-
Blood Mar 2022Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT...
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.
Topics: Busulfan; Child, Preschool; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Tissue Donors; Transplantation Conditioning; Treatment Outcome; Wiskott-Aldrich Syndrome
PubMed: 35100336
DOI: 10.1182/blood.2021014687 -
Journal of Clinical Oncology : Official... Feb 2021Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.
PATIENTS AND METHODS
FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).
RESULTS
Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; < .0001) and 0.02 (95% CI, < 0.01 to 0.05; = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.
CONCLUSION
Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Chemoradiotherapy; Child; Child, Preschool; Equivalence Trials as Topic; Etoposide; Female; Follow-Up Studies; Humans; International Agencies; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Survival Rate; Thiotepa; Vidarabine; Whole-Body Irradiation
PubMed: 33332189
DOI: 10.1200/JCO.20.02529 -
American Journal of Hematology Aug 2022The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC)... (Randomized Controlled Trial)
Randomized Controlled Trial
Treosulfan compared with reduced-intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial.
The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.
Topics: Aged; Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 35617104
DOI: 10.1002/ajh.26620 -
Global & Regional Health Technology... 2022
PubMed: 36628308
DOI: 10.33393/grhta.2022.2412 -
Therapeutic Advances in Hematology 2021Inborn errors of immunity (IEI) are inherited disorders that lead to defects in the development and/or function of the immune system. The number of disorders that can be... (Review)
Review
Inborn errors of immunity (IEI) are inherited disorders that lead to defects in the development and/or function of the immune system. The number of disorders that can be treated by haematopoietic stem-cell transplantation (HSCT) has increased rapidly with the advent of next-generation sequencing. The methods used to transplant children with IEI have improved dramatically over the last 20 years. The introduction of reduced-toxicity conditioning is an important factor in the improved outcome of HSCT. Treosulfan has myeloablative and immunosuppressive properties, enabling engraftment with less toxicity than traditionally used doses of busulfan. It is firmly incorporated into the conditioning guidelines of the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation. Unlike busulfan, pharmacokinetically guided dosing of treosulfan is not part of routine practice, but data are emerging which indicate that further improvements in outcome may be possible, particularly in infants who have a decreased clearance of treosulfan. It is likely that individualized dosing, not just of treosulfan, but of all agents used in conditioning regimens, will be developed and implemented in the future. This will lead to a reduction in unwanted variability in drug exposure, leading to more predictable and adjustable exposure, and improved outcome of HSCT, with fewer late adverse effects and improved quality of life. Such conditioning regimens can be used as the basis to study the need for additional agents in certain disorders which are difficult to engraft or require high levels of donor chimerism, the dosing of individual cellular components within grafts, and effects of adjuvant cellular or immunotherapy post-transplant. This review documents the establishment of treosulfan worldwide, as a safe and effective agent for conditioning children with IEI prior to HSCT.
PubMed: 34094045
DOI: 10.1177/20406207211013985 -
Cancers May 2023(1) Background: Upfront treatment consolidation with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has relevantly contributed to...
(1) Background: Upfront treatment consolidation with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has relevantly contributed to achieving durable remissions following induction treatment in multiple myeloma (MM) patients. The optimization of HDCT regimens can, therefore, essentially contribute to improving the depth and duration of tumor remissions. To date, melphalan at 200 mg/m is the standard HDCT regimen for fit MM patients. In our previous work, we showed promising efficacy and safety results for treosulfan (14 g/m) and melphalan (200 mg/m) (TreoMel) in acute myeloid leukemia (AML) patients receiving ASCT. Based on these data, TreoMel became the standard of care for fit MM patients at our institution. (2) Methods: We identified 115 consecutive MM patients who underwent consolidation with TreoMel between 01/2020 and 08/2022 at the University Hospital of Bern. We analyzed the safety and efficacy data, as well as the treosulfan pharmacokinetics, correlating them with tumor responses. (3) Results: A complete response (CR) rate of 84% was achieved, which is comparable to the CR rate reported for the quadruplet combination. The median PFS was 30 months (95% CI: 20.4-not reached), and the 31-month OS rate was 83%. The median area under the curve (AUC) for treosulfan was 952.5 mg*h/L (range: 527.4-1781.4), and the median peak level was 332.3 mg/L (range: 168-554). The treosulfan pharmacokinetics showed no significant correlation with MM responses after HDCT and ASCT. However, female patients had a significantly higher AUC ( = 0.007) and peak value ( = 0.001), and the higher values were associated with longer hospitalizations. (4) Conclusions: Treatment consolidation with TreoMel HDCT demonstrated a promising efficacy and safety profile in our cohort of MM patients and deserves further investigation in prospective studies.
PubMed: 37345036
DOI: 10.3390/cancers15102699 -
Clinical Pharmacokinetics Oct 2018Treosulfan is a prodrug that undergoes a highly pH- and temperature-dependent nonenzymatic conversion to the monoepoxide {(2S,3S)-1,2-epoxy-3,4-butanediol... (Review)
Review
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.
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.
Topics: Adult; Animals; Busulfan; Child; Hematopoietic Stem Cell Transplantation; Humans; Inactivation, Metabolic; Precision Medicine; Prodrugs; Tissue Distribution; Transplantation Conditioning
PubMed: 29557088
DOI: 10.1007/s40262-018-0647-4 -
Clinical Pharmacology and Therapeutics Jan 2024A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved...
A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.
Topics: Humans; beta-Thalassemia; Busulfan; Hematopoietic Stem Cell Transplantation; Thiotepa; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37846495
DOI: 10.1002/cpt.3078 -
Biology of Blood and Marrow... Feb 2020Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before...
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m (days -6 to -2) and treosulfan 14 g/m (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (n = 22) or a well-matched unrelated donor (n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.
Topics: Busulfan; Clofarabine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Middle Aged; Transplantation Conditioning
PubMed: 31605823
DOI: 10.1016/j.bbmt.2019.09.032 -
Transplantation and Cellular Therapy Feb 2022Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and... (Observational Study)
Observational Study
Impact of Treosulfan Exposure on Early and Long-Term Clinical Outcomes in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Prospective Multicenter Study.
Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationships between systemic treosulfan exposure and early and long-term clinical outcomes in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases remain unclear. In this a multicenter, prospective observational study, we assessed the association between treosulfan exposure and early and, in particular, long-term clinical outcomes. Our study cohort comprised 110 pediatric patients with nonmalignant diseases who underwent HSCT between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected, and treosulfan area under the receiver operating characteristic curve (AUC) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationships between treosulfan exposure and overall survival (OS) and event-free survival (EFS). The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days was evaluated using a multivariable logistic regression analysis. In the overall cohort, OS and EFS at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children age <2 years. The occurrence of grade II-IV acute graft-versus-host disease, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.26-13.68; P = .02) and all-grade mucositis (OR, 4.43; 95% CI, 1.43-15.50; P = .02), but not grade ≥2 mucositis (OR, 1.51; 95% CI, 0.52 to 4.58; P = .46) was related to high treosulfan exposure (>1750 mg*h/L). Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with nonmalignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring, thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether deescalation of treosulfan doses is possible to minimize early and long-term toxicity without compromising efficacy.
Topics: Busulfan; Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Infant; Mucositis; Prospective Studies; Transplantation Conditioning
PubMed: 34607071
DOI: 10.1016/j.jtct.2021.09.018