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Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetics of Cyclophosphamide and Thiotepa in a Conventional Fractionated High-dose Regimen Compared With a Novel Simplified Unfractionated Regimen
    Therapeutic drug monitoring, 2009
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    High-dose alkylating chemotherapy with cyclophosphamide (4000 or 6000 mg/m2) and Thiotepa (320 or 480 mg/m2) has commonly been administered in a fractionated regimen over 4 days. A simplified unfractionated regimen would be preferable, especially because cyclophosphamide and Thiotepa have been shown to influence the metabolism of each other. However, altering a dose regimen can have a profound effect on the pharmacokinetics of the compounds involved. The aim of this study was to investigate the effect of altering the fractionated administration schedule of the CTC regimen on cyclophosphamide and Thiotepa pharmacokinetics. Plasma samples were collected from 124 patients who received a fractionated tiny CTC or CTC regimen of cyclophosphamide (1000 or 1500 mg m(-2) d(-1)), Thiotepa (40 or 60 mg/m2 twice daily), and carboplatin (267 or 400 mg m(-2) day(-1)) for 4 days, and 16 patients who received an unfractionated mini CTC regimen of cyclophosphamide (3000 mg/m2 at day 1), carboplatin (400 mg/m2 at days 1 and 2), and Thiotepa (250 mg/m2 at day 2). Plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined using high-performance liquid chromatography coupled with tandem mass spectrometric detection; plasma concentrations of Thiotepa and tepa were determined using gas chromatography. Pharmacokinetics of cyclophosphamide and Thiotepa were assessed using nonlinear mixed-effect modeling. The study showed that alteration of a fractionated high-dose regimen into a simplified unfractionated regimen resulted in saturation of Thiotepa elimination, with a Vmax of 212 (+/-58) micromol/h and a Km of 13.7 (+/-5.9) microM. This resulted in an increased dose-corrected exposure to Thiotepa (13%) and decreased dose-corrected exposure to its metabolite tepa (21%). Elimination of cyclophosphamide was not shown to be saturable. Dose-corrected exposures to cyclophosphamide and its active metabolite 4-hydroxycyclophosphamide were comparable in both regimens. Because the simplified unfractionated mini CTC regimen was more patient-friendly and because overall dose-corrected exposures to cyclophosphamide and Thiotepa were not affected to a relevant extent, our data suggest that this unfractionated regimen can be used safely in future studies.

  • polymorphisms of drug metabolizing enzymes gst cyp2b6 and cyp3a affect the pharmacokinetics of Thiotepa and tepa
    British Journal of Clinical Pharmacology, 2009
    Co-Authors: Corine Ekhart, Valerie D. Doodeman, Paul H.m. Smits, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    AIMS Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of Thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of Thiotepa and tepa.

  • Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of Thiotepa and tepa
    British journal of clinical pharmacology, 2008
    Co-Authors: Corine Ekhart, Valerie D. Doodeman, Paul H.m. Smits, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    AIMS Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of Thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of Thiotepa and tepa.

  • population pharmacokinetics of Thiotepa and its active metabolite tepa in patients undergoing high dose chemotherapy
    British Journal of Clinical Pharmacology, 2008
    Co-Authors: Alwin D. R. Huitema, Sjoerd Rodenhuis, Matthijs M. Tibben, Ron A. A. Mathôt, Jan H.m. Schellens, Jos H. Beijnen
    Abstract:

    Aims  To study the population pharmacokinetics of Thiotepa and its main metabolite TEPA in patients receiving high-dose chemotherapy consisting of Thiotepa (80–120 mg m−2 day−1), cyclophosphamide (1000–1500 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) for 4 days. Methods  Thiotepa and TEPA kinetic data were processed with a two-compartment model using the nonlinear mixed effect modelling program NONMEM. Interindividual variability (IIV), interoccasion variability (IOV) and residual variability in the pharmacokinetics were estimated. The influence of patient characteristics on the pharmacokinetics was also determined. Results  A total number of 40 patients receiving 65 courses of chemotherapy was included. Clearance of Thiotepa (CL) was 34 l h−1 with an IIV and IOV of 18 and 11%, respectively. The volume of distribution of Thiotepa was 47 l (IIV = 7.5%; IOV = 19%). The fraction of Thiotepa converted to TEPA divided by the volume of distribution of TEPA was 0.030 l−1 (IIV = 39%; IOV = 32%) and the elimination rate constant of TEPA was 0.64 h−1 (IIV = 27%; IOV = 32%). CL of Thiotepa was correlated with alkaline phosphatase and serum albumin. The volume of distribution of Thiotepa and the elimination rate constant of TEPA were correlated with total protein levels and body weight, respectively. Conclusions  A model for the description of the pharmacokinetics of Thiotepa and TEPA was developed. Factors involved in the interpatient variability of Thiotepa and TEPA pharmacokinetics were identified. Since, IOV of both Thiotepa and TEPA was equal to or smaller than IIV, therapeutic drug monitoring based on data of previous courses may be meaningful using this population model.

