Neha Thakre (1)*, Corinna Maier (2)*, Jiuhong Zha (3), Rajeev M Menon (3), Benjamin Engelhardt (1), Johannes E. Wolff (4), Guillermo Garcia-Manero (5), Andrew H. Wei (6), Dale Miles (7), Sven Mensing (1), Sathej Gopalakrishnan (1)
Institution: (1) Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH Co. KG, Ludwigshafen, Germany, (2) Institute of Mathematics, University of Potsdam, Potsdam, Germany; Graduate Research Training Program PharMetrX, Freie Universität Berlin and University of Potsdam, Berlin, Potsdam, Germany, (3) Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA, (4) Oncology Development, AbbVie Inc., North Chicago, IL, USA, (5) Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, (6) The Alfred Hospital and Monash University, Melbourne, Australia, (7) Genentech Inc., South San Francisco, California, USA *Equally contributed to the work
Introduction: Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenia (anemia, neutropenia, thrombocytopenia), hypercellular bone marrow, and dysplastic hematopoietic progenitors. MDS tends to transform to acute myeloid leukemia (AML). Death is commonly caused by the effects of cytopenia, particularly neutropenia leading to infections or thrombocytopenia leading to bleeding [1]. Approximately half of the population with high-risk MDS have a median survival less than 1 year with best supportive care [2]. Finding efficacious treatment regimens in MDS remains a challenge as it involves understanding of both disease induced and treatment related cytopenias.
Objectives: The objective was to develop a semi-mechanistic model of disease progression in MDS, involving all relevant hematopoietic cells which could describe the effect of drug intervention with venetoclax in combination with azacitidine, a hypomethylating agent. The model was subsequently used to simulate different treatment regimens (with respect to venetoclax dose, number of cycles, venetoclax dosing duration in a cycle) and compare the outcomes.
Methods: We developed a semi-mechanistic population pharmacokinetic-pharmacodynamic (PK-PD) model of disease progression in MDS. Homeostasis of neutrophils, red blood cells and platelets along with the effect of drug treatment were modelled using three parallel and competing Friberg type models [3], one for each cell-type. In addition to this, crowding in the bone marrow due to an excess of stem cells, MDS blasts and pro-genitor cells and its effect on hematopoiesis were parameterized. The model was fit to longitudinal data (neutrophil, red blood cell and platelet count in the blood and blasts in the bone marrow) from 57 treatment naïve, higher-risk MDS subjects from an ongoing clinical study of venetoclax (100 mg, 200 mg, 400 mg, 800 mg for 14 or 28 days in each 28-day cycle) in combination with azacitidine (75 mg/m2 on days 1-7 of each cycle). NONMEM® [7.4.2] with SAEM was used to estimate parameters and inter-individual variabilities. Simulations were conducted in R.
Results: The semi-mechanistic PK-PD model described the observed data well and showed adequate predictive ability across all considered cell types. The model was validated through visual predictive checks and numerical predictive checks. Complete remission (CR) rates and marrow complete remission (mCR) rates were predicted close to the observed rates in the clinical study. Simulated efficacy (recovery of blast count, CR and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints are close to the expected outcomes from various dosing regimens.
Conclusions: A semi-mechanistic model describing drug-disease interactions in MDS has been developed that integrates multiple end points and is able to discriminate between disease-driven and drug induced cytopenia. The model may help with exploring the appropriate venetoclax dose modifications for MDS patients with different types of cytopenias.
References:
[1] Dayyani, F, et al. Cause of death in patients with lower-risk myelodysplastic syndrome. Cancer. 2010 May 1; 116.9:2174-2179.
[2] Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-32.
[3] Friberg LE1, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002 Dec 15;20(24):4713-21.
Reference: PAGE () Abstr 9304 [www.page-meeting.org/?abstract=9304]
Poster: Drug/Disease Modelling - Oncology