Bone marrow changes in chronic myelogenous leukaemia after long-term treatment with the tyrosine kinase inhibitor STI571: an immunohistochemical study on 75 patients.

AIMS: To carry out an immunohistochemical study on bone marrow (BM) biopsy specimens in 75 patients with chronic myelogenous leukaemia (CML) on long-term STI571 therapy. METHODS AND RESULTS: Sequential BM specimens taken at intervals of 21 +/- 6 months were investigated by enzyme- and immunohistochemistry including proliferating cell nuclear antigen and apoptosis. Evaluation was performed either by semiquantitative scoring or by morphometry (CD61+ megakaryopoiesis). In 41 patients with chronic phase CML, treatment resulted in a significant decrease in cellularity and neutrophil granulopoiesis contrasting with an accumulation of erythroid precursor cells. Morphometry showed a reduction of abnormal micromegakaryocytes consistent with normalization. Regression of myelofibrosis was identified in eight of 15 patients, whereas progression occurred in 17 patients; mostly in those with acceleration and blastic crisis. The increased post-treatment incidence of reactive lymphoid nodules was remarkable. Myeloblasts, CD34+ progenitors and immature myelomonocytic cells initially decreased, but recurred in 14 patients who later developed a relapse. STI571 exerted an inhibitory effect on cell proliferation associated with enhanced apoptosis in responding patients. CONCLUSION: Long-term treatment with STI571 exerts pronounced changes on BM histopathology that not only involve haematopoiesis and stromal constituents, but also proliferation and apoptosis.

[Regression of the Philadelphia chromosome (bcr/abl)-positive myelo- and megakaryopoiesis after Imatinib (STI571) therapy in chronic myelogenous leukemia (CML)]. / Regression der Philadelphia-Chromosom (bcr/abl)-positiven Myelo- und Megakaryopoiese unter Imatinib(STI571)-Therapie bei chronischer myeloischer Leukämie (CML).

In chronic myeloid leukemia following therapy with Imatinib (STI571) hematologic and cytogenetic response is associated with conspicuous changes of bone marrow morphology. However, it is not known to which extent these alterations are accompanied by a loss of the bcr/abl translocation. To study regression of the leukemic cell population we recruited 14 patients lacking pretreatment. Therapy resulted in a reduction of CD61(+) megakaryopoiesis. Dwarf megakaryocytes characteristic for this disorder were replaced by large, normally appearing cells of this lineage. Morphometric analysis confirmed the significant decrease in the number of micromegakaryocytes and yielded planimetric parameters in keeping with normalization. Moreover, a fluorescence in-situ hybridization study in five patients of this cohort revealed that before therapy 70% of all myeloid cells exhibited the bcr/abl gene. Regarding megakaryopoiesis about 65% of the micromegakaryocytes displayed positive signals. Following treatment these bcr/abl(+) cell populations decreased significantly while the emerging large megakaryocytes lacked a proper labeling. Because cytogenetic response and reduction of atypical micromegakaryocytes are linked, this feature may be useful to monitor therapeutic efficacy.