Imatinib mesylate in polycythemia vera

In the September 15, 2003, issue of Blood,1 Oehler et al describe imatinib mesylate inhibition of the autonomous in vitro proliferation of peripheral blood– and bone marrow–derived polycythemia vera (PV) erythroid burst-forming units (BFU-Es). While their results superficially correlate with the previously published in vivo clinical observations of Silver,2 the conclusions of Oehler et al are at variance with their own data and the known pathophysiology of PV. First, contrary to the authors’ supposition, autonomous in vitro erythroid colony formation does not define the limits of the malignant clone in PV.3 Indeed, PV erythropoietin-independent BFU-Es could give rise to erythropoietin-dependent BFU-Es.4 Second, with respect to the actual suppression of autonomous PV BFU-Es by imatinib mesylate, in 7 of the 13 patients studied, in vitro colony formation was not sufficiently robust for meaningful interpretation of the data, and for the rest, inhibition was not always complete and the dose of imatinib mesylate required was similar to that previously observed to suppress normal marrow BFU-E proliferation.5 Third, and most important, imatinib mesylate failed to significantly inhibit PV BFU-E proliferation in the presence of hematopoietic growth factors. The authors consider this to be due to the proliferation of coexistent normal erythroid progenitor cells without providing actual proof from clonality assays. However, since most, if not all, circulating PV erythroid progenitor cells derive from the malignant clone,6 it is unlikely that normal erythroid progenitor proliferation could account for the growth factor–associated resistance to imatinib mesylate, nor were these cells less sensitive to imatinib mesylate in vitro. Rather, it is more likely that it was the PV erythroid progenitor cells that were resistant. In this regard, it is also important to note that Oehler et al used unfractionated peripheral blood mononuclear cells rather than purified erythroid progenitor cells in their experiments. Since imatinib mesylate inhibits in vitro monocyte proliferation and differentiation,7 given the conditions of their experimental protocol, it is impossible for Oehler et al to determine if the results they observed were a consequence of imatinib mesylate’s effects on monocytes as opposed to erythroid progenitor cells. The hematopoietic growth factor–associated resistance of the erythroid progenitor cells to imatinib mesylate suggests that the drug was indeed acting on the monocytes in the cultured mononuclear cell population. Finally, it is worth emphasizing that PV is a disorder arising in a multipotent hematopoietic progenitor cell, not a committed erythroid progenitor cell. Indeed, the authors appear to have overlooked the observation that c-kit expression in PV is increased in these cells,8 which may account for the observed clinical effects of imatinib mesylate in this disorder.2,9,10 Chemotherapy directed at committed erythroid progenitor cells, even if effective, would be unlikely to have more impact on the natural history of PV than phlebotomy.