in 16% of the patients. After a median follow-up of 715 days, the 2-year overall and DFS estimates were 61% and 55%, respectively. The 2-year incidences of relapse and non-relapse mortality reached 34% and 11%, respectively. In summary, our data confirm promising safety and efficacy of the Treosulfan-based conditioning therapy in AML patients, ClinicalTrials.gov Identifier: NCT01063660.
Dietrich W Beelen - One of the best experts on this subject based on the ideXlab platform.
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Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome mc fludt 14 l a randomised non inferiority phase 3 trial
The Lancet Haematology, 2020Co-Authors: Dietrich W Beelen, Matthias Stelljes, Peter Remenyi, Evamaria Wagnerdrouet, Peter Dreger, Rudolf Trenschel, Christoph Groth, Tamas Masszi, Beate Hauptrock, Thomas LuftAbstract:Summary Background Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with Treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts Findings Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the Treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8–23·6) for patients treated with Treosulfan and 17·4 months (6·3–23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0–70·9) in the Treosulfan group and 50·4% (42·8–57·5) in the busulfan group (HR 0·65 [95% CI 0·47–0·90]; p Interpretation Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the Treosulfan–fludarabine regimen suggest its potential to become a standard preparative regimen in this population. Funding medac GmbH.
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Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial
'Elsevier BV', 2020Co-Authors: Dietrich W Beelen, Matthias Stelljes, Peter Remenyi, Peter Dreger, Rudolf Trenschel, Christoph Groth, Tamas Masszi, Beate Hauptrock, E.-. Wagner-drouet, Thomas LuftAbstract:Background: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with Treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 Treosulfan daily applied as a 2-h infusion for 3 days (days –4 to –2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days –4 and –3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days –6 to –2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008–002356–18) and ClinicalTrials.gov (NCT00822393). Findings: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the Treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8–23·6) for patients treated with Treosulfan and 17·4 months (6·3–23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0–70·9) in the Treosulfan group and 50·4% (42·8–57·5) in the busulfan group (HR 0·65 [95% CI 0·47–0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the Treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the Treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. Interpretation: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the Treosulfan–fludarabine regimen suggest its potential to become a standard preparative regimen in this population. Funding: medac GmbH
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final evaluation of a clinical phase iii trial comparing Treosulfan to busulfan based conditioning therapy prior to allogeneic hematopoietic stem cell transplantation of adult acute myeloid leukemia and myelodysplastic syndrome patients ineligible to standard myeloablative regimens
Biology of Blood and Marrow Transplantation, 2019Co-Authors: Dietrich W Beelen, Miroslaw Markiewicz, Matthias Stelljes, Peter Remenyi, Evamaria Wagnerdrouet, Peter Dreger, Wolfgang Bethge, Fabio Ciceri, Friedrich Stolzel, Christian JunghansAbstract:Background Allogeneic hematopoietic stem cell transplantation (HCT) remains a challenge in elderly and comorbid AML and MDS patients. This patient population is at increased risk for non-relapse mortality (NRM) when treated with standard myeloablative conditioning and was selected to compare a newly developed Treosulfan-based with a well-established reduced intensity busulfan-based preparative regimen in a prospective randomized clinical phase III trial. Methods Adult patients with AML in remission or MDS scheduled for HCT from matched related or unrelated donors, aged ≥50 years or with a comorbidity index (HCT-CI) of >2 were enrolled by a central stratified randomization procedure. Treatment arms consisted of intravenous (IV) Treosulfan (10 g/m²/day [d-4 to d-2]) or IV busulfan (3.2 mg/kg/day [d-4 to d-3]), both combined with IV fludarabine (30 mg/m²/day [d-6 to d-2]). The primary objective was to compare event-free survival (EFS) at two years