Moyo et al. BMC Cancer (2022) 22:1013 https://doi.org/10.1186/s12885-022-10073-w STUDY PROTOCOL Open Access The ABNL‑MARRO 001 study: a phase 1–2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes Tamara K. Moyo1,2, Jason H. Mendler3, Raphael Itzykson4, Ashwin Kishtagari1, Eric Solary5, Adam C. Seegmiller1, Aaron T. Gerds6, Gregory D. Ayers1, Amy E. Dezern7, Aziz Nazha6, Peter Valent8,9, Arjan A. van de Loosdrecht10, Francesco Onida11, Lisa Pleyer12,13, Blanca Xicoy Cirici14, Raoul Tibes15, Klaus Geissler16, Rami S. Komrokji17, Jing Zhang18, Ulrich Germing19, David P. Steensma20, Daniel H. Wiseman21, Michael Pfeilstöecker22, Chiara Elena23, Nicholas C. P. Cross24, Jean‑Jacques Kiladjian25, Michael Luebbert26, Ruben A. Mesa27, Guillermo Montalban‑Bravo28, Guillermo F. Sanz29, Uwe Platzbecker30, Mrinal M. Patnaik31, Eric Padron17, Valeria Santini32, Pierre Fenaux4, Michael R. Savona1*   and On Behalf of the MDS/MPN International Working Group Abstract Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malig‑ nancies 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 inhibi‑ tor cedazuridine to improve decitabine bioavailability. *Correspondence: michael.savona@vanderbilt.edu 1 Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN 777 PRB, USA Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Moyo et al. BMC Cancer (2022) 22:1013 Page 2 of 15 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). Keywords: ABNL MARRO, MDS/MPN, ASTX727, Itacitinib, Phase 1b/2 Background while others are highly symptomatic and succumb rap- Myelodysplastic/Myeloproliferative Neoplasms (MDS/ idly to their disease. Many require regular transfusion MPN) are a heterogeneous group of clonal myeloid support for disease-associated cytopenias and/or cytore- malignancies that harbor features of both myelodysplas- ductive approaches to control leukocytosis or thrombo- tic syndromes (MDS) and myeloproliferative neoplasms cytosis. All share an increased risk of developing acute (MPN). In the adult population, MDS/MPN diagnoses myeloid leukemia and are only curable with allogeneic include chronic myelomonocytic leukemia (CMML), stem cell transplantation. Accepted treatment options, atypical BCR-ABL1 negative chronic myeloid leukemia such as cytotoxic chemotherapy and DNMTi, provide (aCML), myelodysplastic/myeloproliferative neoplasms small, if any, survival benefits [5–8]. In general, patients with ring sideroblasts and thrombocytosis (MDS/MPN- with CMML (median survival 20–40 months [9–12]), RS-T), and myelodysplastic/myeloproliferative neo- atypical CML (median survival 12–37 months [13–17]), plasms unclassifiable (MDS/MPN-U) [1]. Patients with and MDS/MPN-U (median survival of 22–33 months these disorders can present with hepatosplenomegaly, [16, 18]) have inferior survivals relative to patients with constitutional symptoms (including weight loss, night MDS/MPN-RS-T (median survival 76–128 months sweats, and fevers), and/or consequences of hematopoi- [19–21]). etic insufficiency (fatigue, infections, and bleeding), as well as thromboembolic events (especially in the MDS/ Risk assessment MPN-RS-T group). Bone marrow findings usually dem- Of the MDS/MPN overlap disorders, most is known onstrate hypercellularity due to proliferation of one or about CMML in terms of factors predicting survival, and more myeloid lineages, as well as dysplasia of at least one several prognostic tools have been validated in CMML. lineage. Proliferation is often effective in some lineages, Although CMML itself is clinically a heterogeneous with increased numbers of circulating cells that may be entity and survival times range across a wide spectrum, morphologically or functionally dysplastic. Simultane- in virtually all studies, the percentage of blood and bone ously, other lineages may exhibit ineffective production, marrow blasts are the most important factors determin- so that cytopenias may be present as well. ing survival [10–12, 22–25]. Individual prognosis in The World Health Organization (WHO) first classi- CMML is related to myeloproliferative features (mostly fied MDS/MPN overlap syndromes as distinct from both high WBC count, but also splenomegaly, presence of cir- MDS and MPN in 2001 [2]. Prior to the designation of culating immature cells, and /or elevated serum lactate MDS/MPN as a category by the WHO, some cases of dehydrogenase (LDH)), cytopenias (thrombocytopenia, MDS/MPN may have been reported as other myeloid anemia, and/or neutropenia) and features of disease pro- neoplasms or may not have been reported at all. Further- gression (peripheral blasts, bone marrow blasts percent- more, the specific diagnoses and features that define the age, including promonocytes) [11, 22, 25–27]. MDS/MPN have been further refined, leading to reclas- Comprehensive genetic studies have scripted the muta- sification of some myeloid neoplasms. As such, under- tional landscape of MDS/MPN. These genetic altera- standing the true epidemiology of these rare diseases tions further refine prognosis, including chromosomal has been challenging and the frequency likely under- abnormalities [28–30] and gene mutations [22, 31–33]. estimated. CMML is recognized as the most common The latter have recently been included in three distinct of these disorders, with a reported annual incidence of prognostic scoring systems [31–33]. Mutations in ASXL1 approximately 0.4 cases/100,000/year and represents are included in all three, whereas the molecular CMML- approximately 70% of MDS/MPN [3, 4]. specific prognostic scoring system (CPSS-mol) also Patients with MDS/MPN overlap disorders have a includes mutations in SETBP1, NRAS, and RUNX1 [31]. highly variable disease course. Some patients live for A recent study on behalf of the MDS/MPN IWG has vali- many years with stable blood counts and few symptoms dated several prognostic models illustrating comparable Moyo et al. BMC Cancer (2022) 22:1013 Page 3 of 15 performance though significant heterogeneity in pre- Treatment diction outcomes exist among them [34]. These short- Current treatment strategies for MDS/MPN overlap syn- comings could be circumvented by the development of dromes are poorly defined, due in no small part to the personalized predictions using machine learning on large overall rarity of these collective diagnoses, as well as their knowledge databases [35]. striking clinical and genomic heterogeneity precluding a Although many prognostic tools have been validated in single “one-size-fits-all” approach. CMML, only one has been developed for atypical CML Importantly, a small number of patients with dys- [17], and none have been developed for other MDS/MPN plastic CMML were treated on the initial randomized subtypes, and the applicability of prognostic tools devel- azacitidine MDS registration studies and demonstrated oped for MDS or CMML has not been fully explored in similar responses compared to the overall MDS popula- other MDS/MPN entities. In patients with MDS/MPN- tion, which led to the FDA approval of azacitidine for this RS-T, younger age and presence of SF3B1 and/or JAK2 subtype of CMML (i.e. with WBC < 13 × ­109 /μL)[46]. mutations have been associated