Pretreatment Cytogenetic Abnormalities in Polycythemia Vera (PV) Determines the Effectivnes of Imatinib : Studies from a Multi-Institutional Trial.

Abstract

In patients (pts) with hypereosinophilic syndrome imatinib selectively inhibits a receptor for the platelet-derived growth factors, PDGFRA and PDGFRB, and the receptor for stem cell factor (c-kit), the expression of which is increased in PV. Preliminary data suggests imatinib reduces phlebotomy requirements and may suppress endogenous erythroid colonies in PV. One goal of the multi-institutional trial of imatinib in PV (400 mg po/day at initiation) was to determine the possibility of eliminating abnormal cytogenetic clones. Of 27 PV pts enrolled, 20 had cytogenetic studies. Fifteen pts showed a normal initial karyotype and 5 pts (25%) were cytogenetically abnormal at imatinib initiation. These included: trisomy 9 (2 pts), isochromosome for 9p and 9q (1pt), monosomy 21 (1 pt) and del(5)(q15q32) (1pt). Fifteen sequential cytogenetic studies of 180 metaphase cells from 3 pts showing chromosome 9 abnormalities did not show a reduction in the percentage of abnormal cells. In contrast, monosomy 21, present in 5 of 25 metaphases was gradually eliminated with imatinib within 7 months. In the subsequent 8 months two follow up studies demonstrated only normal cells in 40 metaphase and 600 interphase cells. Deletion (5)(q15q32), detected in 55% metaphase and 77% interphase cells (using EGR1 probe), prior to imatinib, was reduced to 23% in interphase cells within 5 months. However, conventional cytogenetics showed 15 of 16 metaphase cells (94%) with del(5q), consistent with a proliferative advantage of the del(5q) clone. In addition, there was marked diminution in splenomegaly. Due to imatinib intolerance and persistent thrombocytosis of over 1 X 106, the drug was discontinued. To further elucidate the mechanism of imatinib in PV, progenitor cells were grown before and during imatinib treatment. Before imatinib, from the marrow sample showing 77% del(5q) cells, both epo- dependent and independent colonies, as well as CFU colonies were examined and all 800 evaluated interphase cells were normal. With a diminution of the del(5q) clone to 23%, 600 cellsi from epo independent colonies did not show del (5q). The inability to detect del (5q) in progenitor marrow cells is consistent with the notion that PV, like CML, has a multistep pathogenesis in which chromosome abnormalities are a later event in clonal progression. These observations further suggest that imatinib did not eradicate rearrangements of chromosome 9. However, 2 of 5 pts with abnormalities, -21 and del(5q), had either complete eradication or diminution of the abnormal cytogenetic clone. These findings suggest that different cytogenetic abnormalities, representing different molecular events, determine the diverse responses to imatinib observed in PV. Thus, cytogenetic abnormalities may be useful in predicting the biologic effect of imatinib in patients with PV.