Journal Article

The ABNL-MARRO 001 study: a phase 1–2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes

Mesa, Ruben A., Kishtagari, Ashwin, Gerds, Aaron T., Itzykson, Raphael, Wiseman, Daniel H., Elena, Chiara, Cross, Nicholas C. P., Savona, Michael R., Platzbecker, Uwe, Padron, Eric, Pfeilstöecker, Michael, Montalban-Bravo, Guillermo, Fenaux, Pierre, Luebbert, Michael, Zhang, Jing, Tibes, Raoul, Valent, Peter, Geissler, Klaus, Ayers, Gregory D., Dezern, Amy E., Santini, Valeria, Kiladjian, Jean-Jacques, van de Loosdrecht, Arjan A., Moyo, Tamara K., Onida, Francesco, Komrokji, Rami S., Solary, Eric, Nazha, Aziz, Sanz, Guillermo F., Pleyer, Lisa, Cirici, Blanca Xicoy, Steensma, David P., Mendler, Jason H., Germing, Ulrich, Seegmiller, Adam C., Patnaik, Mrinal M.

2022

Overview

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 B asket study of N ove l therapy for untreated M DS/MPN a nd R elapsed/ R efractory O verlap 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).

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 5-aza-2'-deoxycytidine / ABNL MARRO / Acetonitriles / ASTX727 / Bioavailability / Biomedical and Life Sciences / Biomedicine / Blood cancer / Bone marrow / Cancer Research / Care and treatment / Chemotherapy / Chronic myelomonocytic leukemia / Cytidine Deaminase / Cytotoxicity / Decitabine - therapeutic use / Diagnosis / Disease / DNA - therapeutic use / DNA methyltransferase / FDA approval / Health Promotion and Disease Prevention / Humans / International cooperation / Investigations / Itacitinib / Janus kinase / Leukemia / Life Sciences / MDS/MPN / Medical prognosis / Medicine/Public Health / Methyltransferases / Monoclonal antibodies / Mutation / Myelodysplastic syndromes / Myelodysplastic-Myeloproliferative Diseases / Myeloproliferative disorders / Oncology / Patients / Phase 1b/2 / Prospective Studies / Pyrazoles / Pyrimidines / Pyrroles / Quality of Life / Response rates / Stem cell transplantation / Study Protocol / Surgical Oncology / Syndrome / Targeted Therapies / Thrombocytopenia / Tumors