with a more favorable out- Additional Phase II studies have confirmed the efficacy of come [19]. In patients with aCML, age > 65 years, female DNMTi therapy for all subtypes of CMML [47, 48], and sex, WBC > 50 × ­109/L, thrombocytopenia, and/or hemo- thus DNMTi are often considered the de facto standard globin < 10 g/dL have been reported to be adverse prognos- of care for higher-risk dysplastic CMML and by exten- tic findings [13, 14, 17]. As with CMML, both proliferative sion the other MDS/MPN syndromes, particularly MDS/ (high WBC) and dysplastic features have prognostic value MPN-U, although DNMTi may not alter the mutational in other adult MDS/MPN subtypes [16, 36]. allele burden or disease biology [49, 50]. Access to DNMTi The mutational profile of rare MDS/MPN subtypes therapy for these patients is also (variably) restricted seems to partially overlap with CMML, but some char- across different healthcare systems. For patients with pro- acteristic patterns have emerged [16, 37, 38]. MDS/ liferative CMML, hydroxyurea was more effective and MPN-RS-T is the most distinct entity from a molecular achieved responses faster than cytotoxic chemotherapy perspective, characterized in most cases by mutations in with etoposide [8]. Despite this, responses were not com- SF3B1 in combination with an MPN driver mutation in plete, and prognosis remained poor. A recently published JAK2. Mutations in several other genes may be present, large (n = 949) retrospective cohort study of CMML with ASXL1 and SETBP1 considered as adverse prog- patients in Austria, patients with higher-risk CMML nostic markers [36]. SETBP1 mutations are most com- (myeloproliferative CMML, blasts ≥ 10%, CMML-1/2, or monly seen in aCML, where they are also considered to higher-risk CPSS) [51] had significantly improved survival confer an adverse prognosis [39]. Somatic mutations in with DNMTi treatment (n = 551) versus other treatments ASXL1, TET2 and SRSF2 are generally common in MDS/ (n = 398; 20.5 months [95% CI 18.5–23.5] vs 14.3 months MPN, including MDS/MPN-U and, like CMML, having [12.2–16.1]; p < 0.0001). However, the European multi- mutations in multiple genes is associated with an adverse center randomized phase III DACOTA trial evaluating prognosis [40, 41]. decitabine ± hydroxyurea versus hydroxyurea in advanced Incorporation of prognostic features in treatment deci- proliferative CMML (NCT02214407) revealed no differ- sions remains challenging, due to the lack of controlled ence in outcomes [52]. While the role of DNMTi therapy trials allowing rigorous identification of predictive fac- in proliferatie CMML is still not entirely clear, allogeneic tors for specific treatments. The CPSS and GFM prog- stem cell transplantation remains the only curative treat- nostic scores have been validated in CMML in the setting ment option for transplant-eligible CMML patients and of DNMTi treatment. In particular, TET2mut/ASXL1wt should be considered for all higher-risk patients [44]. patients have higher response rates and prolonged sur- JAK inhibition has proven effective for a subgroup vival with this treatment [42]. A decision analysis akin to of CMML patients with constitutional symptoms and those performed in MDS [43] has yet to be performed to splenomegaly [53, 54], and the combination of azaciti- identify how prognostic categories could guide the timing dine and ruxolitinib for MDS/MPNs have demonstrated of allogeneic stem cell transplantation, which has been safety and encouraging efficacy [55, 56]. Preliminary restricted to patients with higher-risk disease (eg. CPSS results of the farnesyl transferase inhibitor tipifarnib in intermediate-2/high risk) based on expert consensus [44, MDS/MPN patients have been encouraging and war- 45]. Stem cell transplant is, however, an option for only rant further investigation [57]. Immunotherapies are a small fraction of patients, given the demographics of also being actively investigated in CMML. The mono- this patient population. The AM-001 trial will improve clonal antibody tagraxofusp (SL-401) directed against prospective assessment of the models’ heterogeneity on CD123 and conjugated to a truncated diphtheria toxin overall outcome in MDS/MPNs. reported notable reductions in splenomegaly in CMML Moyo et al. BMC Cancer (2022) 22:1013 Page 4 of 15 patients in an interim analysis [58]. Lenzilumab (KB003), more than 60 institutions across the United States and a GM-CSF neutralizing monoclonal antibody, has shown Europe. The MDS/MPN IWG meets regularly to review promise in preclinical studies and is being actively evolving data that influences both our understand- investigated in early phase clinical trials [59]. Although ing of the pathophysiology of MDS/MPN diseases and thrombopoietin receptor agonists have been success- our approach to treatments. Through these meetings a fully used in lower-risk MDS subtypes with severe multitude of fruitful collaborations have already devel- thrombocytopenia [60, 61], eltrombopag elicited meager oped to drive the field forward, but ABNL-MARRO (A response rates in an early study in CMML patients with Basket study of Novel therapy for untreated MDS/MPN thrombocytopenia and was associated with high risk of and Relapsed/Refractory Overlap Syndromes) repre- developing leukocytosis [62]. Patients with aCML often sents dedication to develop new therapies efficiently present with significant leukocytosis and demonstrate an for MDS/MPN, and ABNL-MARRO 001 (AM-001) is aggressive disease course, for which allogeneic stem cell the inaugural international transatlantic clinical trial. In transplant should be considered. Hydroxyurea is typi- AM-001, a controlled, thoroughly annotated collection of cally recommended for control of leukocytosis. Treat- patient samples will be prospectively established. It will ment with DNMTi can be considered, where accessible, include fresh whole peripheral blood samples to collect particularly in transplant ineligible patients, as well as plasma, serum, and peripheral blood mononucleated the use of JAK inhibitors or dasatinib, with the choice of cells (PBMC), and fresh bone marrow aspirate to collect small molecule inhibitors informed by CSF3R mutation bone marrow mononucleated cells (BMMC) and plasma. analysis. Mutations within the juxta-membrane region Standard assessments for bone marrow core biopsies and of CSF3R (also known as the granulocyte colony-stim- aspirates will include morphology, flow cytometry, and ulating factor receptor) dysregulate JAK family kinases karyotype. Fresh samples will be shipped to one of 2 cen- and enhance sensitivity to JAK1/2 inhibition, whereas tral laboratories located in either the US or Europe. These CSF3R truncation mutations lead to activation of SRC samples will be used to address key questions in MDS/ family kinases and sensitivity to tyrosine kinase inhibi- MPN and will potentially allow identification of key bio- tion with dasatinib [63–65]. logical differences between the different subtypes. Patients with MDS/MPN-RS-T, often characterized by It is now well established that the mutational landscape SF3B1 and JAK2 mutations and with a prognosis