Understanding Hematological Toxicities Using Mathematical Modeling

Abstract

Balancing antitumor efficacy with toxicity is a significant challenge, and drug-induced myelosuppression is a common dose-limiting toxicity of cancer treatments. Mathematical modeling has proven to be a powerful ally in this field, scaling results from animal models to humans, and designing optimized treatment regimens. Here we outline existing mathematical approaches for studying bone marrow toxicity, identify gaps in current understanding, and make future recommendations to advance this vital field of safety research further.

Quantifying Drug‐Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model

“…The final model structure contains the formation of distinct blood cell lineages as branches of transit compartments originated from a common source of early progenitors ( Figure ). Each branch incorporates the dynamics of cell proliferation, lineage differentiation, and negative feedback processes in response to stimuli . These feedback loops connect cells across lineages and regulate the proliferation and differentiation of common progenitors to rescue the depleted populations .…”

“…and . These functions define cross‐lineage effects and most likely describe the impact of signals mediated by lineage‐specific cytokines, such as erythropoietin for erythrocytes, granulocyte colony stimulating factor for neutrophils, and macrophage colony stimulating factor for monocytes, on MPP cell‐fate decision . This is a vital process enabling the rapid recovery following myelosuppression; however, we do not have experimental measurements of such cytokines in this particular study, and as a result we have taken an empirical approach based on deviations of mature circulating cell counts from baseline values.…”

“…Similarly, the effects of cytokines, such as granulocyte‐colony stimulating factor on progenitors’ proliferation and differentiation can be measured and then explicitly considered to predict the rescuing effects of adjuvant therapies during chemotherapy . For this purpose, hypotheses derived from in vitro systems, such as bone marrow organ‐on‐a‐chip, where a niche of HSCs and progenitors sustains a dynamic haematopoietic system, could be integrated into the model to quantify cytokine‐driven feedback dynamics . Other aspects are the investigations of bone marrow microenvironments or niches and the spatial properties of the haematopoietic system.…”

“…Around 10 9 red blood cells and 10 8 white blood cells are generated every hour from a common set of haematopoietic stem cells (HSCs) in the bone marrow of a healthy adult . To enhance our understanding of this process, as well as of the mechanisms behind drug‐induced myelosuppression, it is essential to quantify cell dynamics and interactions across multiple branches of the haematopoietic phylogeny rather than modeling the differentiation of cell lineages in isolation . This task is not trivial because the complexity of the system's dynamics arises from the interaction of multiple cellular prosurvival mechanisms primed by suppressive drug effects.…”

“…6 To enhance our understanding of this process, as well as of the mechanisms behind drug-induced myelosuppression, it is essential to quantify cell dynamics and interactions across multiple branches of the haematopoietic phylogeny rather than modeling the differentiation of cell lineages in isolation. 7 This task is not trivial because the complexity of the system's dynamics arises from the interaction of multiple…”