Trametinib for Refractory Chylous Effusions in Children with Noonan Syndrome

Abstract

BACKGROUND Noonan syndrome (NS) is one of several autosomal dominant multisystem disorders known as RASopathies. Common manifestations of NS include congenital heart defects and cardiomyopathy, lymphatic malformations, and predisposition to myeloproliferative disorders. Chylous fluid accumulation secondary to lymphatic malformations are seen in NS and are a major cause of morbidity and mortality often refractory to conventional medical management. There has been increasing interest in the use of pharmacologic MEK inhibition in the management of these patients given that activating RAS pathway mutations lead to downstream MEK activation that is causative of this pathology. DESIGN/METHODS Three patients with a confirmed diagnosis of NS are described. Each patient developed complications from chylous effusions refractory to conventional management and were subsequently enrolled on-study to treat with compassionate use oral trametinib from Novartis Pharmaceuticals on a single patient Investigational New Drug from the Food and Drug Administration (FDA). All patients were consented to be monitored for one year of therapy following a local protocol approved by the Colorado Institutional Review Board (COMIRB). Patient 1: a 4-year-old female with NS due to a pathogenic germline mutation of the RIT1 gene [c.246T>G, p.Phe82Leu] born with severe hypertrophic cardiomyopathy, mitral valve dysplasia, and pulmonary valve stenosis. She developed bilateral chylous pleural effusions that were refractory to dietary modification, diuretics, octreotide, and sirolimus. Patient 2: a 3-month-old female with NS due to a pathogenic germline mutation of the SOS1 gene [c.1322G>A; p.Cys441Tyr] born with esophageal atresia/tracheoesophageal fistula and moderate pulmonary valve stenosis. She developed bilateral chylous pleural effusions and ascites that were refractory to dietary modification and octreotide therapy. Patient 3: a 4-month-old male with NS due to a gain-of-function mutation of PTPN11 [c.854T>C; p.Phe285Ser] with hypertrophic cardiomyopathy, pulmonary valve stenosis, respiratory insufficiency with suspected pulmonary lymphangiectasia, and persistent chylous pleural effusions in addition to Noonan syndrome-associated myeloproliferative disorder (NS-MPD) that had been refractory to traditional management. RESULTS MEK inhibition with trametinib was used in three patients with NS and life-threatening complications with no medical or surgical treatment options. All three patients had dynamic contrast magnetic resonance lymphangiography (DCMRL) evidence of primary, central lymphatic dysplasia that manifested in lymphatic accumulation affecting cardiorespiratory function, nutrition, and the immune system. DCMRL imaging for patient 2 are highlighted in Figure 1 A and B. Within one month of initiating trametinib oral therapy, all three patients demonstrated response adequate to wean from mechanical ventilation and other supportive care modalities. Serum albumin levels improved as lymphatic leak resolved (Figure 1C). Patient 3 showed improvement in hypertrophic cardiomyopathy as evidenced by a decrease in both NT-proBNP and left ventricular mass by echocardiogram. Patients 1 and 2 demonstrated notable improvements in growth after one year of therapy, with increase in both weight and height percentiles. Patient 3 also presented with NS-MPD that responded with marked improvements in total WBC count as well as absolute monocyte count (Figure 1D). DISCUSSION Our experience adds to the growing body of evidence demonstrating the effectiveness of MEK inhibition on disease processes that are common in patients with NS and other RASopathies. None of the patients in our series experienced significant adverse effects from the medication aside from patient 2 who developed mild dermatitis. The efficacy of this therapy does not appear to be based on the underlying genotype, as each of the three patients we describe had different underlying molecular alterations (SOS1, RIT1, PTPN11). Substantial improvements in a variety of parameters including lymphatic malformations, cardiomyopathy, pulmonary valve stenosis, growth, and NS-MPD highlight the potential utility of trametinib in this patient population. Larger, prospective studies are necessary to confirm the efficacy of MEK inhibition and to assess the long-term safety of its use in this population. Figure 1 Figure 1. Disclosures Nakano: Novartis: Consultancy. OffLabel Disclosure: Trametinib is a MEK1/2 inhibitor that has been approved for the use in certain malignancies. Its off label use in children with Noonan Syndrome with significant lymphatic anomalies is based on the up regulation of the MAPK pathway in these patients.

Successful treatment of refractory chylothorax with MEK inhibitor trametinib in a child with Noonan syndrome: case report

“…MEK inhibition with trametinib as a possible treatment has been described in few case reports of patients with Noonan syndrome and either hypertrophic cardiomyopathy or refractory life-threatening chylothorax. 4 , 5 , 6 , 12 , 13 The literature is sparse however and lacks guidelines regarding best treatment course. Doses between 0.01 to 0.027 mg/kg 4 , 5 , 12 have been reported, and all cases seem to continue on trametinib for a prolonged time and without a predetermined duration (Nakano et al .…”

“…Very few cases have been published reporting successful treatment of patients with trametinib where all conventional treatments had failed. 5 , 6 We present a girl with Noonan’s syndrome, HCM, and refractory chylothorax who developed life-threatening chyle loss related complications. Lymphatic remodelling with complete resolution of chylothorax was achieved by MEK inhibition with trametinib.…”

The incidence and characterization of weight gain associated with MEK inhibitors in pediatric patients

“…Patients who were considered underweight (BMI‐for‐age percentile ≤5%) or at risk for being underweight (BMI‐for‐age percentile 5–10%) demonstrated significant increases in weight‐for‐age percentile that placed 80% of them in a normal BMI class, a potential beneficial side effect for these patients 16 . This may be particularly advantageous for the subset of children with Noonan and Costello syndrome (conditions associated with short stature, feeding difficulties, and delayed growth) where patients have previously been noted to have improvement in their height and weight percentiles after initiation of a MEK inhibitor.…”

A case report of myelodysplastic syndrome in a patient with PTPN11‐related Noonan syndrome

“…Due to thrombocytopenia and anemia, a bone marrow biopsy was performed, which showed hypocellularity without concern for dysplasia or cytogenetic abnormalities. She was started on trametinib for the chylothorax at 1 month of age based on studies showing response in patients with Noonan syndrome, 4,5 with improvement in respiratory symptoms, weaning respiratory support, and removal of chest tubes. She subsequently developed progressive cytopenia, thought to be a side effect of trametinib, so this was discontinued (see Table 1 for clinical course, counts, and bone marrow results).…”