consid- of MDS/MPN, which could be preceded by age-related ered to be generally favorable to MDS with ring sidero- clonal hematopoiesis of indeterminate potential (CHIP) blasts, are often treated with supportive care measures [75], combines a small number of common somatic such as erythropoietin-stimulating agents and red cell mutations in DNA methylation, histone modifier and transfusions for isolated anemia. Due to an increased splicing genes with disease-segregated mutations in sign- thrombosis risk, cytoreductive treatment plus low-dose aling genes, i.e., RAS pathway mutations in proliferative aspirin therapy is often recommended, particularly in the CMML; JAK2, MPL and CALR mutations in MDS/MPN- setting of advanced age, JAK2 mutation, or significant car- RS-T; and CSF3R and RAS pathway mutations in aCML diovascular disease [36, 66]. Efficacy of lenalidomide in [76]. Mutations in SF3B1 are prognostically favorable, patients with MDS/MPN-RS-T has also been described whereas those in SETBP1 and ASXL1 consistently predict [67–71], and the potential use of luspatercept or sotater- shorter survival [32, 77]. Mapping of clonal architecture cept in this population is of significant interest [72, 73]. in CMML identified early clonal dominance, intra-tumor heterogeneity in the hematopoietic stem and progenitor Key discoveries and unanswered questions cell (HSPC) compartment in which mutations accumu- In 2013 and 2014 a consortium of clinical and labora- late mostly linearly, and growth advantage to the most tory experts in MDS/MPN convened in 3 congresses to mutated cells as characteristic disease features [78]. address topical issues. Culminating from those meet- Epigenetic dysregulation in MDS/MPN involves abnor- ings was the publication of proposed uniform response mal histone marking caused by inactivation of chroma- criteria for MDS/MPN [74]. Until that time, MDS/ tin modifiers or abnormal DNA methylation resulting MPN patients were either excluded from clinical tri- from mutations in DNA methyltransferases and/or TET2 als or responses were variably determined using criteria methylcytosine dioxygenase [76]. DNMTi can restore a developed for other myeloid diseases. The development balanced hematopoiesis without necessarily decreasing of uniform response criteria specifically for MDS/MPN mutation allele burden in circulating myeloid cells, argu- would assist with application and translation of clini- ing for a role of epigenetic alterations in disease expres- cal trial results of MDS/MPN patients in the real-world sion and outcome [50]. Analysis of DNA methylation setting. Since the first meetings, the MDS/MPN IWG profiles at diagnosis could generate an epigenetic clas- has expanded to include clinicians and researchers at sifier that predicts response to a demethylating drug Moyo et al. BMC Cancer (2022) 22:1013 Page 5 of 15 [79]. ASXL1 mutations may predict a lower, whereas the MPN but will also establish the overarching ABNL- TET2mut/ASXL1wt genotype may herald a higher rate MARRO framework for future collaborative clinical and of response to DNMTi [42]. Molecular analyses of neo- correlative investigations to further explore clinicopatho- plastic cells collected in AM-001 may extend genomic logic markers of disease severity, prognosis and treatment investigations to noncoding DNA regions, gene expres- response. Centralized pathology and biospecimen man- sion and mRNA splicing analyzed by RNA sequencing, agement systems will allow for correlative studies to be and epigenetic changes that could affect and predict the conducted in order to advance the scientific understand- response to tested drugs. ing of disease pathogenesis and responses to treatment. Experimental models developed in mice suggested that, The international collaborative nature of ABNL-MARRO in myeloproliferative neoplasms, feedback loops between will allow a coordinated approach to both the clinical mature and immature cells of the clone affect the behav- care of MDS/MPN patients and the correlative science, ior of HSPCs, either residual healthy cells or clonal cells whereby different labs will contribute from their respec- that propagate the disease and contribute to its installa- tive strengths, pooling expertise and resources, working tion and development [80, 81]. It could be useful to fur- together towards a common goal rather than competing ther explore the role of mature cells of the leukemic clone in isolation. in MDS/MPN. These cells can be detected and quantified by multiparameter flow cytometry in bone marrow, e.g., Novel agents under investigation in ABNL MARRO‑001 plasmacytoid dendritic cells [82], or in the peripheral The ABNL-MARRO 001 study (NCT04061421) endeav- blood (e.g., monocytes [83, 84]). Analysis of peripheral ors to evaluate the safety and efficacy of oral combina- blood immature granulocytes and T cell subsets could tion therapies in MDS/MPN patients. DNMTi such as provide additional information on disease response to azacitidine and decitabine inhibit DNA methylation and treatments and patient outcome. allow previously silenced genes to be expressed and to Annotation of inflammatory cytokines in plasma or exert direct cytotoxic effects on abnormal hematopoietic serum was recently demonstrated to classify CMML cells in the bone marrow. Although responses to single patients into three groups with distinct clinical and agent DNMTi are limited, DNMTi have been employed genetic features and suggested that a decreased plasma in various myeloid diseases where more effective treat- level in IL-10 correlated with poor overall survival, even ment options are lacking, including in CMML, in MDS, when adjusted for other prognostic features including and in elderly/unfit patients with AML [46, 88–90]. The ASXL1 mutation [85]. Deregulated cytokines could play administration of azacitidine or decitabine is cumber- a key role in disease expression and suggest innovative some for patients, as they are administered daily by sub- therapeutic approaches [86, 87]. To this end, cytokine cutaneous or intravenous routes for 5–7 consecutive levels will be measured in PB and BM plasma samples days each 4-week cycle until disease progression. For collected from patients included in AM-001 in order to patients who do not live-in close proximity to a referral search for mutation-independent predictors of response center, the logistics of this therapy can pose a significant to treatment. We will deploy global approaches to ana- hardship, not to mention the inconvenience of infusion lyzing the plasma proteome, with potential for novel bio- times and the common local effects of large volume marker discovery beyond what has been done before, and subcutaneous administrations. ASTX727 is a novel oral beyond the limitations of a custom panel of the ’expected’ formulation of decitabine together in a fixed dose com- potential biomarkers, with potential for novel discovery. bination with the cytidine deaminase inhibitor cedazu- Testing distinct small molecules in AM-001 will pro- ridine which reduces first pass metabolism of decitabine vide opportunities to study the respectively targeted in the