Avatrombopag for Adults with Early Versus Chronic Immune Thrombocytopenia
Authors: Virk Zain , Leaf Rebecca Karp , Kuter David J , Goodarzi Katayoon , Connell Nathan T. , Connors Jean M. , Al-Samkari Hanny 
Published: December 2023

Background
Avatrombopag (AVA) is a newer thrombopoietin receptor agonist (TPO-RA) with certain advantages over other TPO-RAs. AVA is currently approved to treat adults with immune thrombocytopenia (ITP) in the chronic disease phase (duration &gt;12 months). However, no studies have evaluated the safety and effectiveness of AVA in newly diagnosed ITP (duration &lt;3 months) or persistent ITP (duration 9-12 months), leaving open questions regarding its safety (including thromboembolic risk) and effectiveness in these patients, and also drastically limiting availability of the drug to patients with early ITP, for whom it is off label. We hypothesize that AVA has similar safety and effectiveness in all phases of ITP.
Methods
We performed a multicenter, observational cohort study of all adult patients with primary or secondary ITP at 4 hospitals treated with AVA to compare outcomes of patients with newly diagnosed or persistent ITP versus patients with chronic ITP. We collected patient and disease characteristics and characteristics and outcomes of AVA treatment, including dosing, platelet counts prior to and during treatment, adverse events, concurrent and rescue therapies for ITP, and platelet transfusions. Platelet outcomes included rates of response (R, the primary outcome, defined as platelet count of ≥50 × 10 9/L) and complete response (CR, platelet count ≥100 × 10 9/L), both on at least one measurement without requirement for rescue therapy. The response fraction (RF) and complete response fraction (CRF), fractions between 0 (representing no instance of response at any timepoint for a patient) and 1 (representing a response at all timepoints for a patient) were calculated for each patient from monthly measurements during the first six months of treatment with avatrombopag. Other outcomes included major bleeding, rescue therapy requirements, thrombocytosis, and adverse events.
Results
Patient Population. 75 patients were included, 23 patients with newly diagnosed or persistent ITP (17.7 patient-years of AVA exposure) and 52 patients with chronic ITP (65.3 patient-years of AVA exposure). The median (range) age was 55 (18-80) years in the newly diagnosed/persistent ITP group versus 66 (22-90) years in the chronic ITP group; approximately 65% of patients in each group were female.
Platelet Outcomes. With regards to the primary outcome, R was achieved in a similar proportion of newly diagnosed/persistent ITP patients (91%) as in chronic ITP patients (96%), P=0.58. Similar proportions also achieved a CR: 86% newly diagnosed/persistent ITP patients versus 81% of chronic ITP patients, P=0.78. Mean RF and CRF were also similar between the two groups ( TABLE). The median platelet count at baseline and over the first six months of treatment by disease phase is illustrated in the FIGURE.
Other Outcomes. Incidence of major bleeding and requirement for rescue therapy and platelet transfusion were low in the newly diagnosed/persistent group ( TABLE) and statistically similar to incidences in the chronic group.
Safety. The incidence of thrombocytosis (platelet count ≥400 × 10 9/L on ≥1 measurement) was similar (44% in the newly diagnosed/persistent ITP group and 40% in the chronic ITP group). No patient developed an arterial thromboembolic event. No patient in the newly diagnosed/persistent group developed a venous thromboembolism (VTE) and only one patient in the chronic group developed a VTE. No patient in the newly diagnosed/persistent group discontinued AVA due to an adverse event or safety concern. The rate of thromboembolic complications in the entire cohort including 83.0 patient-years of AVA exposure was 1.2 thromboembolic events per 100 patient-years, considerably lower than prior phase 2 and 3 clinical trials of AVA in ITP (which together documented 11 thromboembolic events occurring over 72.4 patient-years of AVA exposure, or 15.2 thromboembolic events per 100 patient-years).
Conclusions
AVA was safe and effective in patients with newly diagnosed and persistent ITP, with outcomes numerically, statistically, and clinically similar to patients receiving AVA for chronic ITP. Given its lack of dietary restrictions and hepatotoxicity, access to AVA in early ITP could improve disease outcomes and patient health-related quality of life. Further studies are needed to confirm our findings and evaluate the ability of AVA to induce sustained responses off treatment in patients with early ITP.