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GM-CSF does not rescue poor-quality embryos: secondary analysis of a randomized controlled trial.

ABSTRACT: PURPOSE:To evaluate implantation potential of cleavage-stage embryos cultured in medium containing 2 ng/ml granulocyte-macrophage colony-stimulating factor (GM-CSF) versus control medium, according to embryo morphological quality and then transferred on day 3. METHODS:Explorative secondary data analysis of a multicenter, randomized, placebo-controlled, double-blinded prospective study of 1149 couples with embryo transfer after IVF/ICSI. This analysis includes a subgroup of 422 subjects with either single-embryo transfer (SET, N?=?286) or double-embryo transfer of two embryos with equivalent morphological quality (DET, N?=?136). Implantation rate and live birth rate were assessed according to category of morphological embryo quality on day 3. RESULTS:Culture with GM-CSF did not increase the implantation rate for embryos classified as poor quality. A trend towards greater benefit of GM-CSF on implantation and survival until live birth for top-quality embryos (TQEs) compared with poor-quality embryos was observed, although not statistically significant. For TQEs, the percentage of transferred embryos resulting in a live born baby was: 40.9?±?5.3% (GM-CSF) versus 30.5?±?4.6% (control) (P?=?0.24; odds ratio [OR] 1.43, 95% confidence interval [CI] 0.79-2.59), and for embryos with less than 6 cells at day 3 this same rate was: 7.4?±?3.3% (GM-CSF) versus 12.0?±?4.0% (control) (P?=?0.26; OR 0.53, 95% CI 0.17-1.61). CONCLUSION:This exploratory analysis is consistent with GM-CSF protecting morphologically normal embryos from culture-induced stress and does not support an effect of GM-CSF in rescuing poor-quality embryos. ClinicalTrials.gov identifier: NCT00565747.

SUBMITTER: Rodriguez-Wallberg KA

PROVIDER: S-EPMC7181539 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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GM-CSF does not rescue poor-quality embryos: secondary analysis of a randomized controlled trial.

Rodriguez-Wallberg Kenny A KA Munding Bibi B Ziebe Søren S Robertson Sarah A SA Robertson Sarah A SA

Archives of gynecology and obstetrics 20200409 5

<h4>Purpose</h4>To evaluate implantation potential of cleavage-stage embryos cultured in medium containing 2 ng/ml granulocyte-macrophage colony-stimulating factor (GM-CSF) versus control medium, according to embryo morphological quality and then transferred on day 3.<h4>Methods</h4>Explorative secondary data analysis of a multicenter, randomized, placebo-controlled, double-blinded prospective study of 1149 couples with embryo transfer after IVF/ICSI. This analysis includes a subgroup of 422 sub ...[more]

PMID: 32274634

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Project description:Background:To evaluate if it is safe and effective to transfer poor quality embryos. Methods:It was a retrospective analysis using individual patient data with positive controls. All patients undergoing embryo transfers of poor quality embryos on day 3 or on day 5 as part of fresh In Vitro Fertilization (IVF) cycles performed between 2012 and 2016. This study assessed a total of 738 poor quality embryos from 488 IVF programs. 261 embryo transfers were performed on day 3 (402 embryos were transferred) and 227 on day 5 (336 embryos were transferred). Control group consisted of 9893 fair and good quality embryos from 5994 IVF programs. Outcome rates were compared with two-tailed Fisher exact test using fisher.test function in R software. 95% confidence intervals for proportions were calculated using the Clopper-Pearson method with binom.test function in R. The groups of patients with poor vs. good and fair quality embryos were compared by age, body mass index(BMI), number of oocytes, female and male main diagnosis, cycle type, controlled ovarian stimulation (COS) protocol, the starting day of gonadotropin administration, the starting dose of gonadotropins, the total dose of gonadotropins, the total number of days of gonadotropins administration, the starting day of gonadotropin-releasing hormone (GnRH) agonist administration, the total number of ampoules of GnRH-agonist used, day of the trigger of ovulation administration and the type of the trigger of ovulation using the Student's t-test for interval variables and with the chi-square test for nominal variables. Results:No significant differences in the implantation rate, clinical pregnancy rate, miscarriage rate, live births, and the number of children born were found between the groups of poor quality embryos transferred on day 3 and day 5. Though the implantation rate was lower for the group of poor quality embryos, than for the control (13.9% vs 37.2%), statistically significant differences between the proportion of implanted embryos which resulted in clinical pregnancies and live births in both groups were not observed (72% vs 78.2 and 55.8% vs 62.0% respectively). Conclusion:Transfer of poor quality embryos at either day 3 or day 5 have a low potential for implantation, though those embryos which successfully implanted have the same potential for live birth as the embryos of fair and good quality. This study supports that it is safe to transfer poor quality embryos when they are the only option for fresh embryo transfer (ET).

Project description:IntroductionEndogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.MethodsWe reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.ResultsWe discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.DiscussionWe identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

Project description:Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, up to 30% of MM patients are unable to collect optimal numbers of peripheral blood (PB) CD34+ hematopoietic stem and progenitor cells (HSPCs) with standard G-CSF mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended receptor occupancy and enhanced in-vivo activity. The GENESIS Trial is a prospective, phase III, double-blind, placebo-controlled, international, multicenter, superiority trial with 122 adult patients randomized (2:1) to motixafortide+G-CSF or placebo+G-CSF for HSPC mobilization for ASCT in MM (NCT03246529). The primary endpoint of the study was met, with motixafortide+G-CSF enabling 92.5% of patients to collect ≥6x106 CD34+ cells/kg within 2 apheresis procedures versus 26.2% with placebo+G-CSF (p<0.0001). A key, prespecified secondary endpoint was also met, with motixafortide+G-CSF enabling 88.8% of patients to collect ≥6x106 CD34+ cells/kg in 1 apheresis versus 9.5% with placebo+G-CSF (p<0.0001). Motixafortide+G-CSF was safe and well-tolerated, with the most common treatment-emergent adverse events observed being transient, Grade 1/2 injection site reactions (pain: 50%, erythema: 27.5%, pruritis: 21.3%). In addition, extended immunophenotyping and single-cell transcriptional profiling were performed on CD34+ HSPCs mobilized on the GENESIS Trial, as well as a contemporaneous MM cohort undergoing plerixafor+G-CSF mobilization for ASCT and 3 cohorts of allogeneic HSPC donors undergoing single-agent mobilization with motixafortide, plerixafor or G-CSF alone. Motixafortide+G-CSF resulted in a 10.5-fold increase in primitive HSPCs collected versus placebo+G-CSF (p<0.0001); and significantly greater numbers of early stem and progenitors versus both placebo+G-CSF (p<0.0001) and plerixafor+G-CSF (p=0.0327). Motixafortide also preferentially mobilized HSPC subsets with upregulated gene expression pathways associated with enhanced self-renewal, regeneration and quiescence (EGF, NFB/TNF and HBO1). In conclusion, motixafortide+G-CSF mobilized significantly greater CD34+ HSPC numbers within 2 apheresis procedures versus placebo+G-CSF. Motixafortide also preferentially mobilized primitive stem and early progenitor cells with unique transcriptional profiles versus plerixafor and G-CSF.

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GM-CSF does not rescue poor-quality embryos: secondary analysis of a randomized controlled trial.

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GM-CSF does not rescue poor-quality embryos: secondary analysis of a randomized controlled trial.

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