  • Altered cyclophosphamide and Thiotepa pharmacokinetics in a patient with moderate renal insufficiency.
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, J. Martijn Kerst, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    Purpose We report a patient with renal insuYciency (creatinine clearance, CLcr = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m 2 day i1 ), Thiotepa (120 mg/m 2 day i1 ) and carboplatin (AUC = 5 mg min/mL day i1 ) for four consecutive days. Methods Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, Thiotepa, its main metabolite tepa and carboplatin were determined. Results Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, Thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4-hydroxycyclophosphamide increased 11%. Conclusion These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to Thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering Thiotepa to patients with renal insuYciency.

Alwin D. R. Huitema - One of the best experts on this subject based on the ideXlab platform.

  • polymorphisms of drug metabolizing enzymes gst cyp2b6 and cyp3a affect the pharmacokinetics of Thiotepa and tepa
    British Journal of Clinical Pharmacology, 2009
    Co-Authors: Corine Ekhart, Valerie D. Doodeman, Paul H.m. Smits, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    AIMS Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of Thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of Thiotepa and tepa.

  • Pharmacokinetics of Cyclophosphamide and Thiotepa in a Conventional Fractionated High-dose Regimen Compared With a Novel Simplified Unfractionated Regimen
    Therapeutic drug monitoring, 2009
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    High-dose alkylating chemotherapy with cyclophosphamide (4000 or 6000 mg/m2) and Thiotepa (320 or 480 mg/m2) has commonly been administered in a fractionated regimen over 4 days. A simplified unfractionated regimen would be preferable, especially because cyclophosphamide and Thiotepa have been shown to influence the metabolism of each other. However, altering a dose regimen can have a profound effect on the pharmacokinetics of the compounds involved. The aim of this study was to investigate the effect of altering the fractionated administration schedule of the CTC regimen on cyclophosphamide and Thiotepa pharmacokinetics. Plasma samples were collected from 124 patients who received a fractionated tiny CTC or CTC regimen of cyclophosphamide (1000 or 1500 mg m(-2) d(-1)), Thiotepa (40 or 60 mg/m2 twice daily), and carboplatin (267 or 400 mg m(-2) day(-1)) for 4 days, and 16 patients who received an unfractionated mini CTC regimen of cyclophosphamide (3000 mg/m2 at day 1), carboplatin (400 mg/m2 at days 1 and 2), and Thiotepa (250 mg/m2 at day 2). Plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined using high-performance liquid chromatography coupled with tandem mass spectrometric detection; plasma concentrations of Thiotepa and tepa were determined using gas chromatography. Pharmacokinetics of cyclophosphamide and Thiotepa were assessed using nonlinear mixed-effect modeling. The study showed that alteration of a fractionated high-dose regimen into a simplified unfractionated regimen resulted in saturation of Thiotepa elimination, with a Vmax of 212 (+/-58) micromol/h and a Km of 13.7 (+/-5.9) microM. This resulted in an increased dose-corrected exposure to Thiotepa (13%) and decreased dose-corrected exposure to its metabolite tepa (21%). Elimination of cyclophosphamide was not shown to be saturable. Dose-corrected exposures to cyclophosphamide and its active metabolite 4-hydroxycyclophosphamide were comparable in both regimens. Because the simplified unfractionated mini CTC regimen was more patient-friendly and because overall dose-corrected exposures to cyclophosphamide and Thiotepa were not affected to a relevant extent, our data suggest that this unfractionated regimen can be used safely in future studies.

  • Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of Thiotepa and tepa
    British journal of clinical pharmacology, 2008
    Co-Authors: Corine Ekhart, Valerie D. Doodeman, Paul H.m. Smits, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    AIMS Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of Thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of Thiotepa and tepa.

  • population pharmacokinetics of Thiotepa and its active metabolite tepa in patients undergoing high dose chemotherapy
    British Journal of Clinical Pharmacology, 2008
    Co-Authors: Alwin D. R. Huitema, Sjoerd Rodenhuis, Matthijs M. Tibben, Ron A. A. Mathôt, Jan H.m. Schellens, Jos H. Beijnen
    Abstract:

    Aims  To study the population pharmacokinetics of Thiotepa and its main metabolite TEPA in patients receiving high-dose chemotherapy consisting of Thiotepa (80–120 mg m−2 day−1), cyclophosphamide (1000–1500 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) for 4 days. Methods  Thiotepa and TEPA kinetic data were processed with a two-compartment model using the nonlinear mixed effect modelling program NONMEM. Interindividual variability (IIV), interoccasion variability (IOV) and residual variability in the pharmacokinetics were estimated. The influence of patient characteristics on the pharmacokinetics was also determined. Results  A total number of 40 patients receiving 65 courses of chemotherapy was included. Clearance of Thiotepa (CL) was 34 l h−1 with an IIV and IOV of 18 and 11%, respectively. The volume of distribution of Thiotepa was 47 l (IIV = 7.5%; IOV = 19%). The fraction of Thiotepa converted to TEPA divided by the volume of distribution of TEPA was 0.030 l−1 (IIV = 39%; IOV = 32%) and the elimination rate constant of TEPA was 0.64 h−1 (IIV = 27%; IOV = 32%). CL of Thiotepa was correlated with alkaline phosphatase and serum albumin. The volume of distribution of Thiotepa and the elimination rate constant of TEPA were correlated with total protein levels and body weight, respectively. Conclusions  A model for the description of the pharmacokinetics of Thiotepa and TEPA was developed. Factors involved in the interpatient variability of Thiotepa and TEPA pharmacokinetics were identified. Since, IOV of both Thiotepa and TEPA was equal to or smaller than IIV, therapeutic drug monitoring based on data of previous courses may be meaningful using this population model.

  • Altered cyclophosphamide and Thiotepa pharmacokinetics in a patient with moderate renal insufficiency.
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, J. Martijn Kerst, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    Purpose We report a patient with renal insuYciency (creatinine clearance, CLcr = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m 2 day i1 ), Thiotepa (120 mg/m 2 day i1 ) and carboplatin (AUC = 5 mg min/mL day i1 ) for four consecutive days. Methods Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, Thiotepa, its main metabolite tepa and carboplatin were determined. Results Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, Thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4-hydroxycyclophosphamide increased 11%. Conclusion These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to Thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering Thiotepa to patients with renal insuYciency.

Sjoerd Rodenhuis - One of the best experts on this subject based on the ideXlab platform.

  • polymorphisms of drug metabolizing enzymes gst cyp2b6 and cyp3a affect the pharmacokinetics of Thiotepa and tepa
    British Journal of Clinical Pharmacology, 2009
    Co-Authors: Corine Ekhart, Valerie D. Doodeman, Paul H.m. Smits, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    AIMS Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of Thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of Thiotepa and tepa.

