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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Administered parentally, thiotepa has been used for the palliative treatment of a wide variety of solid tumors, such as adenocarcinoma of the breast and ovary. While mainly superseded by other treatments, it has also been used in lymphomas such as lymphosarcoma and Hodgkin’s disease. It is also used as an intracavitary drug (i.e., by intra-pleural, intra-bladder, or peritoneal infusion) administered weekly for four to six weeks for the treatment of bladder or ovarian cancers, or malignant effusions. In intravesical chemotherapy for bladder cancer, thiotepa is used in three ways: first, as a prophylactic agent prior to a cystoscopy biopsy to prevent seeding of tumor cells; second, as an adjunctive therapy at the time of biopsy; and third, sometimes as a therapeutic agent to prevent recurrence after cystoscopic transurethral resection of a bladder tumor (TURBT). Thiotepa is also used in combination with other chemotherapy agents with or without total body irradiation (TBI) as a conditioning treatment prior to allogeneic or autologous hematopoietic progenitor cell transplantation (HPCT) in hematological diseases in adult and pediatric patients, and when high-dose chemotherapy with HPCT support is appropriate for the treatment of solid tumors in adults and children. In 2007 thiotepa was designated as an orphan drug by the EMA and FDA for this purpose.
Acquired Bleeding Disorders Associated with Disease and Medications
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
William A. Rock, Sue D. Walker
Thiotepa dosages within and minimally above the recommended therapeutic doses have been associated with potentially life-threatening hematopoietic toxicity. The toxic effect is dose related. Death from hemorrhage has occurred as a result of the hematopoietic depression. Thiotepa is dialyzable, so treatment options include dialysis and transfusions.
Clinical Pharmacodynamics of Anticancer Drugs
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Howard L. McLeod, William E. Evans
Disposition of the alkylating agent thioTEPA was determined in 13 patients with ovarian cancer receiving 60 to 80 mg IV every 4 weeks.105 Plasma samples were obtained 5 min to 24 h postinfusion and analyzed for thioTEPA and the primary metabolite TEPA. Pharmacokinetics were calculated by noncompartmental methods, while correlations with percent reduction in hematologic parameters were evaluated by linear regression. A significant correlation between thioTEPA plasma AUC and percentage reduction in platelets and leukocytes was observed (r2 = 0.79 and 0.68, respectively). No correlations with TEPA pharmacokinetics were found. Similar findings were observed in 27 patients with a variety of solid tumors receiving thioTEPA 30 to 75 mg/m2.106 Plasma samples were obtained 5 min to 48 h postinfusion and analyzed for thioTEPA and TEPA. Following noncompartmental determination of pharmacokinetic parameters, percent change in leukocyte and platelet counts were fit to linear, exponential, and modified Hill equations. ThioTEPA AUC correlated with neutrophil suppression (r2 = 0.49, p = 0.0003), but not reduction in platelet counts. Despite greater plasma AUC, TEPA did not correlate with either measures of hematologic suppression. As thioTEPA systemic exposure correlates with hematologic toxicity, prospective trials individualizing thioTEPA therapy may be warranted.
Busulfan-based reduced toxicity conditioning regimen used in hematopoietic stem cell transplantation in HLH patients results in sustained donor chimerism
Published in Pediatric Hematology and Oncology, 2021
Erin Goode, Holly Miller, Dana Salzberg, Courtney Campbell, Kristen Beebe, Charlotte Schwalbach, Roberta H. Adams, Alexander Ngwube
Each patient received a busulfan-based conditioning regimen (Figure 1). Intravenous busulfan was administered, starting at 0.7–0.8 mg/kg/dose every 6 hours, from day −5 to day −2, for a total of 16 doses. Therapeutic drug monitoring was performed following the initial busulfan dose and adjustments were made based on target AUC (900–1100 uMol/min for haploidentical transplants and 630–770 uMol/min for matched (MUD) and mismatched (MMUD) unrelated donor transplants, per Gungor et al.11 All patients received anticonvulsant medication while receiving busulfan. For MUD and MMUD HSCTs, fludarabine was administered at 30 mg/m2/dose (if <9 kg, 1.2 mg/kg/dose) on days −8 to −3. Patients receiving haploidentical transplants received additional thiotepa intravenously at 10 mg/kg once on day −6 and fludarabine 40 mg/m2/dose daily on days −5 to −2. All patients also received low dose alemtuzumab at the start of their conditioning regimen to improve engraftment and decrease the risk of graft-versus-host disease (GVHD). Patients receiving MUD and MMUD transplants were given 0.2 mg/kg daily dosing on days −8 to −6. Haploidentical transplant recipients received 0.2 mg/kg daily on days −9 to −6. Donor hematopoietic stem cells were administered not less than 24 hours after completion of the last dose of chemotherapy. Additional GVHD prophylaxis consisted of methotrexate and tacrolimus in patients receiving a MUD or MMUD graft. Post infusion cyclophosphamide, tacrolimus and mycophenolate mofetil were given to patients receiving a haploidentical graft.
