Emerging Marrow Fibrosis Is an Early Indicator of Imatinib Failure and Shortened Survival Time in CML Independent of Hematologic, Cytogenetic and Molecular Response

In chronic myeloid leukemia (CML), imatinib may reverse bone marrow fibrosis (MF) that has occurred before start of therapy. The risk and prognostic relevance of MF evolving during imatinib treatment are unclear as yet. Bone marrow biopsies (n = 1509) taken prospectively from Ph+ CML patients (n = 605) were examined for MF before and during therapy. 107 patients were treated with 400 mg imatinib / day, 208 with interferon-alpha +/− cytosine arabinoside, 154 with hydroxyurea and 136 with busulfan. Imatinib and interferon-alpha +/− cytosine arabinoside were significantly more effective than the other types of therapy regarding reversal of initial MF (P < 0.000005). During the follow-up period of 3 years, imatinib monotherapy was not superior to interferon-alpha or hydroxyurea in preventing evolution of MF: MF affected more than 20 % of patients and developed from small foci with increased fiber deposition to full-stage fibrosis within 1 – 2 years. Hematologic, cytogenetic and molecular response did not protect against evolution of MF as long as a complete molecular remission (i.e. bcr/abl negativity) was not achieved. Evolving MF was an independent significant predictor of therapy resistance and shortened survival time of patients irrespective of the type of treatment (P < 0.00005). Conclusion: Although imatinib reverses initial MF in CML, MF may evolve during imatinib monotherapy indicating an unfavorable course of disease independent of hematologic, cytogenetic and molecular response.