Histamine Monitoring in Patients with CML during Treatment with Imatinib: Comparison to Monitoring by Cytogenetics and BCR/ABL.

Abstract

Abstract The tyrosine kinase inhibitor STI571=imatinib is highly effective in the treatment of chronic myeloid leukemia (CML). Although most patients (pts) show a complete cytogentic response (CCR) to this tyrosine kinase inhibitor, drug resistance may occur. Therefore, monitoring of minimal residual disease (MRD) during imatinib-therapy is of clinical importance. However, most MRD-parameters require special technology and equipment and are expensive. We found that histamine levels are highly upregulated at diagnosis in pts with CML (controls, n=39: median, 55.2 ng/ml, range, 19.1–108 ng/ml vs CML, n=44: median, 5,684.5 ng/ml, range, 181–47,816 ng/ml; p<0.0005) and correlate with the presence of basophils (R=0.87). To define the value of whole blood histamine as a marker of MRD in CML, histamine levels were determined serially by RIA before and during treatment with imatinib in 80 pts with CML (chronic phase, CP, n=70; accelerated phase, AP, n=10). Of the pts with CML-CP, 29 were previously untreated, whereas 41 pts had received interferon-alpha or a bone marrow transplant prior to imatinib. From the 10 pts with CML-AP, 3 had received previous interferon-alpha. Imatinib was given at a dose of 400 mg/day (CML-CP) or 600 mg/day (CML-AP and CP pts who did not respond adequately to 400 mg/day) orally. The rate of complete cytogenetic response (CCR) amounted to 77.6%, the rate of major cytogenetic response was 80%. Blood histamine levels decreased significantly in CML pts during treatment with imatinib, and returned to normal levels in all pts with CCR. In most pts, loss of CCR was accompanied or was preceded by a recurrent increase in histamine as well as an increase in BCR/ABL determined by light cycler-based real time PCR. The pts who did not enter CCR exhibited higher histamine levels and higher levels of BCR/ABL compared to those with continuous CCR (p<0.05). Unexpectedly, whereas the numbers of basophils were found to correlate well with histamine levels during therapy with imatinib (R=0.96), no correlation was found between histamine and Ph+ metaphases (R=0.34) or histamine and percentage of BCR/ABL (R=0.14), suggesting that basophil-histamine is an independent variable. Basophil-histamine should thus be considered as a simple and reliable additional marker to monitor MRD in pts with CML.