Grade 2 acute GVHD is a factor of good prognosis in patients receiving peripheral blood stem cells haplo-transplant with post-transplant cyclophosphamide
Published in Acta Oncologica, 2021
Patrice Chevallier, Ana Berceanu, Pierre Peterlin, Alice Garnier, Amandine Le Bourgeois, Berthe-Marie Imbert, Etienne Daguindau, Béatrice Mahé, Viviane Dubruille, Nicolas Blin, Cyrille Touzeau, Thomas Gastinne, Anne Lok, Benoît Tessoulin, Sophie Vantyghem, Yohan Desbrosses, Céline Bressollette, Alix Duquesne, Marion Eveillard, Yannick Le Bris, Anne Dormoy, Caroline Malugani, Eric Deconinck, Philippe Moreau, Steven Le Gouill, Marie C. Béné, Thierry Guillaume
This cohort also allowed to analyze the impact of the conditioning regimen in haplo-Allo-SCT with PTCY. Surprisingly, CloB2 was associated with a higher rate of graft failure, suggesting that this regimen is not immunosuppressive enough, although ATG was systematically administered with PTCY/cyclosporine and MMF for these patients. Conversely, CloB2 was confirmed to be very efficient for matched grafts, especially in AML [14]. CloB2 conditioning should thus probably not be prescribed for patients receiving a haplo-identical graft. Regarding the TBF regimen, we confirmed a low incidence of relapse [26]. However, NRM was high in this group, resulting in similar OS and DFS compared to CloB2 or Baltimore-based regimens. This was not due to the use of a higher thiotepa dosage (2 days instead of 1) but perhaps to the use of PBSC. Indeed, NRM has been reported to be only of 13% after haplo-Allo-SCT with PTCY and BM as source of graft [15]. Other studies [26,29] have also observed a high incidence of TRM after haplo-Allo-SCT with TBF conditioning, including one showing, as for us, no influence of the intensity of the conditioning regimen [29]. Thus, other regimens with low TRM may be preferred when considering PBSC haplo-Allo-SCT with PTCY, such as a reinforced Baltimore-based regimen with clofarabine (11% of NRM) [13] or treosulfan-based regimen (17% of NRM) [30].
Stem cell transplantation in sickle cell disease: therapeutic potential and challenges faced
Published in Expert Review of Hematology, 2018
Alexis Leonard, John F. Tisdale
In vivo, high-dose CY given on days 3 and 4 post HSCT is highly cytotoxic to both donor and recipient proliferating, alloreactive T cells [60], yet spares HSCs secondary to their high levels of the enzyme, aldehyde dehydrogenase, responsible for metabolizing the drug [61]. GVHD prophylaxis with high-dose CY has proven effective with very low rates of both acute and chronic GVHD after HLA-haploidentical related HSCT (Table 4) [62]. For those patients with evidence of engraftment, this approach showed no acute or chronic GVHD. The regimen was well tolerated with limited serious toxicities, with an OS of 100%. Despite these advantages, rejection was high at around 50% and remains an important obstacle for the haploidentical HSCT model. Preliminary evidence suggests the addition of thiotepa in the preparative regimen may improve donor engraftment without increasing morbidity or mortality [63], and is currently being investigated in a phase II clinical trial (NCT03240731).