Objective: Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-␣-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN).Methods: PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity.Results: Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No doselimiting toxicity (DLT) was seen in patients treated at the 3 g/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 g/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 g/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 g/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage.
Conclusions:The RP2D of PI for pediatric patients with PN is 1 g/kg/wk. Clinical and radiographic improvement and cessation of growth can occur.
Classification of evidence:This study provides Class III evidence that pegylated interferon-␣-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size. Neurology ® 2011;76:265-272 GLOSSARY AUC ϭ area under the curve; DL ϭ dose level; DLT ϭ dose-limiting toxicity; FDA ϭ Food and Drug Administration; IFN ϭ interferon; MTD ϭ maximum tolerated dose; NF1 ϭ neurofibromatosis type 1; NHT ϭ nonhematologic toxicity; PEG ϭ polyethylene glycol; PI ϭ pegylated interferon-␣-2b; PN ϭ plexiform neurofibroma; RP2D ϭ recommended phase II dose; STIR ϭ short T1-inversion recovery; TSH ϭ thyroid-stimulating hormone; VA ϭ volumetric analyses.Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurogenetic disorder characterized by a wide variety of progressive cutaneous, neurologic, skeletal, and neoplastic manifestations.1 PN are one of several types of neurofibromas that may occur in patients with NF1 and are characterized by a proliferation of Schwann cells, fibroblasts, and mast cells occurring along the length of a nerve. They occur in 25%-50% of adults and children with NF1, 2,3 and typically infiltrate adjacent normal tissue, making complete surgical resection usually impossible. As they grow, they frequently become disfiguring as well as disabling or even life-threatening. 4,5 Regrowth following subtotal resection is common.6 Standard chemotherapy is not effective and there is currently no standard medical treatment despite various clinical trials. [7][8][9] Interferons (IFNs) have both antiproliferative and antiangiogenic pr...