  • Pharmacokinetics of Cyclophosphamide and Thiotepa in a Conventional Fractionated High-dose Regimen Compared With a Novel Simplified Unfractionated Regimen
    Therapeutic drug monitoring, 2009
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    High-dose alkylating chemotherapy with cyclophosphamide (4000 or 6000 mg/m2) and Thiotepa (320 or 480 mg/m2) has commonly been administered in a fractionated regimen over 4 days. A simplified unfractionated regimen would be preferable, especially because cyclophosphamide and Thiotepa have been shown to influence the metabolism of each other. However, altering a dose regimen can have a profound effect on the pharmacokinetics of the compounds involved. The aim of this study was to investigate the effect of altering the fractionated administration schedule of the CTC regimen on cyclophosphamide and Thiotepa pharmacokinetics. Plasma samples were collected from 124 patients who received a fractionated tiny CTC or CTC regimen of cyclophosphamide (1000 or 1500 mg m(-2) d(-1)), Thiotepa (40 or 60 mg/m2 twice daily), and carboplatin (267 or 400 mg m(-2) day(-1)) for 4 days, and 16 patients who received an unfractionated mini CTC regimen of cyclophosphamide (3000 mg/m2 at day 1), carboplatin (400 mg/m2 at days 1 and 2), and Thiotepa (250 mg/m2 at day 2). Plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined using high-performance liquid chromatography coupled with tandem mass spectrometric detection; plasma concentrations of Thiotepa and tepa were determined using gas chromatography. Pharmacokinetics of cyclophosphamide and Thiotepa were assessed using nonlinear mixed-effect modeling. The study showed that alteration of a fractionated high-dose regimen into a simplified unfractionated regimen resulted in saturation of Thiotepa elimination, with a Vmax of 212 (+/-58) micromol/h and a Km of 13.7 (+/-5.9) microM. This resulted in an increased dose-corrected exposure to Thiotepa (13%) and decreased dose-corrected exposure to its metabolite tepa (21%). Elimination of cyclophosphamide was not shown to be saturable. Dose-corrected exposures to cyclophosphamide and its active metabolite 4-hydroxycyclophosphamide were comparable in both regimens. Because the simplified unfractionated mini CTC regimen was more patient-friendly and because overall dose-corrected exposures to cyclophosphamide and Thiotepa were not affected to a relevant extent, our data suggest that this unfractionated regimen can be used safely in future studies.

  • Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of Thiotepa and tepa
    British journal of clinical pharmacology, 2008
    Co-Authors: Corine Ekhart, Valerie D. Doodeman, Paul H.m. Smits, Sjoerd Rodenhuis, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    AIMS Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of Thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of Thiotepa and tepa.

  • population pharmacokinetics of Thiotepa and its active metabolite tepa in patients undergoing high dose chemotherapy
    British Journal of Clinical Pharmacology, 2008
    Co-Authors: Alwin D. R. Huitema, Sjoerd Rodenhuis, Matthijs M. Tibben, Ron A. A. Mathôt, Jan H.m. Schellens, Jos H. Beijnen
    Abstract:

    Aims  To study the population pharmacokinetics of Thiotepa and its main metabolite TEPA in patients receiving high-dose chemotherapy consisting of Thiotepa (80–120 mg m−2 day−1), cyclophosphamide (1000–1500 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) for 4 days. Methods  Thiotepa and TEPA kinetic data were processed with a two-compartment model using the nonlinear mixed effect modelling program NONMEM. Interindividual variability (IIV), interoccasion variability (IOV) and residual variability in the pharmacokinetics were estimated. The influence of patient characteristics on the pharmacokinetics was also determined. Results  A total number of 40 patients receiving 65 courses of chemotherapy was included. Clearance of Thiotepa (CL) was 34 l h−1 with an IIV and IOV of 18 and 11%, respectively. The volume of distribution of Thiotepa was 47 l (IIV = 7.5%; IOV = 19%). The fraction of Thiotepa converted to TEPA divided by the volume of distribution of TEPA was 0.030 l−1 (IIV = 39%; IOV = 32%) and the elimination rate constant of TEPA was 0.64 h−1 (IIV = 27%; IOV = 32%). CL of Thiotepa was correlated with alkaline phosphatase and serum albumin. The volume of distribution of Thiotepa and the elimination rate constant of TEPA were correlated with total protein levels and body weight, respectively. Conclusions  A model for the description of the pharmacokinetics of Thiotepa and TEPA was developed. Factors involved in the interpatient variability of Thiotepa and TEPA pharmacokinetics were identified. Since, IOV of both Thiotepa and TEPA was equal to or smaller than IIV, therapeutic drug monitoring based on data of previous courses may be meaningful using this population model.

  • Altered cyclophosphamide and Thiotepa pharmacokinetics in a patient with moderate renal insufficiency.
    Cancer Chemotherapy and Pharmacology, 2008
    Co-Authors: Corine Ekhart, Sjoerd Rodenhuis, J. Martijn Kerst, Jos H. Beijnen, Alwin D. R. Huitema
    Abstract:

    Purpose We report a patient with renal insuYciency (creatinine clearance, CLcr = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m 2 day i1 ), Thiotepa (120 mg/m 2 day i1 ) and carboplatin (AUC = 5 mg min/mL day i1 ) for four consecutive days. Methods Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, Thiotepa, its main metabolite tepa and carboplatin were determined. Results Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, Thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4-hydroxycyclophosphamide increased 11%. Conclusion These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to Thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering Thiotepa to patients with renal insuYciency.