gut and liver. The fixed dose combination (FDC) pathways for their pathogenic roles in MDS/MPN. ASTX727 pill containing 35 mg decitabine and 100 mg cedazuridine administered daily on days 1–5 of each Study rationale and objectives 28-day cycle elicited pharmacokinetic/dynamic proper- Response rates to single agent hypomethylating agents in ties similar to intravenous decitabine dosed at 20 mg/ MDS/MPN are underwhelming, but alternative options m2 daily × 5 days in subjects with MDS [91], and a phase are lacking. Furthermore, there are no approved thera- III study of ASTX727 in MDS and CMML revealed pies for patients who relapse after or who fail to respond pharmacoequivalence between the oral and IV forms of to DNMTi therapy. Both the rarity and heterogeneity of decitabine when oral decitabine is dosed with cedazu- MDS/MPNs have hindered development of therapies for ridine. Likewise, the responses to ASTX727 were similar, these diseases. Leveraging the expertise and cooperativ- or exceeded what was seen in earlier clinical trials and ity of the MDS/MPN IWG research consortium, AM-001 expected with parenteral decitabine [92]. This ASTX727 will not only explore novel treatment strategies for MDS/ FDC 35 mg/100 mg pill will constitute a DNMTi Moyo et al. BMC Cancer (2022) 22:1013 Page 6 of 15 treatment backbone within AM-001. The first novel tar- The Phase 1b study will allow for the determination of geted agent included in AM-001 is itacitinib, a selective the recommended phase 2 dose and schedule of com- inhibitor of JAK1 signaling which mediates pro-growth bination by dose de-escalation. Treatments found to be and pro-inflammatory responses that may drive prolifer- safe in the phase 1b, or single therapies, will advance ation of myeloid cells in the bone marrow. JAK1 signaling directly to the phase 2 portion of the study. The phase may contribute to common presenting symptoms such as 2 study (Fig. 1) will follow a Simon Two-Stage design to fatigue, constitutional symptoms, and weight loss related determine if there is sufficient efficacy to warrant further to cancer-cachexia. Previously, itacitinib has been shown investigation of the treatment combination in larger stud- to reduce myelofibrosis symptom burden and spleen size ies for MDS/MPN patients. The arms are not intended to without significant reductions in hemoglobin or platelets compete against ASTX727 alone or with one another. [93]. Additional arms will include other small molecule Rather, the safety and efficacy of each treatment com- inhibitors (to be determined) that have shown promise in bination will be evaluated independently, and random their development in myeloid diseases. allocation will serve to guarantee that the cohorts enroll equally. Study objectives Study sites and patient selection The primary objectives for the study are to characterize The AM-001 study is the first clinical study to be con- the dose limiting toxicities of novel oral targeted agents ducted within the framework of the ABNL-MARRO in in combination with oral ASTX727 (Phase 1) and to test conjunction with the MDS/MPN IWG. Eligible patients whether the overall response to each therapy warrants (Table 2) will be enrolled at selected MDS/MPN IWG further investigation in more definitive trials in MDS/ member institutions across the US and Europe. Adult MPN patients (Phase 2). Overall response will include patients must have a morphologically confirmed diag- subjects who achieve best response of complete remis- nosis of MDS/MPN based on the 2016 WHO diagnostic sion (CR), partial remission (PR), optimal or partial mar- criteria, including CMML, aCML, MDS/MPN-RS-T and row response (MR), or clinical benefit (CB) as defined MDS/MPN-U. by the MDS/MPN IWG proposed response criteria. The study will evaluate morphologic bone marrow responses Phase 1b safety run‑in and effects of each treatment on patient survival as sec- Each combination therapy will be tested first in a safety ondary objectives. Exploratory objectives (Table 1) are run-in (Phase 1b) to determine the recommended phase also planned to bolster scientific understanding of dis- 2 dose (RP2D) and schedule using a 3 + 3 de-escalation ease pathogenesis and to evaluate methods used for design. The initial dose of ASTX727 will consist of the prognostication and assessment of response to therapy. FDC of oral DAC/cedazuridine (35 mg/100 mg) that has been found to approximate the area under the curve Study design (AUC) of standard dosing of DAC [91]. The starting dose AM-001 is an open label, phase 1b-2 study that will ran- of itacitinib in the initial safety cohort has been extrapo- domly allocate between novel treatment arms in MDS/ lated from phase 1 testing when combined with standard MPN. DNMTi in other myeloid diseases. Each combination therapy will be allowed a maximum of four dose decre- Arm 1: ASTX727 + itacitinib (INCB039110; JAK1 ments in the dose de-escalation design. The RP2D and inhibitor) schedule of each combination therapy will be defined as Arm 2: To be determined the highest dose and schedule at which no more than 1 Arm 3: To be determined of 6 treated subjects experienced a dose-limiting toxicity Table 1 Exploratory objectives of ABNL-MARRO 001 Exploratory Objectives of ABNL-MARRO 001 • To investigate genetic biomarkers of response in MDS/MPN • To characterize molecular responses to individual treatments • To evaluate synergistic effects of hypomethylation by ASTX727 and specific pathway blockade by study compounds • To explore the use of automated quantification of spleen volume from CT exams as a measure of clinical benefit • To test and/or validate diagnostic algorithms and prognostic indices for MDS/MPN patients • To investigate the correlation of patient reported outcomes with disease severity and/or treatment response Moyo et al. BMC Cancer (2022) 22:1013 Page 7 of 15 Fig. 1 Study Design. Once the RP2D and schedule has been determined for a given treatment in the phase 1b, that treatment arm may enter phase 2, which will follow a Simon Two-Stage design. Stage 1 of the phase 2 will include treatment-naïve MDS/MPN patients only. If sufficient efficacy is demonstrated in treatment-naïve patients to proceed to Stage 2 of the phase 2, then patients who have failed or were intolerant to DNMTi-containing regimens, including treatment on other AM-001 arms or prior to enrolling in the study, will also be included. Eligible patients will be randomly allocated to AM-001 arms that are actively accruing and to which they have not had prior exposure. In Stage 2, patients will be stratified based on treatment status (e.g. treatment-naïve vs relapsed/refractory/intolerant) (DLT). Any treatment arm in which more than 1 of 6 beneficial combinations in larger cohorts of patients. Eli- subjects experience a DLT after 4 dose decrements will gible subjects will be randomly allocated into an active, be terminated. The safety run-in will include both treat- non-blinded treatment arm. Treatment will begin at the ment-naïve and relapsed/refractory MDS/MPN patients RP2D and schedule of each combination determined in assigned to a treatment arm based on slot availability. phase 