NT-Probnp As Personalized Medicine Tool and New Biomarker Predicting Response to Chemotherapy and Survival in AML
Authors: Graf Irene , Greiner Georg , Marculescu Rodrig , Gleixner Karoline V. , Herndlhofer Susanne , Stefanzl Gabriele , Knoebl Paul , Jaeger Ulrich , Hauswirth Alexander , Schwarzinger Ilse , Thalhammer Renate , Kundi Michael , Hoermann Gregor , Mitterbauer-Hohendanner Gerlinde , Valent Peter , Sperr Wolfgang R. 
Published: November 2021

Abstract
Acute myeloid leukemia (AML) is a hematologic neoplasm resulting from abnormal proliferation and accumulation of clonal myeloid precursor cells. The course and prognosis of AML vary depending on the type of AML, karyotype, and molecular abnormalities. In addition, patient-related factors and comorbidities are of prognostic relevance. Cardiac comorbidities are of particular importance as they influence treatment tolerability, early death (ED) and survival in patients receiving chemotherapy. Brain natriuretic peptide (NT-proBNP) is a well-established marker of cardiac function and often used to predict treatment tolerability and outcome. However, so far, little is known about the impact of NT-proBNP levels on the clinical course in patients with AML.
We analyzed 312 AML patients (median age: 61 years; range 17-89 years; &lt;60 years: n=141, ≥60 years: n=171; f:m-ratio: 1:1.15; observation period: February 1998 - September 2020) treated with a daunorubicin (day 1-3) and ARA-C (day 1-7)-based induction therapy and consolidation with up to 4 cycles of intermediate-dose (2x1g/m² for 3 day) or high-dose (2x3g/m² for 3 days) ARA-C. In 199 patients (63.8%), elevated NT-proBNP levels were detected, and in 113 (36.2%), NT-proBNP levels were within normal range (0-125 pg/mL). In 20 patients (6.4%) NT-proBNP exceeded 2000 pg/mL. NT-proBNP levels differed significantly between patients aged &lt;60 years (median: 146.7 pg/mL; range: 0.5-15930 pg/mL) and patients ≥60 years (median: 226 pg/mL; range 1-19883 mg/dL; p=0.003). A weak correlation was observed between NT-proBNP levels and other clinical or laboratory parameters like age (R=0.183; p=0.001), lactate dehydrogenase (LDH; R=0.242; p&lt;0.001) and serum creatinine levels (R=0.256; p&lt;0.001). Applying the Charlson comorbidity index (CCI), patients without comorbidities (n=60) had the lowest median NT-proBNP levels followed by those with moderate (n=79), intermediate (n=95), and high-risk comorbidities (n=56) (139.3 pg/mL, 156.0 pg/mL, 199.5 pg/mL, and 307.7 pg/mL, respectively; p=0.028). The Eastern Cooperative Oncology Group (ECOG) performance status was available in 176 patients. Those with ECOG 1 had a significantly higher median NT-proBNP (225.1 pg/mL, range: 0.5-5369 pg/mL) compared to patients with ECOG 0 (133.6 pg/mL, range: 1-15930 pg/mL) (p=0.008). Following induction therapy, 219 patients (70.2%) achieved complete remission (CR), 63 (20.2%) had no remission (NR), and 30 (9.6%) died within 60 days after chemotherapy (ED). Median NT-proBNP levels differed significantly among CR, NR and ED patients, with 153.3, 225.9, and 735.5 pg/mL, respectively (p&lt;0.0001) (Figure 1). The difference in NT-proBNP levels among CR, NR and ED patients was significant in patients aged &lt;60 years and in those aged ≥60 years (p=0.004 and p=0.001, respectively). In multivariate analysis including NT-proBNP together with age, sex, the ELN-2009 classification, white blood count (WBC) and CCI, NT-proBNP remained an independent prognostic factor for treatment response (CR, NR, or ED; p&lt;0.001). In this analysis, age and the ELN-2009 classification were also independent prognostic markers (p=0.014 and p&lt;0.001 respectively). The median overall survival (OS) was 1.38 years (IQR 0.96-1.84) in the total cohort of patients. Significant differences in OS were observed when comparing patients with normal (&gt;125 pg/mL), moderately elevated (125-2000 pg/mL), and highly elevated NT-proBNP levels (p=0.0002). The median OS in these groups was 3.08 (IQR 0.8-16.5), 1.14 (IQR 0.5-4.8), and 0.34 (IQR 0.04-3.7) years, respectively (Figure 2). In multivariate analysis including NT-proBNP, age, ELN-2009 classification, WBC, sex, and CCI, NT-proBNP remained an independent predictive variable for OS (p=0.006). Significant differences were also observed when analyzing OS in patients &lt;60 years (p=0.012) but were not seen in those aged ≥60 years (p=0.203). Similar results were obtained for continuous complete remission (CCR) (median CCR of all patients: 1.6 years), where NT-proBNP was of prognostic significance in the cohort aged &lt;60 years (p=0.011) but not in patients aged ≥60 years.
Together, NT-proBNP is a new emerging biomarker and independent prognostic factor indicating the risk of induction failure, ED and reduced survival in patients with AML. The predictive power of NT-proBNP is particularly strong in AML patients aged &lt;60 years.
Figure 1 Figure 1.

Disclosures
Gleixner: Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria. Knoebl: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hoermann: Novartis: Honoraria. Valent: Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; OAP Orphan Pharmaceuticals: Honoraria. Sperr: AbbVie, BMS-Celgene, Daiichi Sankyo, Deciphera, Incyte, Jazz, Novartis, Pfizer, StemLine, Thermo Fisher: Honoraria, Research Funding.