The MEK inhibitor selumetinib reduces spinal neurofibroma burden in patients with NF1 and plexiform neurofibromas

Abstract

Background: Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF.

Methods: Pediatric and adult patients with NF1 and inoperable PN participating in phase 2 studies of selumetinib for PN were included in this analysis if they had SNF and serial spine magnetic resonance imaging (MRI). Selumetinib was administered orally at the recommended dose of 25 mg/m²/dose twice daily (max 50 mg b.i.d.; 1 cycle = 28 days). We qualitatively assessed the effect of selumetinib on SNF-related spinal canal distortion, cerebrospinal fluid distribution, and spinal cord deformity on MRI.

Results: Twenty-four patients (18 male), median age 16.9 years (range, 6.2-60.3), had SNF, 22 of which were associated with the same nerves as the target PN assessed on the clinical trial. Twenty patients had spinal cord deformity. Twenty-three patients completed at least 12 treatment cycles to date. Eighteen patients showed subtle to a marked improvement in SNF burden, 5 remained stable, and no worsening was observed during treatment.

Conclusions: This is the first study describing the effect of selumetinib on SNF. Of 24 patients, 18 exhibited some improvement of SNF burden on imaging. These findings suggest that selumetinib may prevent the worsening of cord compression, potentially reducing the need for surgical interventions in select patients or benefitting patients who do not have a surgical option. Prospective evaluation of the clinical benefit of selumetinib for SNF is warranted.

Keywords: neurofibromatosis type 1; plexiform neurofibroma; selumetinib; spinal cord deformity; spinal neurofibroma.

Figure 1.

Spinal neurofibroma (SNF) burden characterization. Coronal short T1 inversion recovery MR images demonstrate the SNF distribution: multilevel symmetrical (A), multilevel predominantly one-sided (B), or single spinal nerve root (C). In addition to SNF, extensive plexiform neurofibroma (PN) is seen in the same body region in all 3 patients. The chart below illustrates our method of capturing the presence or absence of SNF-related spinal canal distortion, cerebrospinal fluid (CSF) disruption around the cord or cauda equina, and spinal cord deformity.

Figure 2.

MRI examples of subtle (top row) and marked improvement (rows 2–5) in patients with spinal neurofibroma (SNF) receiving selumetinib therapy. The area of the spinal canal is shown on axial balanced fast field echo sequences. Arrows indicate the SNFs of interest. First row: Bilateral dumbbell tumors compress the spinal cord at the cervical 5–6 level. There is a slight gradual improvement in the narrow wedge shape of the cord and an increase in cerebrospinal fluid (CSF) abundance. Also note the decreasing size of the adjacent brachial plexus plexiform neurofibroma (PN). Second row: SNF in the left cervical 6–7 neuroforamen extends into the central canal and deforms the spinal cord. The size of the mass is markedly reduced after 4 cycles of selumetinib therapy with further improvement through cycle 36. Third row: SNF below the level of the cord (L5-S1) displacing the thecal sac and nerve roots. SNF shrinkage is apparent by cycle 4 and the response is maintained through cycle 36. Fourth row: Lumbar 4–5 level bilateral SNFs completely fill the central canal at baseline. CSF becomes detectable around the nerve roots after 4 treatment cycles and the improvement continues through cycle 30. Fifth row: The spinal cord deformity at C3-4 level is reduced during 24 cycles of therapy. Interruption of selumetinib treatment for 6 months resulted in SNF regrowth; however, improvement is evident again upon retreatment with selumetinib.