with relapse/progression of disease, graft failure, or death reported as events. Secondary endpoints were safety evaluation (according to CTCAE v4.03), engraftment, chimerism, overall survival (OS), relapse/progression incidence (RI), NRM and acute or chronic GvHD. After a previously conducted confirmatory interim analysis (based on 476 patients), which resulted in early termination of patient accrual due to significant non-inferiority of Treosulfan treatment with improved EFS, NRM and OS (Beelen et al., ASH 2017), results of the final analysis of all 570 randomized patients including post surveillance data are provided here. Results Median age of the 551 patients (352 AML; 199 MDS) included in the full analysis set (268 Treosulfan; 283 busulfan) was 60 years (range: 31, 70). Frequencies of early adverse events (d-6 to d+28) and incidences of acute and chronic GvHD were largely comparable between the two regimens, while extensive chronic GvHD was numerically in favor of Treosulfan (19.7% vs. 26.7%; p=0.0750). Primary neutrophil recovery at day +28 was comparable, while the rate of complete donor-type chimerism (day +28) was higher after Treosulfan (93.2% vs. 83.3%; p Conclusions Final evaluation of this phase III trial substantiates the previous confirmatory analysis resulting in significantly improved survival after Treosulfan-based conditioning. Due to the reduction of NRM a major clinical benefit of the new Treosulfan conditioning regimen was demonstrated in the selected AML/MDS patient population.
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final results of a prospective randomized multicenter phase iii trial comparing Treosulfan fludarabine to reduced intensity conditioning with busulfan fludarabine prior to allogeneic hematopoietic stem cell transplantation in elderly or comorbid patients with acute myeloid leukemia or myelodysplastic syndrome
Blood, 2017Co-Authors: Dietrich W Beelen, Matthias Stelljes, Peter Remenyi, Evamaria Wagnerdrouet, Peter Dreger, Wolfgang Bethge, Fabio Ciceri, Rudolf Trenschel, Tamas Masszi, Friedrich StoelzelAbstract:Background Allogeneic hematopoietic stem cell transplantation (aHSCT) is a potentially curative treatment option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). A significant challenge in the management of elderly and comorbid patients with AML or MDS is the high transplantation-related mortality (TRM) associated with standard myeloablative preparative regimens preceding aHSCT. Reduced intensity conditioning (RIC) regimens are less toxic, but have often been associated with a higher relapse risk. Hence, there is a high unmet medical need for preparative regimens that reduce the risk of TRM without increasing the incidence of relapse. Patients and Methods In this prospective, randomized (1:1), group-sequential, open-label, multicenter, phase III trial, we enrolled patients with AML in complete remission (i.e. blast counts 2). The trial was designed to demonstrate at least non-inferiority in event-free survival (EFS) of intravenous (i.v.) Treosulfan (10 g/m²/day [d-4 to d-2]) to i.v. busulfan (3.2 mg/kg/day [d-4 to d-3]), both in combination with i.v. fludarabine (30 mg/m²/day [d-6 to d-2]), within 24 months after aHSCT. Events of EFS were defined as relapse of disease, graft failure, or death, whichever occurred first. Secondary objectives included overall survival (OS), cumulative incidence of relapse/progression, and transplant-related mortality (TRM). Engraftment as well as d+28 and d+100 incidence of complete donor-type chimerism (CC) were also evaluated. Further, occurrence of acute and chronic graft-versus-host disease as well as incidence and severity of adverse events between d-6 and d+28 were compared. Pre- and post-transplant immunosuppressive treatment was standardized in both arms and included ciclosporin and short-course methotrexate; anti-thymocyte globuline was used in case of matched unrelated donors (MUD). A confirmatory interim analysis as pre-specified in the protocol was conducted and the results were reviewed by an independent data monitoring committee (DMC) in Nov 2016. The DMC recommended to stop further patient accrual due to statistically proven non-inferiority of the Treosulfan/fludarabine regimen. All data presented here are derived from the 476 patients included in the confirmatory final analysis. Results Median patient age was 60 years with 94 % of patients aged 50 years or older; 64 % had AML and 76 % underwent MUD-aHSCT. HCT-CI scores were well-balanced between treatment regimens. Both