Background: Improving treatment for patients with severe aplastic anemia (sAA) is a priority. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with sAA not eligible or suitable for allogeneic stem cell transplant. While 50-75% of patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve hematological responses in sAA. Avatrombopag is a second-generation TPO-A, and like eltrombopag, lacks competitive binding with endogenous TPO, suggesting it may also be effective in AA. Avatrombopag has potential advantages over eltrombopag, including dosing, toxicity profile and pharmacokinetics. It has also been shown to have greater in vitro and in vivo pharmacological potency than eltrombopag. However, to date avatrombopag has not been studied in sAA.

Methods: The DIAAMOND Ava-FIRST and DIAAMOND Ava-NEXT trials are investigator-initiated, non-randomised, single-arm registry-based Bayesian Optimal Phase II (BOP2) trials. The FIRST trial is evaluating avatrombopag in addition to IST in patients with untreated sAA. Patients receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily and dose adjusted according to platelet count. Two primary endpoints, complete response (CR) rate and acquired clonal evolution (ACE) at 6 months are monitored at each interim analysis where a go/no-go decision is made by evaluating the posterior probability of the events of interest. The maximum sample size is 50 evaluable patients. The stopping boundaries were calculated with a target false positive rate of 10% under the global null as recommended in phase II studies. The performance of the trial and operating characteristics were assessed with 10,000 simulations. Other trial endpoints which are collected until 24 months following enrolment include rate and time to first hematological response, survival, cytogenetic evolution, progression to hematological malignancy, safety and quality of life. Exploratory assessments of interest include changes in iron studies and marrow iron stores, longitudinal cell free DNA somatic mutation analysis and T-cell receptor repertoire studies. In the NEXT trial, patients with relapsed or refractory sAA, six or more months following at least one course of horse or rabbit ATG are eligible. All patients receive avatrombopag at 60 mg oral daily from day 1 until day 180, further additional IST is at the discretion of the treating clinician. Two primary endpoints, hematological response (HR) rate and ACE are monitored at each interim analysis following which a go/no-go decision is made as described in the FIRST trial. The trials are embedded within the Australian Aplastic Anaemia and Other Bone Marrow Failure Syndromes Registry, which will allow long-term follow-up of participants after completion of the trial (at 24 months).

Progress: The FIRST trial has enrolled 40 patients and the NEXT trial 16 patients. The dosing of avatrombopag was changed after the initial eleven patients were enrolled, when the starting dose was 20 mg daily and increased to a maximum of 60 mg daily over 8 weeks based on hematological response. This change was made based on observed tolerability of the maximum (60 mg) dose and timing of response rates. Interim analyses have been performed for both trials and stopping boundaries for efficacy or safety have not been met.

McQuilten:Abbvie: Research Funding; Amgen: Research Funding; Beigene: Research Funding; BMS/Celgene: Research Funding; CSL: Research Funding; GSK: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Takeda: Research Funding. Batt:Novonordisk: Honoraria. Blombery:Servier: Honoraria; AstraZeneca: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria. Hiwase:Novartis: Speakers Bureau; AbbVie: Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mills:Abbvie: Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting sponsorship; Amgen: Other: Meeting sponsorship; MSD: Other: Meeting sponsorship. Pepperell:Sanofi: Consultancy; Pfizer: Other: travel grant . Szer:Takeda Pharmaceuticals: Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy. Wood:Bristol-Myers Squibb: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Astra Zeneca: Research Funding; CSL Behring: Research Funding; Gilead: Research Funding; Janssen-Cilag: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Antengene: Research Funding.

Avatrombopag for severe aplastic anaemia

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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