1b. Stage 1 of the Two-Stage design will include only treatment-naïve subjects, and no stratification will Phase 2 occur prior to randomization. If sufficient responses For doses that elicited fewer than 2 DLTs in 6 MDS/MPN (including MDS/MPN IWG response categories of CR, subjects, efficacy will then be evaluated in phase 2 using PR, MR, or CB) are seen in the first stage in treatment- a Simon Two-Stage design to allow early discontinuation naïve subjects to warrant further investigation, MDS/ of any futile treatment regimen and to pursue potentially MPN patients who are refractory to or who have relapsed Moyo et al. BMC Cancer (2022) 22:1013 Page 8 of 15 Table 2 Eligibility criteria for ABNL-MARRO 001 Inclusion Criteria • At least 18 years of age and willing and able to meet all study requirements • Morphologically confirmed diagnosis of MDS/MPN, excluding juvenile myelomonocytic leukemia, according to the WHO (2016) diagnostic criteria • Treatment-naïve patients with no prior disease-modifying therapy may enroll in any AM-001 arm that is open to accrual in phase1b or phase 2 • After an appropriate wash-out period, patients who have failed or were intolerant to prior therapy regimens containing a DNMTi may enroll in any arm accruing in phase 1b or in the second stage of the phase 2 • Willing to undergo bone marrow biopsy with aspiration and tissue collection for disease assessment and correlative studies during screening and periodically throughout the trial • Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 • Life expectancy of at least 3 months • For previously treated patients, recovery to Grade ≤ 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia • Adequate hepatic and renal function during screening Exclusion Criteria • Patients will be excluded from arms that contain novel targeted agents to which they have prior exposure, with exception of ASTX727 • Prior receipt of any investigational therapy within 30 days or 5 half-lives before receiving the first dose of AM-001 study therapy • Prior receipt of any systemic non-investigational antineoplastic therapy, excluding hydroxyurea, within 21 days or 5 half-lives before receiving the first dose of AM-001 therapy • Known hypersensitivity to decitabine • Transformation to acute myeloid leukemia • Organ transplant recipients including allogeneic hematopoietic stem cell transplant • History of clinically significant or uncontrolled cardiac disease • History of abnormal EKG or presence of abnormal screening EKG that is clinically significant and contraindicated for clinical study • Known contraindications to use of ASTX727 • Active and clinically significant bleeding • Other active malignancy, excluding non-melanoma skin cancer, cervical carcinoma in situ, breast carcinoma in situ, or localized prostate cancer controlled with hormone therapy • Receipt of wide-field radiotherapy within 28 days or limited-field radiation within 14 days prior to initiating AM-001 treatment • Patients who require continuation of a prohibited concomitant medication • Active, uncontrolled infection • Major surgery requiring general anesthesia within 4 weeks prior to starting AM-001 therapy (other than placement/removal of vascular access devices) • Women who are pregnant or lactating • Women/men who expect to conceive/father children within the projected study period and/or who are unwilling to use highly effective methods of contraception throughout the study duration • Any concurrent serious or unstable medical or psychiatric condition that would jeopardize the patient’s ability to provide informed consent or to comply with the protocol • Any psychological, familial, geographical or sociological condition that would jeopardize the patient’s ability to comply with the study protocol after previous DNMTi therapy will also be included in or who experience disease progression after an initial the second stage, and subjects will be stratified in the response will discontinue treatment within that arm but second stage based on treatment status (treatment- may be re-randomized to another AM-001 arm (if avail- naïve versus relapsed/refractory) prior to randomization able) that has proceeded to the second stage of the phase (Fig. 1, Table 2). 2. All patients enrolled in the study will continue therapy Response to treatment will be assessed after 2 and until progression of disease, unacceptable toxicity, revo- 6 cycles of therapy (e.g., on Cycle 3 Day 1 and Cycle 7 cation of consent, or failure to fulfill reasonable study Day 1) by physical examination, hematologic labora- requirements. tory parameters, bone marrow biopsy and/or aspiration, computed tomography (CT) of the abdomen, and patient Statistical plan reported outcomes according to the modified proposed For the phase 1b, each dose cohort will include a mini- MDS/MPN IWG response criteria. Subjects who have mum of 3 subjects. The first cohort of 3 patients in an definitive disease progression after 2 cycles of therapy AM-001 arm will be enrolled at the starting dose and Moyo et al. BMC Cancer (2022) 22:1013 Page 9 of 15 schedule of ASTX727 and the novel targeted agent as number of responses obtained in the minimum num- defined in the protocol, and no additional cohort will be ber of patients treated. If sufficient responses have been enrolled until the previous cohort has been fully evalu- observed after 6 cycles of therapy (e.g., by Cycle 7 Day 1 ated for toxicity. The DLT evaluation period will be response assessment) in subjects enrolled in stage 1 and defined as the first 28 days after initiation of treatment criteria of the Simon Two-Stage design are met, the arm on any AM-001 arm in the phase 1. If ≤ 1 of 3 subjects will begin enrolling both treatment-naïve and previously in the first cohort experiences a DLT, the cohort will be treated MDS/MPN subjects in stage 2 of the phase 2. If expanded by an additional 3 patients treated with the sufficient responses are observed in the maximum num- same dose/schedule of each drug. If ≤ 1 of 6 subjects ber of subjects enrolled in phase 2 by the second sched- experience a DLT, the RP2D and schedule has been uled response assessment (e.g., Cycle 7 Day 1), the null determined. If > 1 subject in either the first 3 or 6 sub- hypothesis will be rejected, and definitive trials may be jects treated at any dose level experiences a DLT, the warranted. If insufficient responses are observed after all maximum tolerated dose (MTD) has been exceeded, and subjects in either stage have completed six cycles of ther- the dose(s) of either or both drug(s) will be de-escalated apy, the arm will be terminated. in the next cohort of 3 subjects based on planned dose level reductions defined in the protocol. Dose de-escala- Study oversight and guidance tion will continue until the RP2D and schedule is deter- Multiple committees and subcommittees have been mined or until a maximum of 4 dose de-escalations has organized for the development, oversight, and manage- occurred on that arm. Any arm in which more than 1 of ment of AM-001 and for analysis of AM-001 study data. 6 subjects experience a DLT after 4 dose decrements will The Protocol Development