Efficacy and Safety of Avatrombopag in Combination with Immunosuppressive Therapy in Treatment-Naïve Severe Aplastic Anemia: Results of the Diaamond-Ava-First Trial
Authors: McQuilten Zoe K , Fox Lucy C , Heritier Stephane , Fox Vanessa , Young Lauren , Blombery Piers , Cunningham Ilona , Curnow Jennifer , Higgins Alisa , Hiwase Devendra , Filshie Robin , Firkin Frank Caleb , Lacaze Paul , Mason Kylie , Mills Anthony K. , Pepperell Dominic , Patil Sushrut S. , Sutherland Robyn , Stevenson William S. , Szer Jeffrey , Thao Le Thi Phuong , Waters Neil A , Wilson Kate , Ting Stephen , Wood Erica M. 
Published: December 2024

Background
The addition of the thrombopoietin-receptor agonist (TPO-RA) eltrombopag to immunosuppressive therapy (IST) has been shown to improve hematological responses in severe aplastic anemia (sAA) (Peffault de Lattour, NEJM, 2022). Avatrombopag is a second generation TPO-RA that has not been studied in sAA.
Aim
To investigate the efficacy and safety of avatrombopag in addition to IST for patients with previously untreated sAA.
Methods
Investigator-initiated, single arm Bayesian Optimal Phase II trial (ACTRN12619001042134). We enrolled patients aged 18 years or older with sAA (defined as bone marrow cellularity &lt; 30% with at least two of the following: neutrophils &lt;0.5 x109/L; platelets &lt;20 x 109/L; or absolute reticulocytes &lt;60 x 109/L) with no prior antithymocyte globulin (ATG)-based IST. Patients were excluded if they had myelodysplastic syndrome (MDS), inherited bone marrow failure syndrome, cancer within the last 5 years, or were pregnant or breastfeeding. Participants received IST (equine ATG and ciclosporin) plus avatrombopag at a maximum dose of 60mg daily orally, dose adjusted according to platelet count, from days 1 to 180. Participants who achieved a partial response (PR) at day 180, defined as transfusion independent with platelet count &gt;20 x 109/L and neutrophils &gt;0.5 x 109/L, were able to continue avatrombopag for an additional 6 months.
Two co-primary endpoints for efficacy and safety were assessed at 6 months. The primary efficacy outcome was complete response [CR], defined as hemoglobin &gt;10 g/dL, neutrophils &gt;1.0 x 109/L and platelets &gt;100 x 109/L. The primary safety endpoint was acquired clonal evolution [ACE], defined as a new clonal cytogenetic (CG) abnormality or diagnosis of MDS or acute myeloid leukemia (AML). Secondary endpoints included hematological response (overall, complete and partial), ACE and acquired somatic mutations at 6, 12, 18 and 24 months, quality of life and adverse events.
The co-primary endpoints were jointly monitored and reviewed during the trial, where at each interim analysis, a ‘go/no-go’ decision was made by evaluating the posterior probability of events of interest, with a maximum sample size target of 55 patients.
Results
Between October 2019 and August 2023, 56 patients were enrolled from 12 hospitals in Australia, with a median age of 58 years (IQR 40 to 67 years). Thirty-two (57%) were male, 11 (20%) Asian, 41 (73%) Caucasian and 4 (7%) of another ethnicity. Of the 56 participants, 7
did not reach the primary endpoint evaluation at 6 months due to death (n=3), proceeding to allogeneic stem cell transplant (n=2) and withdrawal for other reason (n=2).
Of the 49 participants with evaluable primary outcome data, CR occurred in 17 (35%) participants (95% credible interval 30% to 46%) and ACE occurred in 2 (4%) participants (95% credible interval 3% to 11%) (both CG abnormalities).
At six months, 17 (35%) had a CR, 15 (30%) had a PR, and 17 (35%) had no response, giving an overall response rate of 65%. Thirteen participants who achieved a PR at six months continued on avatrombopag for an additional 6 months.
During trial follow-up, 30 (59%) participants experienced a grade 3 highest adverse event, 8 (16%) grade 4 and there were 3 deaths (two due to sepsis and one due to unrelated malignancy diagnosed after enrolment). Fifteen (27%) experienced grade 3 or higher adverse liver function tests.
With a median follow-up of 20.4 months, two participants had a new CG abnormality, and two had progressed to MDS. No participants had progressed to AML. Quality of life data showed improvements in overall quality of life, physical functioning and fatigue.
Conclusion
Avatrombopag in addition to IST in treatment-naïve sAA patients resulted in CR of 35%, overall response of 65% and ACE of 4% at 6 months. Hematological response was comparable to that reported in the phase III trial of eltrombopag in addition to IST in a similar patient population.