Pretransplant conditioning with fludarabine and IV busulfan, reduced toxicity and increased safety without compromising antitumor efficacy and overall treatment effect?

The combination of the DNA-alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pretransplantation conditioning therapy for myeloid leukemias. However, it is associated with significant nonrelapse mortality, which prohibits dose escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase antileukemic efficacy without jeopardizing patient safety. A preclinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC), and the hypomethylating agent decitabine (DAC) in human acute myeloid leukemia (AML) cell lines. Exposure of KBM3/Bu250 (P53-null) and OCI-AML3 (P53-wild-type) cells to Bu+4HC inhibited cell proliferation by ∼35-39%; addition of DAC increased the inhibition to ∼60-62%. The observed synergistic interactions correlated with DNA damage response activation, increased the production of reactive oxygen species, and decreased mitochondrial membrane potential, release of mitochondrial proapoptotic proteins into the cytoplasm, and induction of caspase-dependent programmed cell death. The Bu+4HC+DAC combination further caused chromatin trapping of DNMT1 with a concomitant increase in DNA damage. In contrast, FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)-positive AML cell lines were not sensitized to Bu+4HC by inclusion of DAC; addition of the FLT3 kinase inhibitor sorafenib sensitized the FLT3-ITD-positive MV4-11 and MOLM13 cell lines to the triple drug combination by inhibiting the FLT3 signal transduction pathway. Our results therefore provide a rationale for the development of personalized conditioning therapy for patients with P53-mutated and FLT3-ITD-positive AML.

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Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells

Valdez

Tang

Yang

et al. 2018

Experimental Hematology

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Consensus recommendations for the role and competencies of the EBMT clinical pharmacist and clinical pharmacologist involved in hematopoietic stem cell transplantation

Langebrake

Admiraal

Maarseveen

et al. 2019

Bone Marrow Transplant

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Total body irradiation + fludarabine compared to busulfan + fludarabine as “reduced-toxicity conditioning” for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT

Giebel

Labopin

Sobczyk‐Kruszelnicka

et al. 2020

Bone Marrow Transplant

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Pretransplant conditioning with fludarabine and IV busulfan, reduced toxicity and increased safety without compromising antitumor efficacy and overall treatment effect?

Cited by 3 publications

References 17 publications

Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells

Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells

Consensus recommendations for the role and competencies of the EBMT clinical pharmacist and clinical pharmacologist involved in hematopoietic stem cell transplantation

Total body irradiation + fludarabine compared to busulfan + fludarabine as “reduced-toxicity conditioning” for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT

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