Myriam Labopin - One of the best experts on this subject based on the ideXlab platform.

  • effect of the Thiotepa dose in the tbf conditioning regimen in patients undergoing allogeneic stem cell transplantation for acute myeloid leukemia in complete remission a report from the ebmt acute leukemia working party
    Clinical Lymphoma Myeloma & Leukemia, 2020
    Co-Authors: Jean Elcheikh, Myriam Labopin, Farouk Alchami, Ali Bazarbachi, Emanuele Angelucci, Stella Santarone, Francesca Bonifazi, Angelo Michele Carella, Luca Castagna, Benedetto Bruno
    Abstract:

    Abstract Background Allogeneic stem cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia (AML) after achieving complete remission (CR). The aim of this study is to evaluate the optimal dose of Thiotepa, administered as part of the Thiotepa-busulfan-fludarabine (TBF) conditioning regimen for allogeneic stem cell transplantation in adults with AML in CR. Patients and Methods In a retrospective multicenter analysis, we identified 240 patients allotransplanted from matched related or unrelated donors or T replete haplo-identical donors. We compared the transplantation outcomes of patients who received 5 mg/kg Thiotepa and 2 days of intravenous busulfan at 6.4 mg/kg (T1B2F) versus those who received 10 mg/kg Thiotepa with 2 days of intravenous busulfan at 6.4 mg/kg (T2B2F). The median follow-up was 20 months. Results On univariate analysis, the incidence of acute graft versus host disease (GVHD) grade II to IV was significantly lower in the T1B2F group (19%) versus 32% in the T2B2F group (P = .029). This result was confirmed on multivariate analysis; acute GVHD was higher for patients receiving T2B2F (hazard ratio, 2.22; P = .024). No significant change in non-relapse mortality, progression-free survival, or overall survival was observed between the 2 groups. Conclusion T2B2F is associated with a higher incidence of acute GVHD compared with T1B2F. These results suggest that a lower dose-intensity of Thiotepa and busulfan in the TBF regimen may yield better results in patients with AML in CR.

  • Thiotepa based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia a matched pair analysis from the acute leukemia working party of the european socie
    American Journal of Hematology, 2017
    Co-Authors: Sandra Eder, Myriam Labopin, William Arcese, Dietrich W Beelen, Jonathan Canaani, Eric Beohou, Jaime Sanz, Juergen Finke, Agostino Cortelezzi, Jakob Passweg
    Abstract:

    The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long-term toxicity for patients conditioned with this regimen. Thiotepa-based conditioning is an emerging radiation-free regimen with recent publications indicative of comparable clinical outcomes to TBI-based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received Thiotepa-based conditioning (n = 180) with those receiving Cy/TBI conditioning (n = 540). The 2-year leukemia-free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for Thiotepa [95% confidence interval (CI): 26.4-42.8] versus 39% for Cy/TBI (95% CI: 34.8-44.5] (P = .33) and 46.5% [95% CI: 38.6-56.1] versus 48.8% [95% CI: 44.2-54] (P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for Thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07-2.95; P = .03) which did not affect OS. Our results indicate that Thiotepa-based conditioning may not be inferior to Cy/TBI for adult patients with ALL.

  • Thiotepa based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia a matched pair analysis from the acute leukemia working party of the european socie
    American Journal of Hematology, 2017
    Co-Authors: Sandra Eder, Myriam Labopin, William Arcese, Reuven Or, Jonathan Canaani, Eric Beohou, Jaime Sanz, Juergen Finke, Agostino Cortelezzi, Dietrich W Beelen
    Abstract:

