A Pharmacokinetic/Pharmacodynamic Model of Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia Patients Treated with Flavopiridol

Abstract

Purpose Flavopiridol, the first clinically evaluated cyclin dependent kinase inhibitor, demonstrates activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS. Experimental Design A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates. Results Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy < 10 cm or > 10 cm during the first two treatments was 0.111 (SE% 13.0%) and 0.265, (SE% 17.9%) respectively, when flavo-G area under the plasma concentration vs. time curve was at its median value in whole patient group. Conclusions This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine if the associations between TLS, gender and glucuronide metabolites are relevant in CLL patients treated with other cyclin dependent kinase inhibitors.

Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia

“…23,24 Importantly, there was no difference in overall toxicity between FLAM and 7+3. TLS was a major concern given the high rates of TLS with flavopiridol in chronic lymphocytic leukemia [25][26][27] and consistent 7%-10% incidence of grade 3 or more TLS in our prior phase II studies. [10][11][12] Three patients treated with FLAM on this study had grade 4 TLS, and 2 patients died due to complications of TLS.…”

Final results of EFC6663: A multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia

“…Evaluation of the activity of alvocidib in combination with additional agents is planned as part of the further clinical development of alvocidib. Future studies should focus on identification of biomarkers of clinical response 29 and risk for TLS 30 . Enhanced supportive care strategies may yield further improvement in patient adherence and response rates.…”

Cyclophosphamide, alvocidib (flavopiridol), and rituximab, a novel feasible chemoimmunotherapy regimen for patients with high-risk chronic lymphocytic leukemia

“…Non-compartmental PK parameters were determined for alvocidib and alvocidib-glucuronide in Phoenix WinNonlin v.6.3. Population PK parameter estimates for both agents were determined by incorporating plasma concentration data versus time, body weight, and sex from this study into a previous dataset and population PK/pharmacodynamic model for alvocidib-induced TLS [14]. …”