Committee has drafted and be terminated and that treatment combination will be refined the protocol based on input of all other commit- deemed too toxic for further evaluation in phase 2. The tee members and will continue to refine the protocol if minimum sample size for the phase 1b evaluation of each amendments are needed. The Patient-Reported Out- treatment arm is 6 patients, and the maximum number of comes (PRO) and Symptom Assessment Committee patients in the phase 1 evaluation of each treatment arm advises on the collection, use and analysis of data col- is 30 (6 subjects × 5 dose levels). lected directly from the study subjects regarding their In phase 2, each arm will follow an optimal Simon personal study experience (including but not limited to Two-Stage design [94]. Criteria for the Simon Two-Stage symptom scores and quality of life metrics). The Cor- design for each arm are based on the results of studies of relative Science and Biospecimen Committee oversees ASTX727 and other DNMTi therapy in myeloid diseases. the collection and utilization of biological specimens col- Accordingly, the null hypothesis that the overall response lected from each subject in conjunction with AM-001. rate (combined CR + MR + PR + CB) is 35% will be tested The Risk Assessment and Criteria Validation Committee against a one-sided alternative. In the first stage, 14 advises on the collection and analysis of data that may treatment-naïve patients will be accrued in each AM-001 be used to devise and/or test prognostication indices arm and will receive treatment at the RP2D and sched- and to validate the MDS/MPN IWG response criteria. ule of the novel targeted agent and of ASTX727, as deter- The Operations Committee assists with all operational mined in the phase 1b. If there are 13 or fewer responses aspects of the study from study inception to completion. in these first 35 patients before the ­7th cycle of therapy, All committees will report to the Executive Commit- the study will be stopped for futility. Otherwise, 52 addi- tee, which oversees all aspects of the trial, and is led by tional patients (including both treatment-naïve subjects the Global Study Chair. The study has a Medical Moni- and subjects relapsed after/refractory to other DNMTI- tor and an independent Data Safety Monitoring Board containing therapies) will be accrued for a total of 87. (DSMB) to ensure the protection of subjects enrolled in The null hypothesis that the true response rate is 35% the study. The DSMB will meet regularly and as needed if or less will be rejected if 38 (44%) or more responses are patient safety issues arise, will report their findings to the observed in 87 patients before the ­7th cycle of therapy. Executive Committee with recommendations on study This design yields a type I error rate of 0.05 and power continuation, and may propose amendments to the study of 85% when the true response rate is 50%. Assuming low protocol as necessary. (35% RR) efficacy, the probability of early termination and expected sample size of any arm is 68% and 51.8 patients, Selected study procedures respectively. The responses of subjects treated in the Subjects will be treated according to the study calen- phase 1 of an arm will not be included in the determi- dar, barring any adverse events that may warrant dose nation of futility or efficacy in phase 2. The actual num- interruption or modification. All protocol-indicated ber of patients treated per arm will be dependent on the treatments in this study are orally self-administered, Moyo et al. BMC Cancer (2022) 22:1013 Page 10 of 15 although some doses will be required to be self-admin- different degrees. A prime example is CMML, for which istered under direct observation of the study staff. Self- diversity in presentation has been well established. Some administration of protocol-indicated medications will be cases present with more prominent dysplastic features recorded in a pill diary which will be reviewed to assess and less monocyte proliferation, and others present with compliance with study medications. more prominent monocytic proliferation and less dyspla- sia [23, 96]. Additionally, clearly diagnosed myelodysplas- Safety analysis tic syndrome or myeloproliferative neoplasms can show After signing the informed consent, adverse events will features that suggest overlap disorders. For example, both be collected as detailed in the schedule of assessments. primary myelofibrosis and polycythemia vera can show Adverse events will be assessed from the time of consent monocytic or neutrophilic progression, making them until at least 30 days after a patient’s last dose on trial or difficult to distinguish from CMML or aCML [97–99]. until the subject initiates anti-neoplastic treatment that is Finally, MDS/MPN must be differentiated from benign not part of AM-001 – whichever occurs first. Safety data proliferations, such as reactive monocytosis. will be reported with summary statistics. Accordingly, central pathology review in AM-001 pre- sents an opportunity to address some of these diagnostic Response assessments difficulties. Entry into the trial will not depend on central Response assessments will occur after 2 and 6 cycles of review, but rather on diagnosis at the local site. However, therapy and at the end of treatment (EOT). Response central pathology review will be performed post hoc with assessments will include assessment of spleen size a goal of verifying local diagnosis and to catalog and eval- and volume by physical examination and CT, respec- uate any differences between local diagnosis and expert tively; evaluation of hematologic laboratory parameters, review. Furthermore, a detailed central pathology review patient-reported symptoms, and bone marrow aspiration will allow evaluation and refinement of the morphologic and/or biopsy. Responses to treatment will be measured component of the response criteria [74]. according to the proposed MDS/MPN IWG response cri- teria [74]. Since these response criteria have not yet been Prognostic indices validated in a large independent study, post hoc analyses A “global” MDS/MPN prognostic index that has been are planned to determine the validity and clinical utility validated across MDS/MPN subtypes and that informs of these criteria across MDS/MPN subtypes. treatment in MDS/MPN remains elusive. Demographic, clinical and pathologic data will be collected from sub- Patient‑reported outcomes jects enrolled in AM-001 to test the applicability of avail- Patients with MDS/MPN overlap syndromes may present able prognostic indices across MDS/MPN subtypes. with a myriad of symptoms that affect quality of life. The Molecular data will also be collected to explore the MDS/MPN IWG response criteria have incorporated the impact of emerging genetic risk factors in these rare and myeloproliferative neoplasm symptom assessment form heterogeneous diseases that may not have been incor- total symptom score (MPN-SAF/TSS) which has been porated into indices that were developed prior to wide- rigorously validated in myelofibrosis. There are currently spread use of genomic analysis. no patient-centered metrics