PB1940 LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR DURING TREATMENT OF CML PATIENTS WITH IMATINIB – A RETROSPECTIVE ANALYSIS

Abstract

Background: Role of pro-angiogenic cytokine vascular endothelial growth factor (VEGF) in the course of chronic myelogenous leukemia (CML) and variations of its levels during treatment with interferon alfa and tyrosine kinase inhibitors (TKI) are being discussed in the literature reports. Aims: Aim of this study was to clarify a possibility to use the monitoring of VEGF levels for prognosis of the long-term progression-free survival of the patients with CML. Methods: Retrospective analysis of the VEGF levels at different time-points was performed in 47 patients with different kinds of response and duration of treatment with imatinib (400-800 mg daily) followed from 2000 to 2018 due to chronic phase CML. Treatment response was evaluated by karyotyping and quantitative real-time polymerase chain reaction (PCR). Serum level of VEGF was determined by immunoenzyme analysis using commercial Biosource kits. Results: All the patients were divided according to the duration of their CML treatment into the following groups. Group 1: 20 patients treated with imatinib mesylate (IM) frontline (3 patients) or as a second line therapy (17 patients) after interferon alfa. Median disease duration was 13 years (11-18). Complete cytogenetic response (CCyR) and major molecular response (MMR) was confirmed in 17 (85%) of the patients. After 10 years of IM treatment BCR-ABL was not detectable in 11 of the patients (64%), other 6 had MMR. Group 2: 10 patients treated with IM frontline. Median duration of CML was 8 years (7-10). All of the patients reached CCyR, in 7 of them MMR was detected (4 – MMR; 3 – BCR-ABL was undetectable). Group 3: 17 patients treated with IM administered after 2-3 lines of prior therapy. Among these patients 12 developed progression to the advanced disease stages by 5 years of treatment, the remaining members of this group were switched to nilotinib due to the lack or loss of response. They subsequently achieved cytogenetic and molecular response. Results of serum VEGF levels at different time-points during 60 months of IM treatment are summarized in Fig.1. The baseline parameters were comparable in all 3 groups. However starting from 1,5 months of treatment in patients of group 1 and 2 serum VEGF started reducing and in some cases with slight fluctuations remained comparable to the healthy individuals during all 60 months of therapy. In patients of the third group who either did not reach hematological and cytogenetic response or lost it during treatment serum VEGF level remained almost unchanged as compared to the baseline. The difference between VEGF values of groups 1,2 and group 3 was found to be significant at 3, 12, 48 and 60 months of IM treatment.Summary/Conclusion: We believe that monitoring of the VEGF serum levels during therapy with IM has 2 aspects. First of all rapid reduction of this cytokine during initial months of treatment may be a sign of high sensitivity of leukemic cells to the medication and optimal expected response which was confirmed in patients of groups 1 and 2 by karyotyping and PCR. Secondly patients with low levels of VEGF not achieving molecular response after 12 months of treatment but who continued IM therapy as the best available option reached optimal response after 24 months. Evaluation of VEGF levels as a marker of angiogenesis intensity in CML may be useful for patients who plan to stop treatment with IM as an addition to molecular monitoring of disease. Lack of reduction of VEGF levels in patients treated with IM in our opinion could be a negative prognostic factor.