regimens were comparable with regard to all safety evaluations between d-6 and d+28. Trilineage engraftment was also similar after both regimens, although the rate of CC at d+28 was significantly higher after Treosulfan. The EFS at 24 months after aHSCT was significantly non-inferior (64.0 % vs. 50.4 %), corresponding to a hazard ratio (HR) of 0.65 in favor of Treosulfan (p=0.0000164). The Kaplan-Meier estimate of OS at 24 months was also significantly superior for patients treated with the Treosulfan as compared to the busulfan regimen (72.5 % vs. 56.4 %; p=0.0082). Estimates of 24-months EFS and OS were consistent within relevant prognostic subgroups. Furthermore, the Treosulfan regimen significantly reduced 24-months TRM (11.3 % vs. 28.2 %; HR 0.54; p=0.0201) in this more vulnerable patient population. Notably, the cumulative incidence of relapse/progression at 24 months was comparable between the two regimens. Conclusions The results of this large randomized, multicenter, phase III trial clearly demonstrate at least non-inferiority of the Treosulfan/fludarabine regimen compared to the RIC busulfan/fludarabine regimen for elderly or comorbid AML and MDS patients undergoing aHSCT. Moreover, the clinical results were consistently in favor of the Treosulfan/fludarabine regimen regarding the most relevant endpoints of aHSCT and thus confirm a major clinical benefit of this regimen as compared to the RIC busulfan/fludarabine regimen in this selected patient population. (Funded by medac GmbH; MC-FludT.14/L, EudraCT no: 2008-002356-18; ClinicalTrials.gov identifier: NCT00822393) Disclosures Masszi: Janssen-Cilag: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. Dreger: medac GmbH, Wedel, Germany: Other: Travel grants. Bethge: medac GmbH, Wedel, Germany: Honoraria, Other: Travel grants. Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Stoelzel: medac: Other: Travel support. Michallet: medac GmbH, Wedel, Germany: Honoraria, Other: Travel grants. Markiewicz: medac GmbH, Wedel, Germany: Other: Travel grants.
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long term outcome after a Treosulfan based conditioning regimen for patients with acute myeloid leukemia a report from the acute leukemia working party of the european society for blood and marrow transplantation
Cancer, 2017Co-Authors: Arnon Nagler, Dietrich W Beelen, Fabio Ciceri, Myriam Labopin, Liisa Volin, Avichai Shimoni, Roberto Foa, Noel Milpied, Jacopo Peccatori, Emmanuelle PolgeAbstract:BACKGROUND Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for patients with acute myeloid leukemia (AML). However, post-HCT relapse and regimen-related toxicity remain significant barriers to long-term survival. In recent years, new conditioning regimens have been explored to improve transplantation outcomes in patients with AML. Treosulfan combines a potent immunosuppressive and antileukemic effect with a low toxicity profile. METHODS To investigate the role of Treosulfan-based conditioning, the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party performed a registry analysis of 520 adult patients with AML who received Treosulfan-based conditioning and underwent HCT between 2000 and 2012, including 225 patients in first complete remission, 107 in second or later complete remission, and 188 with active/advanced disease 188 (88 with primary refractory disease). The median patient age was 57 years (range, 20-73 years). Donors were human leukocyte antigen-identical siblings (n = 187), unrelated donors (n = 235), or mismatched related donors (n = 98). Conditioning regimens included Treosulfan (42 g/m2 [n = 396], 36 g/m2 [n = 109], or 30 g/ m2 [n = 15]) with fludarabine or alkylating agents followed by infusion of hematopoietic stem cells (bone marrow, n = 52; peripheral blood, n = 468). RESULTS At a median follow-up of 61 months, the 5-year overall survival, leukemia-free survival, relapse incidence, and nonrelapse mortality rates were 38%, 33%, 42%, and 25%, respectively. The incidence of grade II-IV acute and chronic graft-versus-host disease was 24% (grade III-V, 11%) and 38%, respectively. Only 11 patients (2%) developed veno-occlusive disease, with two deaths (0.4%) from veno-occlusive disease. CONCLUSIONS Treosulfan-based conditioning regimens provide an acceptable long-term survival with favorable nonrelapse mortality and a very low risk of veno-occlusive disease. Further studies are needed to optimize the Treosulfan-based conditioning regimen for patients with AML. Cancer 2017;123:2671-79. © 2017 American Cancer Society.
