Myelodysplastic syndromes (MDSs) represent a heterogeneous group of hematological stem cell disorders with an increasing burden on health care systems. Evidence-based MDS guidelines and recommendations (G/Rs) are published but do not necessarily translate into better quality of care if adherence is not maintained in daily clinical practice. Guideline-based indicators (GBIs) are measurable elements for the standardized assessment of quality of care and, thus far, have not been developed for adult MDS patients. To this end, we screened relevant G/Rs published between 1999 and 2018 and aggregated all available information as candidate GBIs into a formalized handbook as the basis for the subsequent consensus rating procedure. An international multidisciplinary expert panel group (EPG) of acknowledged MDS experts (n = 17), health professionals (n = 7), and patient advocates (n = 5) was appointed. The EPG feedback rates for the first and second round were 82% (23 of 28) and 96% (26 of 27), respectively. A final set of 29 GBIs for the 3 domains of diagnosis (n = 14), therapy (n = 8), and provider/infrastructural characteristics (n = 7) achieved the predefined agreement score for selection (>70%). We identified shortcomings in standardization of patient-reported outcomes, toxicity, and geriatric assessments that need to be optimized in the future. Our GBIs represent the first comprehensive consensus on measurable elements addressing best practice performance, outcomes, and structural resources. They can be used as a standardized instrument with the goal of assessing, comparing, and fostering good quality of care within clinical development cycles in the daily care of adult MDS patients.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

Introduction: The incidence and prevalence of patients with Myelodysplastic Syndromes (MDS) are continuously rising due to population ageing and diagnostic advances. Consequently, the appropriate use of health care resources and assessment of their impact on relevant outcomes are of growing interest. Several evidence-based guidelines and recommendations (G&Rs) have been published for adult MDS patients. However, publishing G&Rs does not necessarily translate into better quality of care. Several studies have shown that MDS patients are not always treated according to published G&Rs, but systematic investigations have not been done so far. To this aim, we initiated the I-CARE for MDS study with the objectives to i) define relevant guideline-based indicators (GBIs) as measurable elements of practice performance for appropriate care, ii) assess the level of adherence and reasons for non-adherence to GBIs and iii) investigate the impact of adherence/non-adherence to GBIs on MDS relevant outcomes. Here we present results of the development of GBIs for appropriate care in adult MDS patients. Methods: We systematically screened G&Rs from cooperative MDS groups as well as cancer care accreditation/certification programs (table 1). All relevant information was extracted by a structured procedure and summarized as candidate GBIs in a handbook (table 2). We applied a RAND technique with a two-step DELPHI rating procedure to find an expert consensus for the clinically most relevant GBIs (Coulter J et al, J Health Serv Res Policy, 2018). The expert panel group (EPGs) members consisted of 17 internationally acknowledged MDS experts, 7 additional health-professionals (3 nurses, 1 pharmacologist, 1 physiotherapist, 1 psychologist and 1 epidemiologist) and 3 patient advocates. Candidate GBIs were rated using a 9-point Likert-like scale for Relevance, Understandability, Measurability, Behaviorability, Attainability (RUMBA-criteria) and ranked according to the agreement score, defined as % of all EPG members scoring all RUMBA-criteria in the first tertile (9, 8, or 7). Results: We extracted 61 candidate GBIs from G&Rs for the three domains Diagnostics (n=23), Treatment (n=21) and Provider characteristics (n=17). 18 and 16 candidate GBIs were excluded after the first and second round, respectively, remaining with a set of 27 GBIs (figures 1-3). Twelve GBIs were selected for Diagnostics (figure 1). Patient reported outcomes (PROs), Toxicity assessment (TAs) and Geriatric assessment were excluded as there was no agreement among experts on appropriate measurement instruments and concerns for practicability in daily routine. Eight GBIs were selected for Treatment (figure 2). Iron-chelation and Immunosuppressive treatment, even though mentioned in most G&Rs, were excluded, as there were concerns with regard to controversial indications, side effects and benefit for only a minority of patients. Seven GBIs were selected for Provider characteristics (figure 3), which will be generally fulfilled by accreditation or certification of institutions. Agreement scores were generally higher in this domain and required a more stringent threshold for selection of GBIs. Conclusions: Here we report on the development of relevant GBIs for the management of adult MDS patients covering the domains of Diagnostics, Treatment and Provider characteristics. Our preliminary set GBIs represents the most comprehensive integration of current practice based G&Rs and were developed by a structured consensus process involving internationally acknowledged experts. We identified important shortcomings in standardisation, measurability and practicability, especially for PROs and TAs, which asks for improvements in the future. Even though PROs and TAs are generally acknowledged endpoints for efficacy and safety, respectively, they are yet not standardised outside clinical trials or validated to inform routine MDS care. Our preliminary set of GBIs will be tested for applicability/operability as well as validated for their potential impact on relevant outcomes in MDS cohorts. They will eventually enable to systematically monitor, compare and optimize appropriateness of health care provided to MDS patients in everyday clinical practice. As such, GBIs will be important for the realization of a common standard for value-based medicine in economically driven health care systems with limiting resources. Disclosures Fenaux: Celgene Corporation: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding. Germing:Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Pfeilstocker:Janssen-Cilag: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Platzbecker:Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Medina De Almeida:Celgene: Speakers Bureau; Novartis: Speakers Bureau. Mittelman:Novartis: Honoraria, Research Funding, Speakers Bureau. Steensma:H3 Biosciences: Other: Research funding to institution, not investigator.; Stemline: Consultancy; Arrowhead: Equity Ownership; Aprea: Research Funding; Pfizer: Consultancy; Onconova: Consultancy; Astex: Consultancy; Summer Road: Consultancy. Santini:Menarini: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva (Ratiopharm): Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding. Symeonidis:MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. de Witte:Novartis: Research Funding; celgene: Research Funding; Amgen: Research Funding. Bonadies:Novartis: Other: financial support for travel, Research Funding; Celgene: Other: financial support for travel, Research Funding; Janssen: Other: financial support for travel; Roche: ; Amgen: Other: financial support for travel.