MDS-090: Semi-Mechanistic Model to Aid Clinical Understanding of Myelodysplastic Syndromes

Abstract

Context: Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenia, hypercellular bone marrow, and dysplastic hematopoietic progenitors. Death is commonly caused by the effects of cytopenia, leading to infections or bleeding [1]. Finding efficacious treatment regimens in MDS remains a challenge as it involves understanding of both disease induced and treatment related cytopenias. Objective: The objective was to develop a semi-mechanistic model of disease progression in MDS based on clinical data, involving relevant hematopoietic cells that can describe the effect of drug intervention with venetoclax azacitidine combination therapy. The model was subsequently used to simulate different treatment regimens (with respect to dose, dosing duration in a cycle, and number of cycles) and compare the outcomes. Study Design and Data: Data from an ongoing Phase 1b study evaluating the safety and efficacy of venetoclax (400 mg or 800 mg for 28 days or 100 mg to 400 mg for 14 days in each 28-day cycle) with azacitidine (75 mg/m2 on days 1-7 of each cycle) in treatment-naive patients with higher-risk MDS were used for the analysis. The data contained venetoclax concentrations, neutrophil, red blood cell, and platelet count in the blood and blasts in the bone marrow. Methods: An integrated semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accounted for venetoclax PK and azacitidine treatment to describe time dynamics of neutrophils, red blood cells, and platelets. The model also included crowding in the bone marrow due to excess stem cells, MDS blasts, and progenitor cells, and its effect on hematopoiesis. Results: The model described the observed clinical data well and showed predictive ability across considered cell types. Complete remission (CR) and marrow complete remission (mCR) rates were predicted close to observed rates in the study. Simulated efficacy (recovery of blast count, CR, and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints are comparable to the expected outcomes from various dosing regimens. Conclusions: A model describing drug-disease interactions in MDS was developed that integrates multiple end points and differentiates disease driven from drug-induced cytopenia. Reference: [1] Dayyani, F, et al. Cause of death in patients with lower-risk myelodysplastic syndrome. Cancer. 2010 May 1; 116.9:2174-2179. Disclosures: The analysis presented was funded by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication. NT, JZ, RM, BE, JW, SM, and SG are employees of AbbVie and may hold stock. AHW receives honoraria from Novartis, Astellas, Pfizer, Macrogenics, Abbvie, Genentech, Servier, Celgene, Amgen, Astra Zeneca and Janssen. AHW also receives research funding from Novartis, Celgene, Abbvie, Servier, Astra Zeneca and Amgen. AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax. G-GM is an investigator in AbbVie funded Clinical Trials. DM is a Genentech employee and may own stock. C.M. performed the analysis at AbbVie during an internship. C.M. also receives research funding from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grunenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and Sanofi) for the PharMetrX program