Jochen Casper - One of the best experts on this subject based on the ideXlab platform.
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Treosulfan fludarabine and cytarabine as conditioning before allogeneic hematopoietic stem cell transplantation
Blood, 2018Co-Authors: Inken Hilgendorf, Nils Winkelmann, Jochen J Frietsch, Friederike Hunstig, Ulf Schnetzke, Sebastian Scholl, Andreas Hochhaus, Jochen CasperAbstract:Background: The combination of Treosulfan witth fludarabine was successfully introduced into toxicity-reduced conditioning regimens for hematopoietic stem cell transplantation (HCT). However, the risk of post-HCT relapse remains of concern. Here we report for the first time on the results of an individual treatment approach with Treosulfan, fludarabin and cytarabine as conditioning for allogeneic HCT in patients with AML, MPN or MDS. Methods: 22 patients were treated with fludarabine 30 mg/m² given on day -6 to day -2, Treosulfan 14 g/m² administered on days -4 to day -2 and cytarabin 2g/m² given on days -6 and -5. GvHD-prophylaxis consisted of cyclosporine A and methotrexate or MMF. In addition, antithymocyte globulin was applied in case of an unrelated donor. One patient received bone marrow and the remaining patients received peripheral blood stem cells from matched related donors (9%), matched unrelated donors (73%) or mismatched unrelated donors (18%). All patients were considered to have high risk of relapse because of unfavourable cytogenetic features and/or insufficient or missing response to previous treatment. Three patients (14 %) with CML after blast crisis received the combination because of the reported high relapse rate (46%) after three-day scheduled conditioning with Treosulfan [1]. In addition, patients were considered to be ineligible for myeloablative standard conditioning because of multi-morbidity (n = 4; 18% with HCT-CI >2) and/or age >55 years (n = 14; 64%). Results: The median age of patients was 59 (35-68) years. Patients suffered from acute myeloid leukemia (n = 14, 64%), myeloproliferative neoplasia (n = 6, 27%) or myelodysplasic syndrome (n = 2, 9%). The conditioning regime was well tolerated and nearly all patients engrafted and achieved complete donor-type chimerism, except for one who died very early from sepsis. Another patient with underlying myelofibrosis suffered from secondary graft failure on day 100. Two patients developed aGVHD °III/ IV. None of the patients suffered from veno-occlusive disease or severe chronic GVHD. Overall survival and event-free survival at one year reached 60.2% and 59.6%, respectively. Six patients died from infectious disease, two from relapse and one patient from acute GVHD °IV. Conclusion: The combination of cytarabine with the established conditioning of Treosulfan and fludarabine is feasible in patients with high risk of relapse and ineligible for myeloablative standard conditioning. Holowiecki J, Giebel S, Wojnar J et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic 334 haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 335 2008; 142(2): 284-92. Disclosures Hilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Frietsch:Deutsche Krebshilfe: Research Funding. Scholl:Abbivie: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Carreras Foundation: Research Funding; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Jazz Pharma: Membership on an entity9s Board of Directors or advisory committees; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support. Hochhaus:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Casper:Medac: Membership on an entity9s Board of Directors or advisory committees, Other: travel grant, Research Funding.