that have been designed specifically for MDS/MPN or validated in a mixed pop- ulation of MDS/MPN diagnoses. AM-001 will provide Research correlates opportunity to explore the applicability of the MPN-SAF In addition to pathologic specimens for response assess- across these heterogeneous disease groups and to explore ments, additional bone marrow aspirate and peripheral alternative patient-centered metrics, including the blood specimens will be collected in screening prior to EORTC-QLQ C30 and the MDS QUALMS, to further initiation of AM-001 therapy, with each response assess- understand the impact of disease-related symptoms and ment, and at the EOT. These specimens will be pro- how each treatment may affect quality of life. cessed by two centralized laboratories (one in USA and one in EU) and will be used for planned studies to fur- Central pathology ther explore the relationships between the genetic land- Diagnostic criteria for MDS/MPN are now well estab- scape, the variable expression of specified genes/proteins, lished and distinguish this group of diseases from either plasma biomarkers, and patient outcomes (Table 1). The MDS or MPN [1, 95]. Despite this, the diagnosis of these distribution and use of samples by MDS/MPN IWG diseases can be challenging for a number of reasons. members are subject to availability and approval by the First, the diagnosis requires both dysplastic and prolif- AM-001 Executive Board and the Correlative Science erative features, but some cases carry these features to and Biospecimen Committee. Moyo et al. BMC Cancer (2022) 22:1013 Page 11 of 15 Discussion European Union; FDC: Fixed dose combination; GFM: Groupe Francophone des Myelodysplasies; HSPC: Hematopoietic stem and progenitor cell; IWG: ABNL MARRO is an innovative international cooperative International Working Group; LDH: Lactate dehydrogenase; MDS: Myelodys‑ study group designed to address several key challenges in plastic syndromes; MDS/MPN: Myelodysplastic/myeloproliferative neoplasms; MDS/MPN that have long hindered the development of MDS/MPN-RS-T: MDS/MPN with ring sideroblasts and thrombocytosis; MDS/ MPN-U: MDS/MPN unclassifiable; MPN: Myeloproliferative neoplasms; MPN- optimal treatments. By leveraging the MDS/MPN IWG SAF/TSS: MPN symptom assessment form total symptom score; MR: Optimal member sites, AM 001 will meet a clear unmet medical or partial marrow response; MTD: Maximum tolerated dose; PB: Peripheral need and will enroll both treatment-naïve MDS/MPN blood; PBMC: Peripheral blood mononucleated cells; PIM: Proviral integration site of Moloney murine leukemia virus; PR: Partial remission; PRO: Patient- patients of all subtypes and MDS/MPN patients who have reported outcomes; RP2D: Recommended phase 2 dose; USA: United States of relapsed after or who are refractory to DNMTi. Although America; WBC: White blood cell count; WHO: World Health Organization. the study is built to add additional arms in real time, the Authors’ contributions randomization into arms is only to allow equal alloca- T.K.M., J.H.M., R.I., A.K., E.S., A.C.S., and M.R.S. participated in the creation of the tion, and not designed to measure treatments against one protocol and wrote the manuscript. G.D.A assisted with the statistical design another. Rather, the arms will be independently evaluated of the study. A.T.G., A.E.D., A.N., P.V., A.A.V., F.O., L.P., B.X.C., R.T., K.G., R.S.K., J.Z., U.G., D.P.S., D.H.W., M.P., C.E., N.C.P.C., J-J.K., M.L., R.A.M., G.M-B., G.F.S., U.P., M.M.P., for both safety (phase 1b) and efficacy (phase 2) in this E.P., V.S., P.F. participated in the creation of the protocol and reviewed, edited, patient population. If safe and effective, this study could and approved the final manuscript. All authors read and approved the final lead to further randomized studies, and ultimately, an manuscript. expanded armamentarium of treatment options available Funding to both treatment-naïve and relapsed/refractory MDS/ P.V. is supported by the Austrian Science Fund (FWF) grant F4704-B20. For MPN patients. Importantly, we aim to explore all oral this work, M.R.S. is supported by Beverly and George Rawlings Directorship in Hematology Research (M.R.S). ASTX727 is provided by Astex Pharmaceuticals. combination therapies, which could expand both access Itacitinib is provided by Incyte Corporation. Funding for ABNLMARRO 001 is to and palatability of treatment options for patients who supplied by Incyte Corporation. There was no role of the funding body in the currently must travel for daily infusions for up to one design of the study and collection, analysis, and interpretation of data and in writing the manuscript. out of every 4 weeks indefinitely and who may endure local site reactions with subcutaneous administration of Availability of data and materials DNMTi or face problems with venous access. Not applicable. The data collected from this study will provide robust insight into future treatment strategies, with exploration Declarations of risk factors and markers of disease prognosis across Ethics approval and consent to participate MDS/MPN subtypes that may help to guide treatment The ABNL-MARRO 001 study protocol and associated informed consent selection and/or timing. The collection of biospecimens documents (ICDs) were approved by the Vanderbilt University Medical Center Institutional Review Board (Nashville, Tennessee, USA; Approval 11/24/2021; for both planned exploratory research and potential IRB #211924). Participating sites of the ABNL-MARRO 001 study will obtain future studies will further inform our understanding of approval of the study protocol and associated informed consent documents mechanisms of disease, which can then be used to fur- (ICDs) from the local institutional review board/independent ethics commit‑ tee (IRB/IEC). The study is enrolling and registered at www.​clini​caltr​ials.​gov as ther hone the treatment of these rare and heterogeneous #NCT04061421. The study complies with the Declaration of Helsinki and the diseases. principles of Good Clinical Practice guidelines and will be carried out in keep‑ Perhaps most importantly, AM-001 is the inaugural ing with all local legal and regulatory requirements. Prospective study partici‑ pants will be informed orally and in writing of the nature, scope, and possible study that has established the infrastructure and col- outcomes of participation in the trial. An IRB/IEC-approved ICD will be signed laborative network for future prospective interventional by each participant before he/she enrolls in the study. No procedures for the studies to advance treatment and to explore clinical and study may be initiated prior to obtaining signed informed consent. pathologic markers of disease severity, prognosis and Consent for publication treatment response under the umbrella of the ABNL Not applicable. MARRO, an clinical trial platform for the MDS/MPN Competing interests International Working Group. Tamara K. Moyo: None Jason Mendler: Abbreviations None ABNL MARRO: A Basket study of Novel therapy for untreated MDS/MPN and Raphaël Itzykson: Relapsed/Refractory Overlap Syndromes; aCML: Atypical BCR-ABL1 