Enigma portal: Peritoneal effusion in a patient with a myeloproliferative neoplasm

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Abstract 1150: Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351

International audienceAbstract CPX-351 is a liposomal form encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. Cytidine Deaminase (CDA) catabolizes free cytarabine in the liver, but to what extent it could affect as well the pharmacokinetics of liposomal cytarabine is yet to be investigated. Here we have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in adult AML patients treated with CPX-351. Impact of CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)) on cytarabine exposure levels (AUC, trough levels, Cmax) and PK parameters were analyzed. All patients showed febrile neutropenia and one toxic-death was observed. Overall response rate was 75%. The ratio free:total cytarabine monitored in our patients was higher than expected (i.e., 47%). Inter-individual variability on pharmacokinetics parameters and subsequent exposure levels was >60%. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T1/2 = 28 h). Of note, liposomes were observed transiently in bone marrow on D15, with cytarabine levels 2.3-time higher than in plasma. Sequencing CDA gene was not contributive and CDA status was primarily evaluated upon phenotyping patients. PM status was found in 77% of the patients with a marked impact on cytarabine PK parameters, i.e., PM patients had higher exposure than EM patients (AUC: 5536 vs. 1784 ng/mL.h), prolonged half-life (T1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This pilot study suggests that despite being encapsulated in a liposomal vehicle as CPX-351, cytarabine fate in the body is highly dependent upon CDA activity, suggesting that liver metabolism is only partly skipped by the nanoparticle. Here, CDA status proved to have a major impact on cytarabine PK and possibly safety in AML patients treated with CPX-351. Indeed PM patients displayed higher exposure levels with higher risk for severe non-hematological toxicities. This study suggests that CDA status could be used as a covariate to customize CPX-351 dosing in AML patients. Citation Format: Melanie Donnette, Mourad Hamimed, Joseph Ciccolini, Regis Costello, Laure Delassus, Geoffroy Venton, Raphaelle Fanciullino. Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1150

First case of B ALL with KMT2A-MAML2 rearrangement: a case report

Abstract Background A large number of chromosomal translocations of the human KMT2A gene, better known as the MLL gene, have so far been characterized. Genetic rearrangements involving KMT2A gene are frequently involved in lymphoid, myeloid and mixed lineage leukemia. One of its rare fusion partners, the mastermind like 2 (MAML2) gene has been reported in four cases of myeloid neoplasms after chemotherapy so far: two acute myeloid leukemias (AML) and two myelodysplasic syndrome (MDS), and two cases of secondary T-cell acute lymphoblastic leukemia (T-ALL). Case presentation Here we report the case of a KMT2A - MAML2 fusion discovered by Next-Generation Sequencing (NGS) analysis in front of an inv11 (q21q23) present in a 47-year-old female previously treated for a sarcoma in 2014, who had a B acute lymphoid leukemia (B ALL). Conclusion It is, to our knowledge, the first case of B acute lymphoblastic leukemia with this fusion gene. At the molecular level, two rearrangements were detected using RNA sequencing juxtaposing exon 7 to exon 2 and exon 9 to intron 1–2 of the KMT2A and MAML2 genes respectively, and one rearrangement using Sanger sequencing juxtaposing exon 8 and exon 2

Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome

BackgroundThe use of insulin-sensitising agents, such as metformin, in women with polycystic ovary syndrome (PCOS) who are undergoing ovulation induction or in vitro fertilisation (IVF) cycles has been widely studied. Metformin reduces hyperinsulinaemia and suppresses the excessive ovarian production of androgens. As a consequence, it is suggested that metformin could improve assisted reproductive techniques (ART) outcomes, such as ovarian hyperstimulation syndrome (OHSS), pregnancy and live birth rates.ObjectivesTo determine the effectiveness and safety of metformin as a co-treatment during IVF or intracytoplasmic sperm injection (ICSI) in achieving pregnancy or live birth in women with PCOS.Search methodsWe searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, LILACS, the metaRegister of Controlled Trials and reference lists of articles (up to 15 October 2014).Selection criteriaTypes of studies: randomised controlled trials (RCTs) comparing metformin treatment with placebo or no treatment in women with PCOS who underwent IVF or ICSI treatment.Types of participants: women of reproductive age with anovulation due to PCOS with or without co-existing infertility factors.Types of interventions: metformin administered before and during IVF or ICSI treatment.Types of outcome measures: live birth rate, clinical pregnancy rate, miscarriage rate, incidence of ovarian hyperstimulation syndrome, incidence of participant-reported side effects, serum oestradiol level on the day of trigger, serum androgen level, and fasting insulin and glucose levels.Data collection and analysisTwo review authors independently selected the studies, extracted the data according to the protocol and assessed study quality. the overall quality of the evidence was assessed using GRADE methods.Main resultsWe included nine randomised controlled trials involving a total of 816 women with PCOS. When metformin was compared with placebo there was no clear evidence of a difference between the groups in live birth rates (OR 1.39, 95% CI 0.81 to 2.40, five RCTs, 551 women, I-2 = 52%, low-quality evidence). Our findings suggest that for a woman with a 32 % chance of achieving a live birth using placebo or other treatment, the corresponding chance using metformin treatment would be between 28% and 53%.When metformin was compared with placebo or no treatment, clinical pregnancy rates were higher in the metformin group (OR 1.52; 95% CI 1.07 to 2.15; eight RCTs, 775 women, I-2 = 18%, moderate-quality evidence). This suggests that for a woman with a 31% chance of achieving a clinical pregnancy using placebo or no treatment, the corresponding chance using metformin treatment would be between 32% and 49%.The risk of ovarian hyperstimulation syndrome was lower in the metformin group (OR 0.29; 95% CI 0.18 to 0.49, eight RCTs, 798 women, I-2 = 11%, moderate-quality evidence). This suggests that for a woman with a 27% risk of having OHSS without metformin the corresponding chance using metformin treatment would be between 6% and 15%.Side effects (mostly gastrointestinal) were more common in the metformin group (OR 4.49, 95% CI 1.88 to 10.72, for RCTs, 431 women, I-2= 57%, low quality evidence)The overall quality of the evidence was moderate for the outcomes of clinical pregnancy, OHSS and miscarriage, and low for other outcomes. the main limitations in the evidence were imprecision and inconsistency.Authors' conclusionsThis review found no conclusive evidence that metformin treatment before or during ART cycles improved live birth rates in women with PCOS. However, the use of this insulin-sensitising agent increased clinical pregnancy rates and decreased the risk of OHSS.Federal University of São Paulo (UNIFESP/EPM), BrazilNuffield Department of Obstetrics and Gynecology, UKSchool of Women's and Children's Health, Division of Obstetrics and Gynecology, Royal Hospital for Women, AustraliaUniversidade Federal de São Paulo, BR-04042034 São Paulo, BrazilRoyal Hosp Women & IVF Australia, Sch Womens & Childrens Hlth, Div Obstet & Gynaecol, Sydney, NSW, AustraliaFertivitro Ctr Reprod Humana, Human Reprod Ctr, São Paulo, BrazilUniv Estado Para, Dept Publ Hlth, Belem, Para, BrazilCtr Estudos Saude Baseada Evidencias & Avaliacao, Brazilian Cochrane Ctr, São Paulo, BrazilUniversidade Federal de São Paulo, BR-04042034 São Paulo, BrazilWeb of Scienc

Mechanisms regulating expression of the tumor necrosis factor-related light gene. Role of calcium-signaling pathway in the transcriptional control.

LIGHT (TNFSF14) is a newly identified tumor necrosis factor superfamily member involved in the regulation of immune responses by control of activation, maturation, and survival of immune effector cells. Despite the immunological relevance of the LIGHT protein, little knowledge is available as to how light gene expression is regulated. In T-lymphocytes, most LIGHT surface expression and transcript accumulation occurs after T cell activation. In this study, we have shown that these events are blocked at the transcriptional level by cyclosporin A, an immuno-suppressive drug. Besides, we identified a role for Ca2+ -signaling pathways and NFAT transcription factors in T cell activation-induced LIGHT expression. To further investigate this process, we have identified, cloned, and characterized a 2.1-kilobase 5'-flanking DNA genomic fragment from the human light gene. We have shown the transcriptional activity of the herein-identified minimal 5' regulatory region of human light gene parallels the endogenous expression of light in T cells. Moreover, we demonstrated that induced LIGHT promoter activity can be equally blocked by cyclosporin A treatment or dominant negative NFAT overexpression and further identified by site-directed mutagenesis and electrophoretic mobility supershift analysis of a NFAT transcription factor binding site within the human light minimal promoter. Finally, Sp1 and Ets1 binding sites were identified and shown to regulate light basal promoter activity. Thus, the present study establishes a molecular basis to further understand the mechanisms governing human light gene expression and, consequently, could potentially lead to novel therapeutic manipulations that control the signaling cascade, resulting in LIGHT production in conditions characterized by immunopathologic activation of T cells.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Surface expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias: Engagement of CD33 induces apoptosis of leukemic cells

p75/AIRM-1 is a recently identified inhibitory receptor expressed by natural killer and myeloid cells displaying high homology with CD33. Crosslinking of p75/AIRM-1 or CD33 has been shown to sharply inhibit the in vitro proliferation of both normal myeloid cells and chronic myeloid leukemias. In this study, we analyzed acute myeloid leukemic cells for the expression of p75/AIRM-1. p75/AIRM-1 marked the M5 (11/12) and M4 (2/2) but not the M1, M2, and M3 subtypes according to the French–American–British classification. Cell samples from 12 acute myeloid leukemias were cultured in the presence of granulocyte/macrophage colony-stimulating factor. Addition to these cultures of anti-CD33 antibody resulted in ≈70% inhibition of cell proliferation as assessed by [(3)H]thymidine uptake or by the recovery of viable cells. Anti-p75/AIRM-1 antibody exerted a strong inhibitory effect only in two cases characterized by a high in vitro proliferation rate. After crosslinking of CD33 (but not of p75/AIRM-1), leukemic cells bound Annexin V and displayed changes in their light-scattering properties and nucleosomal DNA fragmentation, thus providing evidence for the occurrence of apoptotic cell death. Remarkably, when anti-CD33 antibody was used in combination with concentrations of etoposide insufficient to induce apoptosis when used alone, a synergistic effect could be detected in the induction of leukemic cell death. These studies provide the rationale for new therapeutic approaches in myeloid leukemias by using both chemotherapy and apoptosis-inducing mAbs

Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351

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