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risk adapted Treosulfan based therapy with auto and allo sct for relapsed refractory aggressive nhl a prospective phase ii trial
Bone Marrow Transplantation, 2014Co-Authors: Michael Koenigsmann, Jochen Casper, Sebastian Theurich, Christoph Kahl, N Basara, Herbert G Sayer, Gerhard Behre, Maximilian Christopeit, Martin Mohren, Albrecht ReichleAbstract:Since the outcome of relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL) is highly variable, a risk-adapted treatment approach was evaluated. After two cycles of DHAP, patients received high-dose Treosulfan/etoposide/carboplatinum (TEC) and autologous stem cell rescue. After TEC, low-risk patients with late relapse (>1 year after first CR who achieved CR after DHAP received no further treatment. Patients with late relapse who achieved CR or PR only after TEC underwent a second cycle of TEC. High-risk patients with early relapse/refractory disease received Treosulfan/fludarabine followed by allogeneic transplantation. Rituximab was added in patients with B-cell lymphoma (86%). At entry, 36% of all 57 patients had refractory disease, 32% early and 32% late relapse. During DHAP treatment, progression occurred in 32% of patients. Of 33 patients who received TEC, 5 received second TEC and 15 allogeneic transplantation. Main toxicity after TEC was oral mucositis (CTC grades 3 and 4 in 50% and 13%, respectively). In total, 42% patients achieved CR. Median OS was 21.4 months for all patients and 32.6 for those who underwent allogeneic transplantation. International prognostic index (IPI) at study entry was highly discriminative at predicting OS (P<0.0001). Risk-adapted, Treosulfan-based therapy with auto- and allo-SCT is feasible. Long-term survival is possible with allogeneic transplantation.
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Treosulfan based conditioning prior to allogeneic stem cell transplantation hsct for acute myelogenous leukemia aml a retrospective analysis from the alwp of the ebmt
Blood, 2013Co-Authors: Myriam Labopin, Michael Hallek, Laimonas Griskevicius, Dietrich W Beelen, Liisa Volin, Avichai Shimoni, Slawomira Kyrczkrzemien, Kerstin Schufereckart, I W Blau, Jochen CasperAbstract:Allogeneic Hematopoietic SCT (HSCT) is a curative treatment for high risk AML. However, search continues for novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal anti-leukemia effect. Treosulfan (L-threitol-1, 4-bis-methanesulfonate; dihydroxybusulfan) was shown in preclinical studies to have a myeloablative effect on committed and non-committed stem cells. In addition, it has potent immunosuppressive characteristics, which makes it an attractive candidate for use in conditioning regimens before HSCT. We therefore preformed a retrospective analysis of the data for HSCT with Treosulfan based conditioning using the ALWP data set. We analyzed 795 HSCT in which Treosulfan was used in the pre-transplantation conditioning in adult patients with AML that were transplanted between Jan 2000 and Dec 2011. Out of the 795 AML patients 375 were transplanted in CR1, 197 in CR2 and 223 with active disease. 258 (32%) were transplanted from HLA matched sibling donors, 465 (58%) from unrelated donor and 72 (9%) from family mismatch donor. Mobilized peripheral blood stem cells (PBSC) were used as the graft source for 700 (89%), and bone marrow (BM) for 95 (12%) of the transplants. Conditioning was myeloablative (MAC) in 505 (64%), and reduced toxicity regiments (RTC) in 290 (36%) of the HSCT. Most frequently the Treosulfan based conditioning was combined with Fludarabine (Flu/Treo) and was used in 67% of the MAC and 86% of RTC. In 96 transplants Treosulfan was combined with Cyclophosphamid (Cy) and Etoposide (VP16). Other combinations included Melphalan (n=56), ARA-C (n=19) and Clofarabin (n=7). The median follow-up was 14 mo (1-116). Engraftment was achieved in 96% of the HSCT with no difference between MAC and RTC 95% and 97%, respectively. NRM were 17±4%, 21±2% and 33±3% for patients in CR1, CR2 and advance disease, respectively. Acute GVHD ≥ II occurred in 21% of the HSCT and was the same for MAC and RTC HSCT, while 2 year incidence of chronic GVHD (2y) was seen in 43±2% of HSCT (MAC-45%, RTC-38%). Incidences of relapse were 31±2%, 36±4% and 43±4% for patients transplanted in CR1, CR2 and advance disease, respectively. 