BCR-ABL transcript dynamics support the hypothesis that leukemic stem cells are reduced during imatinib treatment
A partir de données portant sur 477 patients atteints d'une leucémie myéloïde chronique et traités à l'aide d'imatinib, cette étude de modélisation estime les effets du traitement sur la population de cellules souches leucémiques
Purpose: Imatinib induces a durable response in most patients with Philadelphia chromosome-positive chronic myeloid leukemia, but it is currently unclear whether imatinib reduces the leukemic stem cell burden, which may be an important step toward enabling safe discontinuation of therapy. In this paper, we use mathematical models of BCR-ABL levels to make inferences on the dynamics of leukemic stem cells. Experimental Design: Patients with at least one BCR-ABL transcript measurement on imatinib were included (N = 477). Maximum likelihood methods were used to test 3 potential hypotheses of the dynamics of BCR-ABL transcripts on imatinib therapy: 1) mono-exponential, in which there is little if any decline in BCR-ABL transcripts; 2) bi-exponential, in which patients have a rapid initial decrease in BCR-ABL transcripts followed by a more gradual response; and 3) tri-exponential, in which patients first exhibit a biphasic decline but then have a third phase when BCR-ABL transcripts rise rapidly. Results: We found that most patients treated with imatinib exhibit a biphasic decrease in BCR-ABL transcript levels, with a rapid decrease during the first few months of treatment followed by a more gradual decrease that often continues over many years. Conclusions: We show that the only hypothesis consistent with current data on progenitor cell turnover and with the long-term, gradual decrease in the BCR-ABL levels seen in most patients is that these patients exhibit a continual, gradual reduction of the leukemic stem cells. This observation may explain the ability to discontinue imatinib therapy without relapse in some cases.