Brain Natriuretic Peptide (BNP) Level as Marker of Cardiac Function in Imatinib - Treated Chronic Myeloid Leukemia Patients: No Evidence of Cardiotoxicity of Imatinib Therapy.
Authors: Tiribelli Mario , Colatutto Antonio , Marin Luciana , Toffoletti Eleonora , Barbina Giuseppe , Qualizza Ugo , Tonutti Elio , Candoni Anna , Medeot Marta , Damiani Daniela , Morocutti Giorgio , Pierguido Sala , Fanin Renato 
Published: October 2019

Abstract
In the last year, the issue of cardiotoxicity of imatinib mesylate (IM) was on focus. Emerging data seem to deny an increased risk of cardiac events in patients treated with IM, which is the frontline therapy in chronic myeloid leukemia (CML). B-type natriuretic peptide (BNP) is released by the heart in response to myocardial tension and is considered an accurate test for the diagnosis of heart failure. The measurement of BNP in the serum is a rapid and easy tool for evaluation of ventricular function, also in asymptomatic patients. We have measured BNP level in 50 consecutive patients (33 males and 17 females) with IM treated chronic phase CML. Patients were enrolled, after informed consent was obtained, as they presented for a follow-up visit at our Institution. BNP was measured using a direct chemiluminescent sandwich immunoassay: the analytical range extends from 0 to 5000 pg/ml, with a sensitivity <2 pg/ml. Normal range is as follows: <100 pg/dl. Median age was 59 (range: 23–82). Median duration of IM therapy was 38.5 months (range: 1–81). IM mean daily dose at time of sample collection was 404 mg (SD ±121). Thirty three patients (66%) were receiving 400 mg/day, 13 (26%) a lower daily dose (200 mg in 1 case, 300 mg in 12) and 5 patients (10%) had higher IM doses (600 mg in 2, 800 mg in 3). The mean level of BNP in the whole population was 22.0 pg/ml (SD ±26.4); only two patients had values >100 pg/ml. There was a linear correlation between age and BNP levels (t–value=3.850, p=0.0003). Nine out of 24 (37%) patients aged ≥60 had BNP >22 pg/ml, compared to only 1/25 (4%) in the cohort <60 years old (χ2=19.7, p<0.0001). BNP level was not affected by IM daily dose (<400 mg = 34.1±28.6, 400 mg = 18.5±26.2, >400 = 13.5±9.3) or by therapy duration (<36 months = 25.2±30.4, ≥36 months = 19.4±22.6). Considering cardiovascular risk factors, 18 patients (36%) had hypertension, while diabetes and hyperlipemia were present in 2 and 4 cases, respectively. Patients with hypertension had higher levels of BNP (34.9±35.1 vs 14.8±16.5, p=0.03), despite an equivalent IM dose (378±81 vs 419±138 mg) and treatment duration (39.5 vs 30.5 months). No patient experienced major cardiac adverse event during IM therapy. An echocardiogram was performed in the two patients with higher BNP values: both of them were older than 60 and suffered from hypertension, but echocardiogram revealed a normal left ventricular ejective function (LVEF ≥65%). To further assess IM impact on BNP levels, five consecutive patients, who were diagnosed with CML during study period, were tested for BNP before start of IM therapy and after 1, 2 and three months of therapy. No significant modification in BNP level was observed during treatment with IM. In conclusion, Imatinib therapy does not cause an increase in BNP levels. This gives an indirect confirm to the cardiac safety profile of the drug, as indicated also by the lack of major cardiac toxicities in our patients. BNP levels were affected by hypertension and by advanced age, but the latter could be a bias due to a higher incidence of hypertension in the elderly cohort.