ArticlesImatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial
Introduction
Neurofibromatosis type 1 (NF1) is the most common human genetic cancer predisposition syndrome, causing substantial morbidity and mortality in roughly one in 3000 individuals.1, 2 The disorder results from autosomal dominant mutations in the NF1 tumour suppressor gene that encodes a Ras GTPase named neurofibromin.3 Deficiency of neurofibromin leads to hyperactivation of the Ras signalling cascade and other signal transduction networks.4, 5 In around 40% of patients with NF1,6 the aberrations in these cellular signalling networks culminate in development of tumours known as plexiform neurofibromas, which occur as multiple primary tumours, each with their own growth characteristics. They arise from loss of heterozygosity in individual Schwann cells in almost any anatomical location where Schwann cells reside. These locally invasive tumours can be painful, disfiguring, and life-threatening when localised near vital structures such as upper airway or major nerves and blood vessels.7, 8 Due to their slow-growing nature, plexiform neurofibromas are highly refractory to radiotherapy and chemotherapy, and surgery is often extremely challenging because of localisation of these tumours.7 In view of the limited viable treatment options, there is an urgent medical need for novel therapeutic approaches to allow successful management of plexiform neurofibromas.
The kinase inhibitor imatinib mesylate reduces tumour size of plexiform neurofibromas in a preclinical mouse model of NF1 that fully recapitulates the development of plexiform neurofibromas detected in patients with NF1.9, 10 Mechanistically, this effect is attributed at least in part to targeting cellular phospho-signalling cascades in the tumour microenvironment.8, 11 On the basis of these findings, we administered imatinib mesylate (350 mg/m2 per day) to a patient with NF1 with life-threatening airway compression by a plexiform neurofibroma, and achieved a greater than 50% reduction in tumour size within 3 months of therapy, resulting in substantial symptomatic relief.8 To build on these findings and establish whether imatinib mesylate could decrease the volume of individual plexiform neurofibromas in other patients with NF1, we undertook a phase 2 open-label trial of this oral small-molecule kinase inhibitor in patients with NF1 and clinically significant plexiform neurofibromas.
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Patients
Patients were recruited from the Indiana University School of Medicine Neurofibromatosis Clinic, Indianapolis, IN, USA, and the Neurofibromatosis Clinic at the University of Texas Southwestern Medical Center/Children's Medical Center, Dallas, TX, USA, or by self-referral. Patient entry criteria included: age of 3–65 years; clinical diagnosis of NF1; and presence of clinically significant plexiform neurofibromas defined as potentially life-threatening tumours, tumours impinging on vital
Results
Between June 1, 2006, and March 30, 2009, 36 patients were enrolled (table 1), three patients from the University of Texas Southwestern and 33 from Indiana University. Of the 36 patients enrolled (19 male and 17 female), the median age was 13 years (IQR 7·5–23; table 1). The study group included patients within the age range of 3–52 years; most patients (n=17) were children and adolescents (table 1). The localisation of plexiform neurofibromas varied, with almost half of the tumours localised
Discussion
Findings from this open-label phase 2 trial suggest that high-dose oral imatinib mesylate may have a role in the treatment of clinically significant plexiform neurofibromas in children and adults with NF1 (panel). To our knowledge, this is the first successful reduction in volume of plexiform neurofibromas using targeted oral chemotherapy.
We noted objective responses to imatinib mesylate in 26% of the evaluable patients enrolled in the study. The rationale for presentation of the data in terms
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