2y OS and DFS were 61±3% and 51±3% for patients in CR1, 53±4% and 43±4% in patients with CR2 and 32±4% and 24±3% in patients with advanced disease. LFS was similar for MAC and RTC HSCT 60±5% and 50±8% for patients transplanted in CR1 from sibling donors while 43±6% and 50±6% for those transplanted from unrelated donors, respectively. Relapse rate were also similar 30±4% and 39±8% vs. 35±6% and 28±6% for transplants from siblings and unrelated donors, respectively. While NRM was 9±3% and 11±5% vs. 22±4% and 21±5% for HSCT from siblings vs. unrelated with MAC vs. RTC, respectively. In conclusion: Treosulfan mostly in combination with Fludarabin for conditioning prior to HSCT is associated with good engraftment, acceptable rates of NRM, GVHD, OS and LFS for patients in both CR1 and CR2. Further studies analyzing the use of Treosulfan in pre-HSCT conditioning regiments are in need. Disclosures: No relevant conflicts of interest to declare.
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allogeneic hematopoietic sct in patients with aml following Treosulfan fludarabine conditioning
Bone Marrow Transplantation, 2012Co-Authors: Jochen Casper, Rudolf Trenschel, Liisa Volin, Jerzy Holowiecki, Hannes Wandt, Kerstin Schaefereckart, Tapani Ruutu, H Einsele, Gernot Stuhler, Lutz UharekAbstract:An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on Treosulfan and fludarabine, has recently been identified. The safety and efficacy of this new conditioning regimen has been investigated prospectively in patients with AML. A total number of 75 patients with AML in CR were treated with 3 × 14 g/m(2) Treosulfan and 5 × 30 mg/m(2) fludarabine, followed by matched sibling or unrelated SCT. Patients were evaluated for engraftment, adverse events, GVHD, and for non-relapse mortality, relapse incidence, overall and disease-free survival (DFS). All patients showed primary engraftment of neutrophils after a median of 20 days. Non-hematological adverse events grade III-IV in severity included mainly infections (59%) and gastrointestinal symptoms (7%). Acute GVHD grade II-IV occurred in 21% and extensive chronic GVHD occurred in 16% of the patients. After a median follow-up of 715 days, the 2-year overall and DFS estimates were 61% and 55%, respectively. The 2-year incidences of relapse and non-relapse mortality reached 34% and 11%, respectively. In summary, our data confirm promising safety and efficacy of the Treosulfan-based conditioning therapy in AML patients, ClinicalTrials.gov Identifier: NCT01063660.
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allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies after dose escalated Treosulfan fludarabine conditioning
Journal of Clinical Oncology, 2010Co-Authors: Jochen Casper, Liisa Volin, Jerzy Holowiecki, Hannes Wandt, Tapani Ruutu, Wolfgang Knauf, Daniel Wolff, Igor Wolfgang Blau, Kerstin Schafereckart, Sebastian GiebelAbstract:Purpose Treosulfan was introduced recently as a conditioning agent for allogeneic blood stem-cell transplantation. The favorable nonhematologic toxicity profile at 3 × 10 g/m2 was the basis for dose escalation in this prospective, multicenter trial. Patients and Methods Fifty-six patients with various hematologic malignancies who were not eligible for standard conditioning were treated with one of three doses: 10 g/m2, 12 g/m2, or 14 g/m2 of intravenous Treosulfan, which was administered on days −6 to −4 combined with fludarabine 30 mg/m2 on days −6 to −2. Patients in complete remission (CR; 42%) or non-CR (58%) received grafts from matched related (47%) or matched unrelated (51%) donors; one patient had a mismatched related donor (2%). Results No engraftment failure occurred. Overall, extramedullary toxicity and the nonrelapse mortality rate at 2 years (20%) were low and did not increase with dose. Cumulative incidence of relapse/progression reached 31%. The overall survival and progression-free survival...
