The ABNL-MARRO 001 study: a phase 1–2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes
Authors: Moyo Tamara K. , Mendler Jason H. , Itzykson Raphael , Kishtagari Ashwin , Solary Eric , Seegmiller Adam C. , Gerds Aaron T. , Ayers Gregory D. , Dezern Amy E. , Nazha Aziz , Valent Peter , van de Loosdrecht Arjan A. , Onida Francesco , Pleyer Lisa , Cirici Blanca Xicoy , Tibes Raoul , Geissler Klaus , Komrokji Rami S. , Zhang Jing , Germing Ulrich , Steensma David P. , Wiseman Daniel H. , Pfeilstöecker Michael , Elena Chiara , Cross Nicholas C. P. , Kiladjian Jean-Jacques , Luebbert Michael , Mesa Ruben A. , Montalban-Bravo Guillermo , Sanz Guillermo F. , Platzbecker Uwe , Patnaik Mrinal M. , Padron Eric , Santini Valeria , Fenaux Pierre , Savona Michael R. ,   On Behalf of the MDS/MPN International Working Group
Published: September 2022

Abstract
Background
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response.

Methods
ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability.

Discussion
Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population.

Trial registration
This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).