The Residual Malignant Cells Could Be Masked by Therapeutic Use of Granulocyte-Colony Stimulating Factor in the Patients with AML1/ETO+ Acute Myelogenous Leukemia.

Abstract

Among 200 AML cases for the past 7 years, we observed 6 cases with acute myelogenous leukemia(AML) which showed remission by morphologic criteria in BM examination, but revealed clonal changes in most cells by FISH after G-CSF administration. Remarkably, 5 of 6 cases were AML with AML1/ETO rearrangement, and FISH study revealed that most of AML1/ETO+ cells were mature neutrophils, suggesting differentiation of leukemic cells. A true remission of leukemia was probably never achieved with G-CSF alone and 4 of 6 cases have relapsed and 3 have died. Most cases of present study had infections or were suspected as infection, thus G-CSF which was administered and endogenously produced by infection seems to bring synergic effect (Table 1). To elucidate the mechanism involved in this finding, we measured the numbers of G-CSF receptor (G-CSFr) in AML1/ETO positive (Kasumi-1) and negative AML cell lines (CTV-1), and in leukemic cells from 8 patients with AML1/ETO positive and negative AML by flow cytometry. The number of G-CSFr was 2,673/cell in AML1/ETO+ Kasumi-1 cell line and 522/cell in AML1/ETO− CTV-1 cell line(Table 2). In 8 patients with AML, the number of baseline G-CSFr in AML1/ETO+ AML cells was significantly higher than that in AML1/ETO− AML cells (mean number 446.2 VS 226) (p value =0.0029). We assume that therapeutic G-CSF administration could result in differentiation and proliferation of AML1/ETO+ leukemic cells due to higher expression of G-CSF receptor. In conclusion, we strongly recommend that complete remission should be confirmed by FISH test, because malignant clone can be differentiated and masked in morphological examination or conventional cytogenetic test, especially for AML1/ETO+ AML.Table 1Clinical and laboratory summary of casesCase No.Initial diagnosisFollow-up*CytogeneticsFISH% Blast in BMCytogeneticsFISHOther findingsOutcomes1t(8;21)(q22;q22)AML1/ETO: 94.5%0%(PB)-AML1/ETO:95.5%(PB)PneumoniaRelapse2t(8;21)(q22;q22)AML1/ETO: 98%39%-AML1/ETO:99%Suspected infection, G-CSF administrationRelapse, death3t(8;21)(q22;q22)AML1/ETO: 47%0.5%t(8;21)(q22;q22)AML1/ETO:55%Suspected infection, G-CSF administrationAlive4t(8;21)(q22;q22)AML1/ETO: 94.5%3.9%t(8;21)(q22;q22)AML1/ETO:77.5%FeverRelapse, death5t(8;21)(q22;q22)AML1/ETO: 93.5%0.3%Normal karyotypeAML1/ETO:33.5%G-CSF administrationRelapse6Trisomy 8Trisomy 8: 98.5%28.1%Trisomy 8Trisomy 8:96.5%Candidiasis, G-CSF administrationDeath* when showing discrepancy between morphologic examination and FISH testTable 2Quantitation of G-CSF receptors in Kasumi-1 and CTV-1 cell lineG-CSF receptor (PE molecule per cell)BaselineAfter G-CSF administrationKasumi-1 cell line2,6731,953CTV-1 cell line522556