    The optimal conditioning regimen to employ before hematopoieitic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while Cy/TBI is the most commonly used myeloablative regimen, there are concerns regarding long term toxicity for patients conditioned with this regimen. Thiotepa based conditioning is an emerging radiation free regimen with recent publications indicative of comparable clinical outcomes to TBI based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received Thiotepa-based conditioning (n=180) with those receiving Cy/TBI conditioning (n=540). The 2 year leukemia-free survival and overall survival rates of both conditioning regimens were comparable, 33% for Thiotepa [95% confidence interval (CI): 26.4 - 42.8] versus 39% for Cy/TBI (95% CI: 34.8 - 44.5] (P=0.33) and 46.5% [95% CI: 38.6 - 56.1] versus 48.8% [95% CI: 44.2 - 54] (P=0.9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for Thiotepa conditioning compared to Cy/TBI (HR=1.78, 95% CI, 1.07-2.95; P=0.03) which did not affect overall survival. Our results indicate that Thiotepa based conditioning may not be inferior to Cy/TBI for adult ALL patients. This article is protected by copyright. All rights reserved.

  • Thiotepa based versus total body irradiation based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission a retrospective analysis from the acute leukemia working party of the
    European Journal of Haematology, 2016
    Co-Authors: Sandra Eder, Myriam Labopin, William Arcese, Reuven Or, Ignazio Majolino, Andrea Bacigalupo, Gennaro De Rosa, Liisa Volin, Dietrich W Beelen, Hendrik Veelken
    Abstract:

    Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a Thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after Thiotepa-containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for Thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (Thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (Thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the Thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including Thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting.

  • Thiotepa based vs tbi based myeloablative conditioning prior to allogeneic stem cell transplantation hsct for acute myeloid leukemia aml in first complete remission cr1 a retrospective analysis from the alwp of the ebmt
    Blood, 2013
    Co-Authors: Sandra Eder, Myriam Labopin, William Arcese, Ignazio Majolino, Andrea Bacigalupo, Gennaro De Rosa, Liisa Volin, Dietrich W Beelen, Hendrik Veelken, Nicolaas Schaap
    Abstract:

    Background Thiotepa (N,N'N'-triethylenethiophosphoramide), which is an alkylating compound, has an antineoplastic activity and has been used in oncology (e.g. breast-, ovarian- and bladder cancer) for decades. In the recent years, and because of its good safety profile, Thiotepa has been increasingly used both for autologous and allogeneic hematopoietic stem cell transplantation conditioning. Interestingly, this agent has a very active myeloablative activity but also its mechanism of action can mimick the effect of radiation. With this background, the aim of this study was to compare outcome of patients receiving a myeloablative conditioning consisting of either high dose TBI or Thiotepa-based chemotherapy. Methods Inclusion criteria were adults with AML, first allograft in CR1 from an HLA-matched sibling donor (MSD) or an unrelated donor (UD) between 2000 and 2011 and myeloablative conditioning. We first compared patient and transplant characteristics between the two types of conditioning, and then performed a pair-matched analysis. Results The number of patients was 2833 in the TBI group and 102 in the Thiotepa group. Patients who received Thiotepa were older (49y vs 40y, p<10-4), transplanted more recently (2009 vs 2006, p<10-4) and later after the diagnosis of AML (183 days vs 143 days, p<10-4). The percentage of secondary AML was also higher in the Thiotepa group (14% vs 6%; p=0.0002). There was no difference regarding patient/donor gender, type of donor and source of stem cells. In this cohort, we were able to match 96 patients who received Thiotepa with 185 patients who received high dose TBI. Matching factors were: age at transplantation (10 years classes), year of transplant, interval from diagnosis to transplant (less or more than median day), secondary AML and type of donor (MSD/UD). The characteristics of the 2 groups are summarized in [Table 1][1]. View this table: Table 1 Matched Analysis: 96 Thiotepa and 185 TBI (7 with 1 control and 89 with 2 controls) Median dose of TBI was 12 Gy (range, 8-16). In this group, TBI was combined with Cyclophosphamide (84% of cases), Fludarabine (14%) or other compounds (2%). On the other hand, Thiotepa was administered with Cyclophosphamide (45%), Fludarabine (54%) with/without Busulfan and other combinations (1%). Engraftment occurred in 96% of patients using Thiotepa-based conditioning versus 99% after TBI (p=0.11). The interval from transplant to neutrophils count>500/µL was 16 days (range, 9-42) versus 17 days (range, 9-81) in the 2 groups, respectively (p=0.23). Acute GvHD grade II+ was observed in 25 patients (27%) after Thiotepa-containing regimen versus 42 patients (25%) after TBI (p=0.78). 2-years cumulative incidence of chronic GVHD was 48±4% and 41±6% in the 2 groups, respectively (p=0.15). The 2-year cumulative incidences of non-relapse mortality (NRM) was 21±4% versus 27±4% (p=0.57) and relapse incidence (RI) was 18±4% versus 21±3% (p=0.71) in the Thiopeta and TBI groups, respectively. The 2-year leukemia-free survival (LFS) and overall survival (OS) were 61±5% and 64±5% in the Thiotepa group versus 51±4% and 52±4% in the TBI group (LFS: p=0.40; OS: p=0.25). Conclusion This pair-matched analysis suggests that a Thiotepa-based myeloablative conditioning regimen prior to allogeneic HSCT in AML in first CR, can allow achieving similar results to high-dose TBI-based myeloablative conditioning. Also, given the deleterious long term side effects of TBI, it is likely that a Thiotepa-based myeloablative conditioning would represent an attractive and valid alternative to TBI. Prospective trials are currently planned in this setting. Disclosures: Bacigalupo: ADIENNE : Speakers Bureau. Mohty: Riemser : Research Funding. [1]: #T1

