Cytostatic conditioning in experimental allogeneic bone marrow transplantation: Busulfan causes less early gastrointestinal toxicity but Treosulfan results in improved immune reconstitution

Bouazzaoui, Abdellatif; Dickhöfer, Sabine; Kreuz, Marina; Huber, Elisabeth; Holler, Ernst; Wolff, Daniel

doi:10.3109/08923973.2014.895743

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…In Bouazzaoui et al's study, Flu-Bu conditioning resulted in a delayed aGVHD and improved survival compared to TBI conditioning [20]. In our study, all allotransplanted mice conditioned with Bu-Cy or Flu-Bu developed lethal aGVHD with typical manifestations and histopathological changes starting from day +7.…”

Section: Discussionsupporting

confidence: 53%

“…We found that increasing the dose of Cy (300 mg/kg) or decreasing the doses of Bu (80 mg/kg) and Flu (100 or 250 mg/kg) resulted in quick death or inhomogeneous survival of the mice. Recommended from previous publications [12, 20], we determined Bu (100 mg/kg)-Cy (200 mg/kg) and Flu (500 mg/kg)-Bu (100 mg/kg) to be the optimal conditioning doses. After transplantation, the syngeneic recipients did not develop clinical manifestations of aGVHD and survived more than 45 days.…”

Section: Discussionmentioning

confidence: 99%

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Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

et al. 2016

BioMed Research International

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Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a major cause of nonrelapse mortality after allo-HSCT. A conditioning regimen plays a pivotal role in the development of aGVHD. To provide a platform for studying aGVHD and evaluating the impact of different conditioning regimens, we established a murine aGVHD model that simulates the clinical situation and can be conditioned with Busulfan-Cyclophosphamide (Bu-Cy) and Fludarabine-Busulfan (Flu-Bu). In our study, BALB/c mice were conditioned with Bu-Cy or Flu-Bu and transplanted with 2 × 107 bone marrow cells and 2 × 107 splenocytes from either allogeneic (C57BL/6) or syngeneic (BALB/c) donors. The allogeneic recipients conditioned with Bu-Cy had shorter survivals (P < 0.05), more severe clinical manifestations, and higher hepatic and intestinal pathology scores, associated with increased INF-γ expression and diminished IL-4 expression in serum, compared to allogeneic recipients conditioned with Flu-Bu. Moreover, higher donor-derived T-cell infiltration and severely impaired B-cell development were seen in the bone marrow of mice, exhibiting aGVHD and conditioned with Flu-Bu. Our study showed that the conditioning regimen with Bu-Cy resulted in more severe aGVHD while the Flu-Bu regimen was associated with more extensive and long standing bone marrow damage.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

et al. 2016

BioMed Research International

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“…Sjoo et al [9] have shown that treatment with treosulfan induces only a short production of IL-2 and had no effect on the synthesis of tumor necrosis factor-α and INF-γ as compared with busulfan. Bouazzaoui et al [33] showed in another murine model that conditioning with busulfan resulted in less tissue damage and lower expression of tumor necrosis factor-α than treosulfan; however, GVHD was not increased with treosulfan because of marked reduction of production of INF-γ Most prior clinical studies suggested a lower GVHD rate with treosulfan conditioning [4,14,19]. This is probably related to the cytokine milieu associated with treosulfan and to the limited mucositis with this regimen.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation

Shimoni

Labopin

Savani

et al. 2018

Biology of Blood and Marrow Transplantation

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Dose intensity of the conditioning regimen has significant impact on the outcomes after stem cell transplantation (SCT) for acute myeloid leukemia. Most studies have shown more relapse, less nonrelapse mortality (NRM), and similar overall survival after reduced-intensity and myeloablative conditioning. There are limited data on the dose equivalence and expected outcomes of treosulfan-based compared with busulfan-based conditioning. We compared SCT outcomes after fludarabine with either intravenous busulfan at a myeloablative dose (FB4, 12.8 mg/kg, n = 1265) or a reduced dose (FB2, 6.4 mg/kg, n = 1456) or treosulfan at 42 g/m (FT14, n = 403) or 36 g/m (FT12, n = 168). Median patient age was 48, 60, 57, and 60 years in the FB4, FB2, FT14, and FT12 groups, respectively (P < .0001). Two-year overall survival was 58%, 53%, 53%, and 51%, respectively (P = .25). Multivariate analysis identified advanced age, advanced disease status, and secondary leukemia to be associated with worse survival. Relapse rate was 30%, 35%, 34%, and 40%, respectively. Relapse was more common after FB2, advanced age and disease status, secondary leukemia, and sibling donors. NRM was 17%, 18%, 21%, and 16%, respectively. NRM was least common after FT12 and more common with advanced age and disease status and unrelated donors. Treosulfan-based regimens were associated with lower rates of graft-versus-host disease. There was no difference in any outcome among patients in first complete remission at transplantation. However, there was better survival with treosulfan-based conditioning in advanced leukemia. In conclusion, survival is determined mostly by disease biology and is similar after various regimens. Treosulfan-based conditioning is more similar to myeloablative than to reduced-intensity conditioning but can be administered safely in older patients, with lower rates of graft-versus-host disease and possibly better outcomes in patients with active leukemia.

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“…10 In contrast, allogeneic mice displayed a high pathology score in liver, lung, small intestine, colon, and skin, whereby the difference between IgY-fed animals and controls was significant for the colon only (4.07 6 0.57 vs 5.58 6 0.51; P , .05). The impact of IgY on colon pathology is expected because the colon Cytokine levels on day 28 after alloBMT.…”

Section: And Ernst Hollermentioning

confidence: 95%

Reduction of aGVHD using chicken antibodies directed against intestinal pathogens in a murine model

Bouazzaoui

Huber

Dan

et al. 2017

Blood

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Cytostatic conditioning in experimental allogeneic bone marrow transplantation: Busulfan causes less early gastrointestinal toxicity but Treosulfan results in improved immune reconstitution

Abstract: Conditioning with Treo/Flu or Bu/Flu results in decreased aGVHD severity compared to TBI. Moreover, Treo/Flu was associated with improved immune reconstitution despite the early toxicity.

Cited by 6 publications

References 39 publications

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation

Reduction of aGVHD using chicken antibodies directed against intestinal pathogens in a murine model

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