Thiotepa improves allogeneic bone marrow engraftment without enhancing stem cell depletion in irradiated mice

Abstract

Summary:The polyfunctional alkylating agent thiotepa (N, NЈ, NЉ-Thiotepa (TT) has long been considered for inclusion triethylene thiophosphoramide) (TT) has now been in cliniin clinical bone marrow transplant (BMT) conditioning cal use for more than 40 years. Myelodepression is well regimens in an attempt to prevent allograft rejection recognized as the major dose-limiting toxicity and there is and leukemia relapse. These studies have been encourcurrent interest in applying escalating doses of TT in conaged by initial murine experiments showing a clear junction with autologous bone marrow transplantation improvement in allogeneic bone marrow engraftment (BMT) (eg Refs 1-3). This agent has also been considered with addition of TT to total body irradiation (TBI)for inclusion in the conditioning regimen prior to allogeneic where it was assumed that TT enhances donor-type BMT 4-7 and there is at least experimental evidence for chimerism via ablation of competing stem cells in the enhanced engraftment of donor stem cells when TT was recipient. The aim of the present study was to re-evaluadded to total body irradiation (TBI). 8 The latter finding in ate the hematological toxicity of TT among different an H-2-incompatible allogeneic BMT model in mice was stem cell subsets that included primitive cells capable attributed to the reduction of stem cell competition through of long-term repopulation and to assess how the combiadditional myeloablation and this effect has been compared nation of TT with TBI influences the development of with host stem cell toxicity afforded by another alkylating donor engraftment in both syngeneic (B6-Gpi-1 a → B6-agent, busulfan. However, it has since been appreciated that Gpi-1 b ) and H-2 compatible allogeneic (BALB.B10 → while the acute myelodepression caused by various cyto-B6) BMT models. At 24 h after TT (20 mg/kg) the femtoxic agents generally reflects depletion of committed prooral content of different stem cell subsets was detergenitor cell populations in the bone marrow, it may not mined from the frequency of transient repopulating, necessarily follow that primitive stem cells capable of longand the more primitive cobblestone area-forming, cells term repopulation are similarly affected. 9-11 The aim of the (CAFCs) growing in stroma-supported cultures. This present study was to re-address the hematological properassay showed a large TT-induced depletion (2% ties of TT with respect to survival of the different progenisurvival) of early clones developing at day 7 in culture tor and stem cell subsets in the mouse bone marrow by but survival recovered towards normal for later appearenumerating cobblestone area-forming cell (CAFC) subsets ing clones developing from more primitive CAFC subafter treatment. We then evaluated how the combination of sets. The sparing of these primitive stem cells was TT with TBI influences the magnitude of short-and longreflected as undetectable levels of donor marrow term engraftment of transplanted marrow cells using conrepopulation in recipients given TT ...

The role of thiotepa in allogeneic bone marrow transplantation for genetic diseases

“…TTP has proved to be highly myelosuppressive in a murine model 21 and, recently, to possess immunosuppressive properties too. 23 Overall rates of toxicity were lower than those previously reported in patients with hematological malignancies who received TTP as part of their conditioning; [34][35][36][37] this may be due to the less aggressive chemotherapy given to children with genetic diseases prior to BMT. In this study, mucositis and gastrointestinal tract (GIT) toxicity were the predominant complications, which conforms to the reports from the MD Anderson group [34][35][36][37] and our previous observations.…”

“…In murine models there is evidence of enhanced engraftment of donor stem cells, using TTP in the pre-transplant preparative regimen. 21,23 This finding is attributed generally both to the reduction of stem cell competition through additional myeloablation and, recently, to the immunosuppressive properties of TTP. 23 Our study analyzes engraftment, transplant-related complications and toxicity, including GVHD, survival, diseasefree survival (DFS) and disease recurrence, in 26 consecutive patients suffering from genetic diseases who received a combination of BU-TTP-CY as a conditioning regimen for T cell-depleted allogeneic BMT.…”

Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies

“…Preliminary results from studies at our center indicate that an intravenous formulation of busulfan is well tolerated and provides consistent drug plasma concentrations. 27 In this study we were able to individualize and maintain BU exposure within a desired range in most patients. This approach allowed successful engraftment with minimal 'BU-specific' toxicities.…”

“…Our success with engraftment was probably the result of the immunosuppressive effect contributed by the addition of thiotepa in the conditioning regimen. 16,27 Children often have difficulty ingesting a large quantity of oral BU, and vomiting is more frequent when a large dose is ingested over a short period of time. In our patients, exposure to high-dose thiotepa prior to BU administration may have increase the likelihood of emesis.…”

Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide

“…17 Its dosage can be escalated more than 15 times with HSC support. There are no significant overlapping dose-limiting toxicities between thiotepa and BU or CY.…”