eP282: Alpelisib for the treatment of PIK3CA-related head and neck lymphatic malformations and overgrowth

PIK3CA-related overgrowth spectrum (PROS) and large PIK3CA-associated lymphatic malformations of the head neck (HNLM) pose unique treatment challenges. Traditional therapies often include multiple invasive (ie, sclerotherapy or surgery) interventions with suboptimal functional cosmetic outcomes. HNLM is most common pathology in PROS, additional may facial infiltrating lipomatosis (FIL), megalencephaly capillary malformation syndrome (MCAP), Klippel-Trenaunay-Weber congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis spinal (CLOVES). Though disease can occur anywhere body, involvement uniquely problematic. Infiltration compression airway cause respiratory distress, obstructive sleep apnea death. This risk be dynamic for that rapidly swell inflammation, placing child at acute compromise. Speech articulation, velopharyngeal function, mastication, swallowing all impaired by oral pharyngeal regions inducing pain bleeding. Invasive therapies, a mainstay, have limited effectiveness depending on location extent. The PI3K inhibitor alpelisib has previously demonstrated efficacy some individuals but there are no data FIL. We describe five children FIL monotherapy compared to historical cohort similar not receiving alpelisib. Expanded access authorization was obtained administer (ages 2-12 years). Molecular diagnosis an activating PIK3CA variant established using tissue-based testing (VANSeq panel) and/or cell free DNA from cyst fluid. All received 50 mg/day per Novartis protocol. A comparison selected based patients genotype, extent (n=10). Outcome measures included malformation/facial volume change as determined standardized photography imaging, patency, patient parent reported improvement (eg, bleeding, difficulty chewing speaking). Decreased affected region had seen treated individuals. Patients reduction mucosal edema bleeding patency improvement. There were significant adverse side effects Participant 1 now 4 year-old unilateral stage III malformation. At time initiation, ongoing consideration tracheostomy placement due impingement. Tissue confirmed p.Glu542Lys PIK3CA. After alpelisb speech dysarthria, fluency improved, while stopped. 2 12 who extensive bilateral V cervicofacial HNLM, underwent 19 surgical procedures including tracheostomy, prior revealed p.Glu545Lys Prior direct laryngoscopy diffuse absence normal hypopharyngeal anatomy glottic inlet obstruction edematous involved epithelium. tongue size, swelling decreased first month, dysarthria improved. 10 months therapy, repeat laryngeal landmarks, without dependence. 3 IV requiring endotracheal intubation supraglottoplasty G-tube infancy. Sirolimus used one month age until years. During this did need tracheotomy other procedures. two years initiated after sirolimus size decreased. Snoring apneic events ceased improved fluency. left-sided associated left facial/auricular hemihypertrophy sebaceous nevus, causing feeding problems Numerous emergent tonsillectomy, supraglottoplasty, total parotidectomy buccal dissection. Affected tissue found harbor c.3140A>G (p.His1047Arg) Facial asymmetry oropharyngeal occlusion worsened, sided tonsillectomy performed 8 so could removed. Ongoing caused persistent drooling, necessitated specialized diet made verbal impossible. Left ear induced ipsilateral conductive hearing loss canal occlusion. alpelisib, symptomatic drooling Now, 18 into visibly decreased, snoring absent, intelligible dysfluency present, secondary widely patent canal, oropharynx visible despite residual asymmetry. 5 HNLM. She upper lip microcystic adjacent mucosa. Malformation biopsy Three therapy resulted near normalization her disease. control continued symptoms/overgrowth, such dependance, dysfunction, well intermittent treatments same our study participants being Participants FIL, decrease region, improvement, avoidance anticipated minimal effects. One avoided major surgery longer dependent since starting therapy. Two symptoms, ability eat speak. resolution near-resolution Finally, near-complete soft No spontaneous comparable those These suggest promising