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  • Thiotepa based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia a matched pair analysis from the acute leukemia working party of the european socie
    American Journal of Hematology, 2017
    Co-Authors: Sandra Eder, Myriam Labopin, William Arcese, Dietrich W Beelen, Jonathan Canaani, Eric Beohou, Jaime Sanz, Juergen Finke, Agostino Cortelezzi, Jakob Passweg
    Abstract:

    The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long-term toxicity for patients conditioned with this regimen. Thiotepa-based conditioning is an emerging radiation-free regimen with recent publications indicative of comparable clinical outcomes to TBI-based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received Thiotepa-based conditioning (n = 180) with those receiving Cy/TBI conditioning (n = 540). The 2-year leukemia-free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for Thiotepa [95% confidence interval (CI): 26.4-42.8] versus 39% for Cy/TBI (95% CI: 34.8-44.5] (P = .33) and 46.5% [95% CI: 38.6-56.1] versus 48.8% [95% CI: 44.2-54] (P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for Thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07-2.95; P = .03) which did not affect OS. Our results indicate that Thiotepa-based conditioning may not be inferior to Cy/TBI for adult patients with ALL.

  • Thiotepa based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia a matched pair analysis from the acute leukemia working party of the european socie
    American Journal of Hematology, 2017
    Co-Authors: Sandra Eder, Myriam Labopin, William Arcese, Reuven Or, Jonathan Canaani, Eric Beohou, Jaime Sanz, Juergen Finke, Agostino Cortelezzi, Dietrich W Beelen
    Abstract:

    The optimal conditioning regimen to employ before hematopoieitic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while Cy/TBI is the most commonly used myeloablative regimen, there are concerns regarding long term toxicity for patients conditioned with this regimen. Thiotepa based conditioning is an emerging radiation free regimen with recent publications indicative of comparable clinical outcomes to TBI based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received Thiotepa-based conditioning (n=180) with those receiving Cy/TBI conditioning (n=540). The 2 year leukemia-free survival and overall survival rates of both conditioning regimens were comparable, 33% for Thiotepa [95% confidence interval (CI): 26.4 - 42.8] versus 39% for Cy/TBI (95% CI: 34.8 - 44.5] (P=0.33) and 46.5% [95% CI: 38.6 - 56.1] versus 48.8% [95% CI: 44.2 - 54] (P=0.9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for Thiotepa conditioning compared to Cy/TBI (HR=1.78, 95% CI, 1.07-2.95; P=0.03) which did not affect overall survival. Our results indicate that Thiotepa based conditioning may not be inferior to Cy/TBI for adult ALL patients. This article is protected by copyright. All rights reserved.

  • Thiotepa based versus total body irradiation based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission a retrospective analysis from the acute leukemia working party of the
    European Journal of Haematology, 2016
    Co-Authors: Sandra Eder, Myriam Labopin, William Arcese, Reuven Or, Ignazio Majolino, Andrea Bacigalupo, Gennaro De Rosa, Liisa Volin, Dietrich W Beelen, Hendrik Veelken
    Abstract:

    Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a Thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after Thiotepa-containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for Thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (Thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (Thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the Thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including Thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting.