negative Research Funding Janssen Novartis, Abbvie chronic myeloid leukemia; AM-001: ABNL-MARRO 001 study; AUC​: Area under Honoraria: Abbvie, Amgen, Astellas, BMS/Celgene, Daiichi-Sankyo, Jazz, the curve; AZA: Azacitidine; BM: Bone marrow; BMMC: Bone marrow mononu‑ Karyopharm, Servier cleated cells; CB: Clinical benefit; CHIP: Clonal hematopoiesis of indeterminate Consulting: Abbvie, Amgen, Novartis, Otsuka Pharma, Jazz Pharmaceuticals, potential; CMML: Chronic myelomonocytic leukemia; CPSS: CMML-specific Karyopharm, StemLine. prognostic scoring system; CPSS-mol: Molecular CMML-specific prognostic Ashwin Kishtagari: scoring system; CR: Complete remission; CT: Computed tomography; DAC: None Decitabine; DLT: Dose-limiting toxicity; DNMTi: DNA methyltransferase Eric Solary: inhibitor(s); DSMB: Data safety monitoring board; EOT: End of treatment; EU: Advisor: Stemline therapeutics. Moyo et al. BMC Cancer (2022) 22:1013 Page 12 of 15 Adam Seegmiller: Mrinal M. Patnaik: None Advisory board for Kura Oncology and Stem Line therapeutics. Aaron T. Gerds: Eric Padron: Consulting/Advisory: Celgene (Bristol-Myers Squibb), Pfizer, Kartos Therapeu‑ Research funding: Kura Oncology, Incyte Corporation, and BMS, and serves as tics, CTI Biopharma, Promedior. a consultant for Taiho Oncology and Blueprint Medicines. Research funding: Roche, Celgene (Bristol-Myers Squibb), Incyte, Imago Valeria Santini: Biosciences. Honoraria: Celgene/Bristol-Myers Squibb, Novartis, Janssen-Cilag. Gregory D. Ayers: Consulting or Advisory Role: Celgene/Bristol-Myers Squibb, Novartis, Menarini, None Takeda, Pfizer, Geron, Gilead Sciences. Amy E. DeZern: Research Funding: Celgene. Consulting honoraria from Abbie, Taiho, Novartis. Travel, Accommodations, Expenses: Janssen-Cilag, Celgene. Aziz Nazha: Pierre Fenaux: Amazon (own stocks). Research support, as GFM chairperson, from AbbVie, Celgene, Janssen, Speaker Bureau: Incyte Corporation, Novartis. Novartis. Data monitoring committee: MEI Pharma. Michael R. Savona: Advisory Board / Consulting (pharmaceutical/biotechnology): Karyopharma, Research funding from ALX Oncology, Astex, Incyte, Takeda and TG Therapuet‑ Abbvie, Daiichi Sankyo. ics; consults or serves on advisory or DSMB for AbbVie, BMS, Forma, Geron, Peter Valent: Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, TG Therapeutics; COI—study related: no. and has equity in Karyopharm and Ryvu. COI—unrelated to this study: P.V. received honoraria from Celgene/BMS, Novartis, AOP Orphan Pharmaceuticals, Pfizer, and Incyte. Author details 1 Arjan A. van de Loosdrecht: Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, None 2220 Pierce Avenue, Nashville, TN 777 PRB, USA. 2 Levine Cancer Institute, Francesco Onida: Charlotte, NC, USA. 3 James P. Wilmot Cancer Institute, University of Rochester None. Medical Center, Rochester, NY, USA. 4 Paris Diderot University, Paris, France. 5 Lisa Pleyer: Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France. 6 Cleveland Honoraria from AbbVie, Agios, Bristol Myers Squibb (BMS), Celgene, Inflection Clinic, Cleveland, OH, USA. 7 Johns Hopkins University, Baltimore, MD, USA. 8 Point Biomedical Advisors, and Novartis. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Blanca Xicoy Cirici: Medical University of Vienna, Vienna, Austria. 9 Ludwig Boltzmann Institute None for Hematology and Oncology, Medical University of Vienna, Vienna, Austria. 10 Raoul Tibes: VU University Medical Center, Amsterdam, Netherlands. 11 Fondazione IRCCS Employment: AstraZeneca. Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy. 12 Klaus Geissler: Third Medical Department With Hematology, Medical Oncology, Rheumatology Speaker and Consultancy Honoraria: Abbvie, Celgene, Novartis. and Infectiology, Paracelsus Medical University, Salzburg, Austria. 13 Salzburg Rami S. Komrokji: Cancer Research Institute Center for Clinical Cancer and Immunology Trials, Speaker bureau: JAZZ, BMS. Salzburg, Austria. 14 Institut Català d’Oncologia‑Hospital Germans Trias i Pujol, Honoraria/consulting: Jazz, BMS, Geron, Abbvie, Acceleron, Novartis. Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Jing Zhang: Bellaterr, Spain. 15 Mayo Clinic, Scottsdale, AZ, USA. 16 Sigmund Freud University, None Vienna, Austria. 17 H. Lee Moffitt Cancer Center, Tampa, FL, USA. 18 University Ulrich Germing: of Wisconsin-Madison, Madison, WI, USA. 19 Department of Hematology, Speakers Honoraria: Celgene, Jazz, Novartis, Janssen. Oncology, and Clinical Immunology, University of Duesseldorf, Duesseldorf, Institutional Research Support: Celgene, Novartis. Germany. 20 Dana-Farber Cancer Institute, Boston, MA, USA. 21 University David P. Steensma: of Manchester, Manchester, UK. 22 Hanusch Hospital and Ludwig Boltzmann Employment: Novartis. Institute for Hematology and Oncology, Vienna, Austria. 23 University of Pavia, Daniel H. Wiseman: Pavia, Italy. 24 School of Medicine, University of Southampton, Southampton, Research funding: Astex. UK. 25 Université de Paris, APHP, Hôpital Saint-Louis, Centre d’Investigations Speaker/consultancy honoraria: Novartis, StemLine, Takeda, Celgene. Cliniques, INSERM CIC 1427, Paris, France. 26 University of Freiburg, Freiburg, Michael Pfeilstoecker: Germany. 27 Mays Cancer Center at UT Health San Antonio MD Anderson, San Speaker and Consultancy Honoraria: Abbvie, Astellas, Takeda, Celgene, and Antonio, TX, USA. 28 MD Anderson Cancer Center, Houston, TX, USA. 29 Hospital Novartis. Universitario Y Politécnico La Fe, Valencia, Spain. 30 University Hospital Leipzig, Chiara Elena: Leipzig, Germany. 31 Mayo Clinic, Rochester, MN, USA. 32 MDS UNIT, University Advisory boards for Novartis, Pfizer, Gilead. of Florence, HematologyFlorence, Italy. Nicholas C.P. Cross: Novartis: consultancy and research support; Incyte: consultancy. Received: 21 January 2022 Accepted: 9 September 2022 Jean-Jacques Kiladjian: Novartis, Celgene, Abbvie, AOP Orphan: advisory boards. Michael Lübbert: Research Support: Janssen, Cheplapharm, TEVA. Travel Support: Janssen. References Ruben Mesa: 1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloom‑ Consultant: Novartis, Sierra Oncology, La Jolla, Samus. field CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Research Support – Incyte, CTI, Celgene, Abbvie, Imago. Organization classification of myeloid neoplasms and acute leukemia. Guillermo Montelban-Bravo: Blood. 2016;127:2391–405. None 2. Jaffe ES. 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An oral fixed-dose com‑ • support for research data, including large and complex data types bination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haema‑ • gold Open Access which fosters wider collaboration and increased citations tol. 2019;6(4):e194–203. • maximum visibility for your research: over 100M website views per year 92. Savona MR, McCloskey JK, Griffiths EA, Yee KWL, Al-Kali A, Zeidan AM, Deeg HJ, Patel PA, Sabloff M, Keating M-M, et al. Clinical Efficacy and At BMC, research is always in progress. Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelod‑ ysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia Learn more biomedcentral.com/submissions (CMML). Blood. 2020;136(Supplement 1):37–8.