Inference Of Imatinib (Im) Effects On Leukemic Stem Cell (Sc) Compartment Via Mathematical Modeling Of Iris Treatment Response Data

7056 Background: Continuous treatment of chronic phase CML (CML-CP) patients with imatinib (IM) induces durable responses in majority of patients with a decreasing rate of relapse (Hochhaus et al, Blood. 2007;110). We present a mechanistic mathematical model which uses 6-year follow up data from the International Randomized Study of Interferon Versus STI571 (IRIS) trial (O'Brien et al, N Engl J Med. 2003;348:994) to explore IM effects on leukemic stem cells (SCs) across the patient population. Methods: The model approximates hemopoiesis as a 4-stage process in which only the first stage, corresponding to the SC compartment, is capable of self-renewal. Leukemic SCs, early and late progenitors were assumed to have higher self-renewal and expansion/differentiation rates than their normal counterparts. Model parameters describing the patient population distributions of leukemic/total SC ratio at diagnosis and sensitivity of leukemic cells to IM, were then fitted to individual cytogenetic and molecular response (CR/MR) data from 200 randomly selected newly-diagnosed CML-CP patients with 6-year follow-up. Results: Based on our analysis, successful characterization of the wide range of clinically observed treatment responses requires the inhibition of the leukemic SC compartment by IM. The median predicted inhibition of the leukemic SC proliferation rate was 79%. The model further predicted that after 6 years of IM treatment, 45% of patients would achieve a leukemic/total SC ratio below 0.1. Conclusions: We have developed a mathematical model of IM effects on CML-CP based on 6-year CR and MR data from the IRIS trial. In contrast to prior reports (Michor et al, Nature. 2005;435), our modeling predicts that IM reduces the leukemic SC compartment in most CML-CP patients, which could provide a mechanistic rationale for the decreasing rate of relapse observed in the study population. [Table: see text]