  • Thiotepa based vs tbi based myeloablative conditioning prior to allogeneic stem cell transplantation hsct for acute myeloid leukemia aml in first complete remission cr1 a retrospective analysis from the alwp of the ebmt
    Blood, 2013
    Co-Authors: Sandra Eder, Myriam Labopin, William Arcese, Ignazio Majolino, Andrea Bacigalupo, Gennaro De Rosa, Liisa Volin, Dietrich W Beelen, Hendrik Veelken, Nicolaas Schaap
    Abstract:

    Background Thiotepa (N,N'N'-triethylenethiophosphoramide), which is an alkylating compound, has an antineoplastic activity and has been used in oncology (e.g. breast-, ovarian- and bladder cancer) for decades. In the recent years, and because of its good safety profile, Thiotepa has been increasingly used both for autologous and allogeneic hematopoietic stem cell transplantation conditioning. Interestingly, this agent has a very active myeloablative activity but also its mechanism of action can mimick the effect of radiation. With this background, the aim of this study was to compare outcome of patients receiving a myeloablative conditioning consisting of either high dose TBI or Thiotepa-based chemotherapy. Methods Inclusion criteria were adults with AML, first allograft in CR1 from an HLA-matched sibling donor (MSD) or an unrelated donor (UD) between 2000 and 2011 and myeloablative conditioning. We first compared patient and transplant characteristics between the two types of conditioning, and then performed a pair-matched analysis. Results The number of patients was 2833 in the TBI group and 102 in the Thiotepa group. Patients who received Thiotepa were older (49y vs 40y, p<10-4), transplanted more recently (2009 vs 2006, p<10-4) and later after the diagnosis of AML (183 days vs 143 days, p<10-4). The percentage of secondary AML was also higher in the Thiotepa group (14% vs 6%; p=0.0002). There was no difference regarding patient/donor gender, type of donor and source of stem cells. In this cohort, we were able to match 96 patients who received Thiotepa with 185 patients who received high dose TBI. Matching factors were: age at transplantation (10 years classes), year of transplant, interval from diagnosis to transplant (less or more than median day), secondary AML and type of donor (MSD/UD). The characteristics of the 2 groups are summarized in [Table 1][1]. View this table: Table 1 Matched Analysis: 96 Thiotepa and 185 TBI (7 with 1 control and 89 with 2 controls) Median dose of TBI was 12 Gy (range, 8-16). In this group, TBI was combined with Cyclophosphamide (84% of cases), Fludarabine (14%) or other compounds (2%). On the other hand, Thiotepa was administered with Cyclophosphamide (45%), Fludarabine (54%) with/without Busulfan and other combinations (1%). Engraftment occurred in 96% of patients using Thiotepa-based conditioning versus 99% after TBI (p=0.11). The interval from transplant to neutrophils count>500/µL was 16 days (range, 9-42) versus 17 days (range, 9-81) in the 2 groups, respectively (p=0.23). Acute GvHD grade II+ was observed in 25 patients (27%) after Thiotepa-containing regimen versus 42 patients (25%) after TBI (p=0.78). 2-years cumulative incidence of chronic GVHD was 48±4% and 41±6% in the 2 groups, respectively (p=0.15). The 2-year cumulative incidences of non-relapse mortality (NRM) was 21±4% versus 27±4% (p=0.57) and relapse incidence (RI) was 18±4% versus 21±3% (p=0.71) in the Thiopeta and TBI groups, respectively. The 2-year leukemia-free survival (LFS) and overall survival (OS) were 61±5% and 64±5% in the Thiotepa group versus 51±4% and 52±4% in the TBI group (LFS: p=0.40; OS: p=0.25). Conclusion This pair-matched analysis suggests that a Thiotepa-based myeloablative conditioning regimen prior to allogeneic HSCT in AML in first CR, can allow achieving similar results to high-dose TBI-based myeloablative conditioning. Also, given the deleterious long term side effects of TBI, it is likely that a Thiotepa-based myeloablative conditioning would represent an attractive and valid alternative to TBI. Prospective trials are currently planned in this setting. Disclosures: Bacigalupo: ADIENNE : Speakers Bureau. Mohty: Riemser : Research Funding. [1]: #T1