title: Explaining the in vitro and in vivo differences in leukemia therapy.
abstract: The majority of patients with chronic myeloid leukemia in early chronic phase (CML-ECP) who are treated with imatinib achieve a complete cytogenetic response with a significant reduction in the risk of progression to advanced phases. Recent studies show that therapy of CML-ECP with nilotinib leads to a faster and deeper response compared to imatinib. However, in vitro data indicates that there is no detectable difference in inhibition of signaling downstream of Bcr-Abl between the two agents, and that neither drug induces apoptosis of CML CD34 (+) cells. We use a computational model of hematopoiesis and CML combined with serial quantitative data of disease burden under imatinib and nilotinib therapy to explain this apparent disconnect between in vivo and in vitro responses. We show how a subtle difference in the differentiation rate of CML cells under therapy with either agent, with marginal impact onto the in vitro studies, translates into a significantly different reproductive fitness of treated cells in vivo, providing a sizeable difference, hence providing an explanation for the superior response observed with nilotinib.
authors.affiliation: Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Lenaerts
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.forename: Arne
authors.initials: A
authors.lastname: Traulsen
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Pacheco
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.forename: David
authors.initials: D
authors.lastname: Dingli
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib