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Single arm phase II trial assessing the safety, compliance with and activity of Bezafibrate and medroxyProgesterone acetate (BaP) therapy against myeloid and lymphoid cancers.

ABSTRACT: We previously reported the safety and efficacy of low dose BaP [Bezafibrate (Bez) and Medroxyprogesterone acetate (MPA)] in 20 acute myeloid leukaemia (AML) patients for whom chemotherapy was not an option. This study provided evidence that BaP had anti-AML activity and improved haemopoiesis; absence of haematological toxicity allowed continuous daily administration. Similarly a previous trial in endemic Burkitt lymphoma demonstrated anti-B cell lymphoma activity of low and high dose BaP again in the absence of toxicity. We conducted a study to further evaluate the safety and activity of high dose BaP therapy in adults with AML (and high risk Myelodysplastic Syndromes (MDS)), chronic lymphocytic leukaemia (CLL) or B-cell Non-Hodgkin Lymphoma (BHNL). Eighteen patients were recruited to the study over 20 months, 16 AML/MDS, 1 CLL, and 1 BNHL. Although MPA was well tolerated throughout the study, only 2 patients were able to tolerate Bez treatment for their whole trial duration, indicating that Bez escalation is not feasible in the setting of adult AML/MDS. Thus there has been no obvious benefit in improved haemopoiesis or overt anti-leukaemia activity from the attempts to escalate BaP dose over previous published studies. Since current therapeutic options in MDS are restricted it may be now of value to continue to evaluate low dose BaP based approaches in low risk MDS rather than AML/high risk MDS. Furthermore, screening of low dose BaP against libraries of other already available dugs may identify an addition to BaP that augments the anti-neoplastic efficacy without significant toxicity.

SUBMITTER: Murray J

PROVIDER: S-EPMC6463739 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Single arm phase II trial assessing the safety, compliance with and activity of Bezafibrate and medroxyProgesterone acetate (BaP) therapy against myeloid and lymphoid cancers.

Murray Jim J Pratt Guy G Jacob Abe A Clark Fiona F Blundred Rachel R Fox Sonia S Bishop Rebecca R Wheatley Keith K Khanim Farhat F Bunce Chris C Drayson Mark M

Contemporary clinical trials communications 20190410

We previously reported the safety and efficacy of low dose BaP [Bezafibrate (Bez) and Medroxyprogesterone acetate (MPA)] in 20 acute myeloid leukaemia (AML) patients for whom chemotherapy was not an option. This study provided evidence that BaP had anti-AML activity and improved haemopoiesis; absence of haematological toxicity allowed continuous daily administration. Similarly a previous trial in endemic Burkitt lymphoma demonstrated anti-B cell lymphoma activity of low and ...[more]

PMID: 31011660

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Project description:Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?In vitro MPA treatment suppressed expression of CD40 and CD80 by human primary DCs responding to Toll-like receptor 3 (TLR3) agonist stimulation (i.e. DC activation). Moreover, this MPA-mediated decrease in CD40 expression impaired DC capacity to stimulate T cell proliferation (i.e. DC function).MPA is the active molecule in Depo-Provera(®) (DMPA), a commonly used injectable hormonal contraceptive (HC). Although DMPA treatment of mice prior to viral mucosal tissue infection impaired the capacity of DCs to up-regulate CD40 and CD80 and prime virus-specific T cell proliferation, neither DC activation marker expression nor the ability of DCs to promote T cell proliferation were affected by in vitro progesterone treatment of human DCs generated from peripheral blood monocytes.This cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs.Human DCs isolated from peripheral blood mononuclear cells by negative immunomagnetic selection were incubated for 24 h with various concentrations of MPA. After an additional 24 h incubation with the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C), flow cytometry was used to evaluate DC phenotype (i.e. expression of CD40, CD80, CD86, and HLA-DR). In separate experiments, primary untouched human DCs were sequentially MPA-treated, poly I:C-activated, and incubated for 7 days with fluorescently labeled naïve allogeneic T cells. Flow cytometry was then used to quantify allogeneic T cell proliferation.Several pharmacologically relevant concentrations of MPA dramatically reduced CD40 and CD80 expression in human primary DCs responding to the immunostimulant poly I:C. In addition, MPA-treated DCs displayed a reduced capacity to promote allogeneic CD4(+) and CD8(+) T cell proliferation. In other DC: T cell co-cultures, the addition of antibody blocking the CD40-CD154 (CD40L) interaction mirrored the decreased T cell proliferation produced by MPA treatment, while addition of recombinant soluble CD154 restored the capacity of MPA-treated DCs to induce T cell proliferation to levels produced by non-MPA-treated controls.While our results newly reveal that pharmacologically relevant MPA concentrations suppress human DC function in vitro, additional research is needed to learn if DMPA similarly inhibits DC maturation and function in the human female genital tract.Identification of a mechanism by which MPA impairs human DC activation and function increases the biological plausibility for the relationships currently suspected between DMPA use and enhanced susceptibility to genital tract infection.Funding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no con?icts of interest to declare.

Dataset Information

Single arm phase II trial assessing the safety, compliance with and activity of Bezafibrate and medroxyProgesterone acetate (BaP) therapy against myeloid and lymphoid cancers.

Publications

Single arm phase II trial assessing the safety, compliance with and activity of Bezafibrate and medroxyProgesterone acetate (BaP) therapy against myeloid and lymphoid cancers.

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