TPO Mimetics: Can More Than One Agent Be Used in a Patient?

Recently, advances in TPO mimetics have expanded therapeutic options for adult patients with chronic ITP. Seven second generation TPO agonists have been reported in the literature. Evidence suggests that non-peptide versus peptide TPO mimetics bind differently to the TPO receptor. Romiplostim, a subcutaneous peptide TPO mimetic has recently been FDA approved. Eltrombopag, Ligand L4665-08, and Aka-Rx 501 are oral non-peptide TPO mimetics undergoing clinical study.

The question arises if a patient fails or succeeds one TPO mimetic can the patient be treated with another agent and have a response. We present two cases of patients who were treated with two agents.

Patient #1 was initiated on Aka-Rx 501 as she could not tolerate steroids and refused splenectomy. She was able to maintain a platelet count >50,000 for a period of six months without any bleeding. As the study did not have an extension, following a washout period she was enrolled in Ligand L4665-083 with a platelet count of 1,000. Within a week her platelet count rose to 97,000. Her platelet count, on a stable dose of Ligand progressively fell over two weeks and dropped to 2,000 with bleeding. She was then initiated on a higher dose of study medication.

The second patient had an eight year history of ITP refractory to IVIG and steroids. She was initially enrolled in AMG 531, and was able to maintain a platelet count greater than 50,000 for over six months. Her platelet count began to progressively decline to zero. Antibody tests were negative and a bone marrow biopsy was normal.

After a washout period, the patient was enrolled in AkaRx 501 Cl-003. One week later her platelet count rose to 64,000. She sustained a platelet count of greater than 30,000 and was initiated on the rollover study after four weeks. At week twelve, her platelet count as in the prior study fell to 0 with a concomitant CNS bleed.

These two cases demonstrate the use of two different TPO mimetics in a given patient. The first patient was treated with two oral non-peptide TPO mimetics, with a sustained response to one agent and a quick response followed by a rapid loss of response to the second agent. The second patient was treated initially with a peptide TPO mimetic followed by a non-peptide TPO mimetic, both times demonstrating an initial brisk response, long with one and short-lived with the second, which was eventually lost. These data suggest that more than one agent can be used in a given patient.