Eneida R Nemecek - One of the best experts on this subject based on the ideXlab platform.
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Treosulfan fludarabine and low dose total body irradiation for children and young adults with acute myeloid leukemia or myelodysplastic syndrome undergoing allogeneic hematopoietic cell transplantation prospective phase ii trial of the pediatric blood and marrow transplant consortium
Biology of Blood and Marrow Transplantation, 2018Co-Authors: Eneida R Nemecek, R A Hilger, Alexia Adams, Bronwen E Shaw, Deidre M Kiefer, Jennifer Lerademacher, John E Levine, Gregory A Yanik, Wing Leung, Juliean TalanoAbstract:Abstract This multicenter study evaluated a Treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based Treosulfan 10 g/m2/day (BSA ≤ .5 m2), 12 g/m2/day (BSA > .5 to 1.0 m2), or 14 g/m2/day (BSA > 1.0 m2) on days −6 to −4; fludarabine 30 mg/m2/day on days −6 to −2; and a single fraction of 200 cGy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based Treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based Treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.
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allogeneic hematopoietic cell transplantation using Treosulfan based conditioning for treatment of marrow failure disorders
Biology of Blood and Marrow Transplantation, 2017Co-Authors: Lauri Burroughs, Juliean Talano, Jennifer Domm, Akiko Shimamura, Kelsey Baker, Colleen Delaney, Haydar Frangoul, David A Margolis, Scott K Baker, Eneida R NemecekAbstract:Abstract Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other nonmalignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant-related mortality, particularly in patients with comorbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome, n = 3; Diamond Blackfan anemia, n = 4; GATA2 deficiency, n = 2; paroxysmal nocturnal hemoglobinuria, n = 4; and an undefined marrow failure disorder, n = 1) who underwent HCT on a prospective, phase II, multicenter clinical trial. Patients were given HLA-matched related (n = 2) or unrelated (n = 12) grafts after conditioning with Treosulfan (42 g/m2), fludarabine (150 mg/m2), ± thymoglobulin (n = 11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of Treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.
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Treosulfan based conditioning and hematopoietic cell transplantation for nonmalignant diseases a prospective multicenter trial
Biology of Blood and Marrow Transplantation, 2014Co-Authors: Eneida R Nemecek, Juliean Talano, Lauri Burroughs, Troy R Torgerson, Barry E Storer, Jennifer DommAbstract:Abstract Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of Treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with Treosulfan (total dose, 42 g/m2), fludarabine (total dose, 150 mg/m2), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of Treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.
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prospective phase ii multicenter study of conditioning with Treosulfan fludarabine and low dose 2 gy total body irradiation followed by hematopoietic cell transplantation from related or unrelated donors for acute myeloid leukemia and high risk myelodysplastic syndrome
Blood, 2012Co-Authors: Boglarka Gyurkocza, Joachim Baumgart, Eneida R Nemecek, Barry E Storer, Colleen Delaney, Jonathan A Gutman, Eileen Sickle, Merav Bar, Frederick R Appelbaum, Joachim H DeegAbstract:Abstract Abstract 963 Background: We showed previously that a transplant conditioning regimen of Treosulfan combined with fludarabine was associated with low non-relapse mortality (NRM) and a high probability of survival in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with low or intermediate risk cytogenetics (Nemecek et al, BBMT 2011). Relapse rates were high, however, in patients with high-risk cytogenetics, which resulted in a 2-year relapse-free survival of 39% in this group. Objective: The objective of the present study was to reduce the relapse incidence and improve overall survival (OS) in patients with high-risk AML or MDS by adding low-dose TBI (2 Gy) to the Treosulfan plus fludarabine regimen. Patients and methods: Ninety-six patients with AML (n=60) or MDS (n=36) were enrolled. Patients were 60 years of age or younger (median age: 