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In chronic myeloid leukemia (CML), imatinib may reverse bone marrow fibrosis (MF). Whether the unfavorable prognosis of MF is also reversed and whether imatinib guarantees against evolution of MF are unclear as yet. Fifty-nine patients with Ph+ CML treated with > or = 400 mg imatinib/day were examined for MF in 6- to 12-month intervals. Imatinib effectively reversed initial MF (P

Imatinib may reverse bone marrow fibrosis (MF) in chronic myeloid leukemia (CML). The risk of emergence or relapse of MF and its prognostic relevance are not known as yet. 110 patients with Ph+ CML recruited in two trials and treated with 400 mg imatinib / day were examined for the risk of MF and its prognostic significance. Imatinib effectively reversed pretreatment MF (P = 0.0002), and pretreatment fiber increase did not significantly reduce the probability of achieving a hematologic, cytogenetic and major molecular response. However, during a follow-up period of 4 years, small foci with fiber increase (FFI) and MF relapsed in 13 % (5 / 38) of patients, and among patients with an initial normal fiber content (n = 72), FFI emerged in 26 % with transformation to full-blown MF in 38 % of them. FFI occurred in 3 / 27 cases with a major molecular response. The risk of emergence or relapse of FFI amounted to 13.7 % and of full-blown MF to 5.9 % per year, and the risk of acceleration and death increased to 90 % two years after occurrence of MF. FFI could be predicted neither by the risk score (Sokal, Hasford) nor the hematologic, cytogenetic and molecular response, nor by clonal evolution during imatinib treatment. In multivariate analysis, emergence or relapse of FFI and MF turned out to be a significant independent predictor of imatinib failure (P = 0.0003) as well as of acceleration and death of patients (P < 0.0009). CONCLUSION: Although imatinib reverses initial MF in CML, it does not guarantee against relapse or emergence of MF which affects ~ 6 % of patients per year and therefore, may become a major problem during long-term therapy of CML. Focal evolution of MF should be included in the definitions of imatinib failure and accelerated phase, and continuing imatinib treatment at the current dose is no longer appropriate for patients with emergence of FFI or MF during therapy - regardless of the degree 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.