The development of intrapulmonary shunting caused by luspatercept in low grade myelodysplastic syndrome: a case report

Background: Cytopenias are the hallmark manifestation of myelodysplastic syndrome (MDS) as patients frequently suffer from transfusion-dependent anemia. Luspatercept is part of a new family of drugs approved for transfusion-dependent MDS that bind transforming growth factor-β (TGF-β) family ligands to decrease SMAD signaling, resulting in an increase of circulating mature red cells. However, disruption of the TGF-β/SMAD pathway carries risks given its wide-ranging influence on the development and structure of blood vessels. Here we present the case of a patient with MDS presenting with refractory hypoxia from an intrapulmonary shunt secondary to the development of microvascular pulmonary arteriovenous malformations (PAVM) after starting luspatercept. Case Description: The patient reported progressive shortness of breath while receiving luspatercept and was eventually referred to a pulmonary clinic who discovered the shunt via a bubble echocardiogram. A broad cardiac and autoimmune work-up was unremarkable. Her hypoxia was out of proportion to spirometric and imaging findings. A computed tomography (CT) pulmonary angiogram did not reveal any large vascular malformations. Conclusions: The decision was made to stop the drug and her hypoxemia resolved within weeks in parallel with resolution of the shunt as the patient returned to room air and her prior functional baseline. In this report, the complex mechanism of luspatercept is discussed with a literature review on the clinical trials leading to its approval in MDS patients. Furthermore, we connect the pathophysiology between the formation of this patient's telangiectasias leading to her PAVM with the disruption of the TGF-β/SMAD pathway from luspatercept use.