Pulmonary arterial hypertension in pediatric patients undergoing high-dose carboplatin/thiotepa and stem cell transplant

Abstract

Patient 1 is a five-year-old girl who presented to the hospital with nausea, vomiting, and headaches. Imaging demonstrated a posterior fossa mass with associated hydrocephalus. Surgical resection was urgently performed and pathology showed medulloblastoma, WHO Grade IV, with extensive metastatic disease. The patient was enrolled on the Head Start 4 study and treated with three induction cycles of vincristine, cisplatin, cyclophosphamide, etoposide, and methotrexate followed by three tandem cycles of consolidation chemotherapy consisting of carboplatin and thiotepa followed by autologous hematopoietic stem cell transplant (HSCT). Pre-induction echocardiography was normal. One month after her third autologous HSCT, the patient presented to the pediatric intensive care unit due to tachypnea and oxygen desaturation. Chest computed tomography (CT) ruled out pulmonary emboli but demonstrated pulmonary artery dilation and multiple patchy ground glass opacities in the lung parenchyma. Echocardiogram demonstrated an estimated systolic pulmonary artery pressure (PAP) measuring three-quarters systemic. N-terminal pro brain natriuretic peptide level (NT-pro BNP) peaked at 4454 pg/mL (normal <125 pg/mL). She was started on digoxin, furosemide, and spironolactone. Due to limitations in gait, she was unable to complete a 6-min walk test. History was significant for prematurity completing 27 weeks gestation, but with no home oxygen requirement at time of neonatal intensive care unit discharge. Pulmonology was involved in care with no concern for chronic lung disease or interstitial lung disease, but she did have evidence of moderate obstructive sleep apnea on polysomnography. Swallow studies demonstrated no aspiration and she was treated for gastroesophageal reflux. There was no family history of pulmonary hypertension. Cardiac catheterization confirmed pulmonary arterial hypertension (PAH) with a mean PAP of 34mmHg and pulmonary vascular resistance index (PVRi) of 5.4 Wood Units m. Sildenafil was initiated and titrated up to 10 mg TID. Supplemental oxygen was required for 10 weeks. With continued therapy, clinical symptoms improved and echocardiogram findings and NT-pro BNP levels normalized in four months. The patient was weaned off digoxin and diuretics. One year later, sildenafil was also discontinued. Unfortunately, she had tumor recurrence and suffered a severe stroke six months later. She died while in hospice care. Patient 2 is a 6-month-old male infant who presented to the hospital with macrocephaly, vomiting, lethargy, and abnormal eye movements. Brain MRI demonstrated a large, heterogeneous mass in the right temporal-parietal region requiring emergent debulking. Pathology revealed an atypical teratoid rhabdoid tumor, WHO grade IV. Treatment as per a modified version of Children’s Oncology Group (COG) protocol ACNS0333 was initiated with induction therapy consisting of three cycles of vincristine, cisplatin, cyclophosphamide, etoposide, and methotrexate followed by consolidation chemotherapy with