The Role of Her2/Neu in ALL: Long Term Clinical Follow-up of Surface-Positive Patients and Induction of NK Cell ADCC by Trastuzumab in Vitro
Authors: Haen Sebastian P. , Schmiedel Benjamin J , Roth Nora , Faul Christoph , Möhle Robert , Schmalzing Marc , Kanz Lothar , Vogel Wichard , Salih Helmut R 
Published: October 2019

Abstract
Abstract 1421
In about one third of patients, acute lymphoblastic leukemia (ALL) cells express Her2/neu (p185Her-2). In epithelial malignancies Her2/neu contributes to oncogenic transformation and metastatic potential, and overexpression often is associated with poor prognosis. Previous reports also suggested an inferior prognosis in patients with Her2/neu-positive ALL, but as of now no study has performed survival analyses. In breast cancer patients, targeting of Her2/neu with the monoclonal antibody Trastuzumab results in improved disease outcome, and induction of antibody dependent cellular cytotoxicity (ADCC) and cytokine release of NK cells contributes to the same. Most recently, application of Trastuzumab in patients with relapsed or refractory ALL was shown to yield promising results, but the mechanisms by which Trastuzumab mediates its efficacy have not been studied so far. Here, we studied patient records and flow cytometry data on Her2/neu expression of patients treated for ALL at our hospital between 2000 and 2011 and determined the effect of Trastuzumab and/or Rituximab on NK cell reactivity against ALL blasts in vitro. In 57 patients (37 men, 20 women, median age at diagnosis 42 years, range 17–83 years) data on Her2/neu expression were available. Her2/neu expression was detected in 15/57 patients (26%). Clinical follow up was assessed for all 57 patients. Median follow-up was 44 months (range 0.5–356 months) until death or last follow-up visit. Overall, 60% of the patients had died at the end of follow-up (25 of 42 Her2/neu-negative and 9 of 15 Her2/neu-positive patients, respectively). Median survival times were 43 (Her2/neu-negative, range 0.5–356 months) and 41 months (Her2/neu-positive, range 3.5–138 months; p = 0.81. Kaplan Meyer regression analysis). Also, median time to relapse was comparable in both groups (22.5 months vs. 15.5 months; p = 0.77). In functional analyses with NK cells, incubation of Her2/neu-positive CD20-positive ALL blasts with Trastuzumab or Rituximab comparably induced ADCC and cytokine release of NK cells. Only minor additional effects were observed upon combined application of both antibodies. When blasts from Her2/neu-negative ALL patients were employed (phentotype CD20-positive Her2/neu-negative or CD20-negative Her2/neu-negative), no effect of Trastuzumab was observed, and Rituximab exerted effects solely with blasts from CD20-positive ALL patients. Taken together, in our patient cohort Her2/neu expression on ALL blasts was not associated with time to relapse or overall survival and thus did not appear to be an additional risk factor. Rather, Her2/neu is a promising target for antibody therapy, especially in patients with Her2/neu-positive CD20-negative ALL, as treatment with Trastuzumab is suitable to induce ADCC and cytokine production of NK cells also against Her2/neu-positive CD20-negative ALL blasts.

Disclosures:
No relevant conflicts of interest to declare.