High NGF Receptor Expression on ALL Blasts - A Novel Independent Prognostic Marker Identifying Patients with Favorable Outcome.
Authors: Troeger Anja , Glouchkova Ludmila , Laws Hans-Juergen , Hanenberg Helmut , Meisel Roland , Janka-Schaub Gritta , Goebel Ulrich , Dilloo Dagmar 
Published: April 2020

Abstract
Despite the very good overall prognosis of childhood acute lymphoblastic leukemia (ALL), longtime survival may only be maintained if immunological control mechanisms prevent immune escape of leukemic blasts. Under physiological conditions members of the NGF/TNF receptor family are of outstanding importance for B cell/T cell interaction. There is growing evidence that nerve growth factor (NGF) itself also contributes to maintenance of immune system homeostasis. The NGF receptor (NGFR) promotes mitotic cell cycle arrest and induces pro-apoptotic programs depending on the developmental stage of cells. It has moreover become clear, that high NGFR expression level has a favorable impact on the clinical outcome in diverse non-neuronal neoplasma. Due to its potential role in tumorigenesis and immunomodulatory functions, we prospectively studied NGFR expression on primary precursor B (BCP) ALL blasts of pediatric patients (pts) (n=75). All pts (&lt;17y) were treated according to the Co-ALL 1997 study protocol. Blasts exclusively exhibited an immunophenotype of c-ALL (n=52) or pre-B-ALL (n=23). The criteria for prognostic classification into high risk (HR; n=30) and low risk (LR; n=45) pts at initial diagnosis include leukocyte count (WBC), age, genetic translocations and the in vitro resistance to chemotherapeutic agents (PVA score). In flow cytometry analysis half of the pts expressed no or low level NGFR (&lt;10%) (median: 9%; range 0–91%). Mean level assessed in those pts overexpressing NGFR beyond 10% was 50%±25% (±SD). In terms of the above mentioned prognostic discrimination criteria we found significantly lower NGFR expression in BCP-ALL blasts of HR pts (6%; 0–83%) compared to the LR group (22%; 0–91%) (p=0.027). When looking at the risk factors individually, pts with high initial WBC exhibited significantly lower NGFR levels in contrast to those with low WBC at diagnosis (7%; 0–83% vs 16%; 0–91%; p= 0.037). Also blasts carrying the prognostically positive tel-aml rearrangement showed significantly higher NGFR expression compared to those without cytogenetic aberrations (7%; 0–85% vs 36%; 1–91%; p=0.028). However, we detected no association between NGFR expression level and pt age, the examined immunophenotypes or PVA score. Of note, NGFR expression was significantly lower in the 15 pts who subsequently developed relapse (3%; 0–50%) compared to those remaining in remission (12%; 0–91%) (p=0.042). Whereas NGFR expression displayed no impact on overall survival, relapse free (RFS) and event-free survival (EFS) was significantly better in pts expressing high surface NGFR level (RFS 100% vs 72% p=0.006; EFS 90% vs 70%, p=0.04) in Kaplan Meier analysis. Multivariate Cox regression analysis for determination of the relative prognostic importance of the different risk parameters revealed that in addition to WBC (p= 0.007) high NGFR expression (p=0.042) is independently associated with superior EFS in our pediatric ALL pt cohort. Thus, high NGFR expression is a novel, independent prognostic marker that identifies a group of pediatric ALL patients with favorable outcome. Conversely, pts with no or low NGFR level are at high risk to suffer from relapse.