What is luspatercept-aamt?
Luspatercept-aamt is a recombinant fusion protein that consists of a modified extracellular domain of the human activin receptor type IIB (ActRIIB) linked to the human immunoglobulin G1 Fc domain.
How does luspatercept-aamt work?
The ActRIIB receptor and its ligands are part of the transforming growth factor-[beta] (TGF-[beta]) superfamily which modulate erythrocyte differentiation in the bone marrow. The Smad 2/3 signaling pathway negatively regulates erythroid differentiation in beta thalassemia. Luspatercept-aamt prevents activin binding and subsequently decreases aberrant Smad 2/3 signaling increasing erythroid maturation.
What is luspatercept-aamt approved for?
Luspatercept-aamt is approved for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions.
What is the basis for this approval?
Luspatercept-aamt was approved for the treatment of anemia in patients with beta thalassemia based on the BELIEVE trial, a phase III, multicenter, randomized, double-blind, placebo controlled trial in adult patients requiring regular red blood cell transfusions (Blood 2018;132(Suppl 1):163). Regular transfusion was defined as 6-20 red blood cell units per 24-week period and no transfusion-free period longer than 35 days. Patients (n=336) were randomized 2:1 to either luspatercept-aamt or placebo in combination with best supportive care, which included red blood cell transfusions and iron-chelating agents. Luspatercept-aamt was administered at an initial dose of 1 mg/kg subcutaneously every 3 weeks for at least 48 weeks. The dose was titrated up to 1.25 mg/kg based on response. The primary endpoint was a reduction of red blood cell transfusions by at least 33 percent from baseline with a reduction of at least 2 units per 12 consecutive week period. A total of 48 out of 224 patients (21.4%) receiving luspatercept-aamt achieved the primary end point versus 5 of 112 (4.5%) of patients receiving placebo (OR 5.79, P <0.0001).
How do you administer this drug for the treatment of beta thalassemia?
When treating anemia in patients with beta thalassemia, luspatercept-aamt is administered at an initial dose of 1 mg/kg subcutaneously every 3 weeks. The dose of luspatercept-aamt should be increased to 1.25 mg/kg every 3 weeks if the patient's red blood cell transfusion does not decrease after at least 6 weeks (2 doses) at the initial dose. Discontinue luspatercept-aamt if transfusion burden does not decrease after 3 doses at the maximum dose level or if unacceptable toxicity occurs.
Are there any pre-medications needed?
No antiemetics or other pre-medications are recommended with this luspatercept-aamt. Hypersensitivity reactions have been reported with luspatercept-aamt.
What are the common side effects associated with luspatercept-aamt (> or =20%)?
The most common adverse events were headache, increased serum bilirubin, bone pain, and muscle pain.
What are the uncommon side effects associated with luspatercept-aamt (less than 10%)?
Uncommon side effects include increases in systolic blood pressure, presyncope, ischemic stroke, portal vein thrombosis, pulmonary embolism, cerebrovascular accident, deep vein thrombosis, vertigo, elevated uric acid, nausea, increased serum alkaline phosphatase, increased direct serum bilirubin, hypersensivity reactions, antibody development, and influenza.
Are there any important drug interactions I should be aware of?
There are no drug interactions reported with luspatercept-aamt. Concomitant use of iron-chelating agents did not lead to clinically significant differences in the luspatercept-aamt pharmacokinetics.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Mild to moderate renal or hepatic impairment did not have a significant effect on the pharmacokinetics of luspatercept-aamt and no dose adjustments are needed. Dosing has not been studied in patients with severe renal or hepatic impairment.
What should my patients know about luspatercept-aamt?
* Patients should avoid additional risk factors for thromboembolic events.
* Women should avoid pregnancy due to the risk for embryo-fetal toxicity and should use effective contraception during treatment and at least 3 months after the last dose of luspatercept-aamt.
What useful links are available regarding luspatercept-aamt for the treatment of AML?
* FDA Approval Announcement: https://bit.ly/2SEGSuh
Any ongoing clinical trials related to luspatercept-aamt?
Luspatercept-aamt is being studied in myelodysplastic syndrome and myelofibrosis patients with anemia. There are also ongoing studies with non-transfusion dependent beta thalassemia in adults and transfusion dependent beta thalassemia in pediatric patients. More information is available about these clinical trials at https://clinicaltrials.gov.
CHELSEA MINOR, PHARMD, BCPS, BCOP, is a Clinical Pharmacist of Hematology and Bone Marrow Transplant at Washington University School of Medicine, St. Louis, Mo. JANELLE E. MANN, PHARMD, BCOP, is the Manager of Clinical Pharmacy Services and practices as an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.