Efficacy of Chemotherapy in Acute Leukemia Patients Resistant to Previous Standard Treatment According to the Series Measurement of WT1 Gene Expression

Abstract

Aim. To estimate the efficacy of chemotherapy in acute leukemia patients resistant to previous standard treatment according to the series measurement of WT1 expression. Materials & Methods. The series measurement of WT1 expression formed the basis of the efficacy estimation of induction chemotherapy in 31 patients (15 men and 16 women aged from 3 months to 68 years; the median age was 28 years) with prognostically unfavourable variants of acute myeloid (AML) and lymphoblastic leukemia (ALL) (23 AML and 8 ALL patients). The WT1 gene expression was measured at baseline and 2-3 weeks after the treatment by the quantitative real-time PCR. The threshold level for detection was 250 copies of WT1/10<sup>4</sup> copies of ABL. The cytogenetic profile of leukemia cells was assessed by standard cytogenetics and FISH. Results. The baseline expression level of WT1 varied from 305 to 58,569 copies/10<sup>4</sup> copies of ABL. The expected reduction of WT1 expression after the first induction chemotherapy treatment was reported in 22/23 (96 %) AML patients and in 6/8 (75 %) ALL patients. According to our results WT1 expression reached the threshold in 13/31 (42 %) patients, including 9 AML patients and 4 ALL patients. After 11/31 (35 %) patients received the second course of treatment, WT1 expression level became normal in 8 cases (5 ALL and 3 AML patients). Despite high dose chemotherapy, HSCT and such agents as blinatumomab and gemtuzumab, an unfavourable outcome was observed in 18/31 (58 %) patients including 6 patients with complex karyotype (CK+) and 2 patients with monosomal karyotype (MK+). Once the MK+ and CK+ combination was observed, in another case the MK+ was combined with the prognostically unfavourable inv(3)(q21q26) inversion. Conclusion. Our results show that the molecular monitoring should be included as part of treatment of the prognostically unfavourable acute leukemia. The WT1 gene was shown to be the most appropriate marker. WT1 expression was shown to correlate with the common fusion genes allowing to estimate the blast cell count at the molecular level.

Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamicin and hematopoietic stem cell transplantation

“…All the patients were resistant to standard chemotherapy, thus using Gemtuzumab ozogamicin (GO, Mylotarg) in subsequent treatment. One of these patients and his WT1 changes was earlier reported as a case No.22 [13]. These data were supplemented by new results concerning BAALC gene expression.…”

“…It should be noticed here that our choice of Mylotarg was determined by some biological effects of this drug. Firstly, we have recently revealed unexpected response of leukemic cells to this drug, accompanied by elevation of WT1 gene expression [13]. Secondly, some data suggest a direct action of Mylotarg upon immature precursor cells with CD34 + CD38 --phenotype [16].…”

“…One line of evidence is based on some cases of acute promyelocytic leukemia (APL), where higher level of gene WT1 expression was coupled to lower blast cell numbers in bone marrow [12]. Moreover, this conclusion is also supported by similar discrepancy between higher WT1 gene expression and lower numbers of bone marrow blasts in 30% to 40% AML patients, both before and after HSCT [6,9,10,13,14]. In our opinion, this phenomenon may be also explained by presence of active expression of WT1 gene by more mature precursors [12,15].…”

Clinical significance of BAALC overexpression for predicting post-transplant relapses in acute myeloid leukemia

“…It is essential that the above-mentioned precursor cells with CD34+/CD38-phenotype may be responsible to regulate size of blast cell population, which, in turn, is able to express WT1 gene mRNA. Therefore, the latter gene is considered to be a basic molecular marker for AML relapses [19]. Since both these markers are functionally associated with changing levels of leukemic cells in AML patients treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT), the parallel study of their expression seems to be quite important both in clinical and tumor biology aspects [5,20].…”