Clinical trial with Imatinib Mesylate for plexiform neurofibromas in Neurofibromatosis type 1 patients

Background: Neurofibromatosis type 1 related-plexiform neurofibromas (PNFs) are invasive and growing tumours, with substantial clinical consequences and with a potential risk of transformation into malignant peripheral nerve sheath tumours (MPNSTs). On the basis of recent studies, a clinical trial to test the hypothesis that inhibition of c-kit signalling pathways by Imatinib Mesylate (IM) results in objective reduction and/or inhibition of the growth of PNF was performed. Furthermore, circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) were evaluated as target and response indicator biological markers for the tyrosine kinase inhibitor treatment. Methods: 7 patients (aged 5-35 years) with genetically NF1 confirmed diagnosis and suffering from extensive and infiltrative mainly paraspinal located PNFs were enrolled in the study. The trial consisted in oral administration of IM at the dose of 220 mg/m2 twice a day for children and 400 mg twice a day for adults, for 12 months, unless severe toxicity. Immunohistochemistry was performed for confirmation of c-Kit and PDGF-β expression tumour biopsies in all PNFs. Every patient was followed longitudinally 12 months after drug discontinuation. Serum CECs and EPCs were evaluated at baseline and regularly during the treatment. Results: Only two patients completed the 12-month treatment with an adequate dosage; 1 patient required a lower dosage due to renal failure. Two patients withdrew from the study prematurely because of severe side effects (gastric bleeding and arthrosynovitis respectively), and two others because of evidence of non PNFs additional symptomatic growing lesions. All the patients have a sustained stabilization of PNFs volume progression rate (range 0.8 - 4.5%) over time during the follow-up (range 2.5 – 4.8%). The investigation 3 of angiogenic factors, revealed higher levels of viable and apoptotic CECs (p=.012 and p=.038 respectively), CD109+ CECs (p=.002) and VEGFR2+(p=.007) at baseline compared to healthy controls. During the treatment, a close to significance reduction of CD109+ CECs (p= .052), CD140b+ PPC (p= .052), and vital CECs (p= .072) were observed. No relationship between angiogenic factors and clinical or neuroradiological severity and evolution was noted during IM treatment (p=.470 and p=.510 respectively). Conclusions: Patients with extensive and complex PNFs with a primary paraspinal location had not an objective response to IM treatment; however, disease stability lasting 12 months after drug discontinuation was observed in all patients. CECs and EPCs seem to be indicators of anti-angiogenetic Imatinib Mesylate activity rather than useful biomarkers for predicting response or forecasting progression. A better knowledge of natural history of PNFSs in NF1 is needed before performing new clinical trial.