Venetoclax penetrates in cerebrospinal fluid of an acute myeloid leukemia patient with leptomeningeal involvement

Condorelli, Angelo Giuseppe; Matteo, Cristina; Leotta, Salvatore; Schininà, Giovanni; Sciortino, Roberta; Piccolo, Gianna Maria; Parrinello, Nunziatina Laura; Proietto, Maria; Camuglia, Maria Grazia; Zucchetti, Massimo; Milone, Giuseppe; Raimondo, Francesco Di

doi:10.1007/s00280-021-04356-5

Cited by 10 publications

(8 citation statements)

References 14 publications

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“…Venetoclax concentrations were evaluated 23, 30, and 37 days after initiating treatment in another male adult patient presenting with a complete remission in the bone marrow after hematopoietic stem cell transplant, but with a blast crisis detected in the CNS, and formerly receiving other chemotherapy. The CSF-TPRs were 0.32–0.40%, corresponding to CSF-UPRs of at least 32–40% [ 96 ].…”

Section: Resultsmentioning

confidence: 99%

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Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces—A Review

et al. 2023

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Orally administered, small-molecule anticancer drugs with tumor-specific cellular protein targets (OACD) have revolutionized oncological pharmacotherapy. Nevertheless, the differences in exposure to these drugs in the systemic circulation and extravascular fluid compartments have led to several cases of therapeutic failure, in addition to posing unknown risks of toxicity. The therapeutic drug monitoring (TDM) of OACDs in therapeutically relevant peripheral fluid compartments is therefore essential. In this work, the available knowledge regarding exposure to OACD concentrations in these fluid spaces is summarized. A review of the literature was conducted by searching Embase, PubMed, and Web of Science for clinical research articles and case reports published between 10 May 2001 and 31 August 2022. Results show that, to date, penetration into cerebrospinal fluid has been studied especially intensively, in addition to breast milk, leukocytes, peripheral blood mononuclear cells, peritoneal fluid, pleural fluid, saliva and semen. The typical clinical indications of peripheral fluid TDM of OACDs were (1) primary malignancy, (2) secondary malignancy, (3) mental disorder, and (4) the assessment of toxicity. Liquid chromatography–tandem mass spectrometry was most commonly applied for analysis. The TDM of OACDs in therapeutically relevant peripheral fluid spaces is often indispensable for efficient and safe treatments.

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Section: Resultsmentioning

confidence: 99%

“…Acetonitrile-n-butylchloride 1:4 was used for extracting erlotinib [ 50 ]. Erlotinib [ 45 ] and venetoclax [ 96 ] were extracted by applying hexane-ethylacetate 1:1. In a single case, the method of LLE was not detailed [ 58 ].…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces—A Review

et al. 2023

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“…17 None of analyses mentioned CSF samples. There is little evidence that VEN is effective for patients with hematological malignancies and central nervous system (CNS) involvement, although some observations have been made in cases of a CLL patient, 28 an AML patient 29 and an acute promyelocytic leukemia (APL) patient 30 suggest that blood-brain barrier is crossed by VEN, which reaches potential therapeutic concentrations. In addition, Badawi et al reported the pharmacokinetics of VEN in plasma and CSF samples from pediatric patients with R/R malignancies from a Phase 1 study, which demonstrates VEN's ability to cross into the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

Zhao,

Guo,

Zhu

et al. 2024

DDDT

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Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V 2 /F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V 2 /F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V 2 /F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

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“…It seems that this conclusion was inappropriate for our research, as some patients with bone involvement achieved noteworthy outcomes. In addition, VEN can cross the blood–brain barrier and play a role in the treatment of leptomeningeal relapse in patients with AML [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Real-world experience with venetoclax-based therapy for patients with myeloid sarcoma

Jian,

Cha,

Lin

et al. 2024

Discov Onc

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Background The treatment of myeloid sarcoma (MS) is challenging and has not markedly improved patient prognosis. The introduction of venetoclax (VEN) has changed the treatment of MS, and venetoclax-based therapy has been described as very promising in several case reports. Methods In this retrospective study, we analyzed the treatment outcomes of 14 patients with MS treated with venetoclax-based therapy at The First Affiliated Hospital of Xiamen University from January 2020 to October 2023 Results The cohort consisted of 7 (50%) women and 7 (50%) men with an average age of 37.5 years. Four patients (28.6%) had isolated MS de novo, 2 (14.2%) were diagnosed synchronously with AML, and 8 (57.2%) had isolated extramedullary relapse. The most common sites for MS in our cohort were the skin and lung, followed by the spinal canal, soft tissue, bone and kidney. Five patients were affected at more than three sites. Nine patients received VEN in combination with azacytidine, and 5 patients received VEN in combination with other agents. The median number of venetoclax therapies administered was 2 cycles (range: 1–10 cycles). A response was observed in all patients included in the study, with 8 patients (57.2%) achieving a CR and 3 patients (21.4%) achieving a PR, corresponding to an ORR (including CR and PR) of 78.6%. The median follow-up time for all patients was 13 months (range 1–44 months), and the 1 year OS for all patients was 67.7%. Conclusions Venetoclax-based therapy shows excellent efficacy and safety in MS patients in the “real world” at a single institution, and a corresponding prospective study is needed to verify this conclusion.

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Venetoclax penetrates in cerebrospinal fluid of an acute myeloid leukemia patient with leptomeningeal involvement

Cited by 10 publications

References 14 publications

Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces—A Review

Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces—A Review

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

Real-world experience with venetoclax-based therapy for patients with myeloid sarcoma

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