50 years) and had high-risk MDS, unfavorable or intermediate-risk AML in first complete remission (CR) or any AML beyond first CR. Cytogenetic risk in AML was stratified using the Southwest Oncology Group criteria, while the World Health Organization-based Prognostic Scoring System was used in patients with MDS. Patients received intravenous (IV) Treosulfan, 14 g/m2/day on days -6 to -4, IV fludarabine 30 mg/m2/day on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of marrow (n=11) or peripheral blood stem cells (n=85) from related (n=27) or unrelated (n=69) donors. Donors were single HLA allele-level mismatched in 9 patients and HLA-matched at the allele level in 87 patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate (10 mg/m2 on days +1, +3, +6 and +11 post-HCT) and tacrolimus (days –1 to +180). Results: All evaluable patients engrafted. With a median follow-up of 12.8 (range, 0.2 – 34.7) months in surviving patients, the estimated 2-year progression-free survival and OS were 59% and 68%, respectively. The cumulative incidences of relapse or progression and NRM at 2 years were 30% and 11%, respectively ( Figure 1 ). The incidences of grade II (grades III-IV) acute and extensive chronic GVHD at 2 years were 48% (11%) and 40%, respectively. Relapse occurred in 39% of patients with AML and 18% of patients with MDS ( Figure 2 A). OS was 61% among patients with AML and 79% in patients with MDS ( Figure 2 B). In univariate analyses, cytogenetic risk status did not impact relapse for the entire cohort nor for patients with AML or MDS analyzed separately ( Figures 3 A and 3 B). As a result, 2-year OS rates were similar in patients with favorable/intermediate and unfavorable cytogenetic risk AML (64% and 57%, respectively) or in good/intermediate and poor risk MDS (88% and 71%, respectively). Patients with AML with minimal residual disease (MRD; n=10) or in refractory relapse (n=4) at the time of HCT, had higher relapse rates (87% vs. 25%) and lower OS (25% vs. 81%) at 2 years than patients in remission without MRD at the time of HCT. Conclusions: In summary, Treosulfan, in combination with fludarabine and low-dose TBI was an effective conditioning regimen for allogeneic HCT in patients with AML (in CR at the time of HCT) or MDS. Relapse and OS rates in patients with high-risk cytogenetics did not differ significantly from those in patients with low or intermediate risk karyotypes. The relapse rate was particularly low in patients with MDS, including those with high risk cytogenetics, and further trials with Treosulfan-based regimens are warranted. For patients with AML who have residual disease at HCT novel regimens need to be developed. The data suggest that in patients with AML high risk as defined by cytogenetics had a different impact on outcome than high risk as defined by other parameters, such as tumor burden. Download : Download high-res image (27KB) Download : Download full-size image Download : Download high-res image (21KB) Download : Download full-size image Download : Download high-res image (19KB) Download : Download full-size image Disclosures: Gyurkocza: medac GmbH, Hamburg, Germany: Research Funding. Off Label Use: Off-label usage of Treosulfan, fludarabine, methotrexate and tacrolimus will be discussed. Sickle: medac GmbH, Hamburg, Germany: Research Funding. Baumgart: medac GmbH, Hamburg, Germany: Employment. Deeg: medac GmbH, Hamburg, Germany: Research Funding.
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conditioning with Treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high risk hematologic malignancies
Biology of Blood and Marrow Transplantation, 2011Co-Authors: Eneida R Nemecek, R A Hilger, Katherine A Guthrie, Mohamed L Sorror, Brent L Wood, K Doney, Bart L ScottAbstract:In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n = 44), acute lymphoblastic leukemia (ALL; n=3), or myelodysplastic syndrome (MDS; n=13) were conditioned for allogeneic hematopoietic cell transplantation with a Treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous Treosulfan, 12 g/m2/day (n = 5) or 14 g/m2/day (n = 55) on days −6 to −4, and Flu (30 mg/m2/day) on days −6 to −2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a Treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare Treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.
