Toward a more patient‐centered drug development process in clinical trials for patients with myelodysplastic syndromes/neoplasms (MDS): Practical considerations from the International Consortium for MDS (icMDS)

Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health‐related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient‐reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high‐quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS‐focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time‐to‐event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision‐making for this patient population

The Challenging World of Cytopenias: Distinguishing Myelodysplastic Syndromes From Other Disorders of Marrow Failure

Over the past decade, our understanding of bone marrow failure has advanced considerably. Marrow failure encompasses multiple overlapping diseases, and there is increasing availability of diagnostic tools to distinguish among the subtypes. Identification of genetic alterations that underlie marrow failure has also greatly expanded, especially for myelodysplastic syndromes. Molecular markers are increasingly used to guide the management of myelodysplasia and may distinguish this diagnosis from other marrow failure disorders. This review summarizes the current state of distinguishing among causes of marrow failure and discusses the potential uses of multiple diagnostic and prognostic indicators in the management of myelodysplastic syndromes and other bone marrow failure disorders

Comparison of clinical outcomes and prognostic utility of risk stratification tools in patients with therapy-related vs de novo myelodysplastic syndromes: a report on behalf of the MDS Clinical Research Consortium

While therapy-related (t)-myelodysplastic syndromes (MDS) have worse outcomes than de novo MDS (d-MDS), some t-MDS patients have an indolent course. Most MDS prognostic models excluded t-MDS patients during development. The performances of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Global Prognostic System (MPSS), WHO Prognostic Scoring System (WPSS) and t-MDS Prognostic System (TPSS) were compared among patients with t-MDS. Akaike information criteria (AIC) assessed the relative goodness of fit of the models. We identified 370 t-MDS patients (19%) among 1950 MDS patients. Prior therapy included chemotherapy alone (48%), chemoradiation (31%), and radiation alone in 21%. Median survival for t-MDS patients was significantly shorter than for d-MDS (19 vs 46 months, P<0.005). All models discriminated survival in t-MDS (P<0.005 for each model). Patients with t-MDS had a significantly higher hazard of death relative to d-MDS in every risk model, and had inferior survival compared to patients with d-MDS within all risk group categories. AIC Scores (lower is better) were 2316 (MPSS), 2343 (TPSS), 2343 (IPSS-R), 2361 (WPSS) and 2364 (IPSS). In conclusion, subsets of t-MDS patients with varying clinical outcomes can be identified using conventional risk stratification models. The MPSS, TPSS and IPSS-R provide the best predictive power

Disparities in Participation in Interventional Clinical Trials for Myelodysplastic Syndromes

Abstract Background: Only a minority of patients diagnosed with myelodysplastic syndromes (MDS) enroll in interventional clinical trials, which impedes development of novel therapies. Factors contributing to low trial accrual are incompletely understood but have been hypothesized to include the older age and frail nature of many patients with MDS, narrow trial eligibility criteria, lack of "precision medicine" agents, perception of MDS as an indolent or lower-risk disease, and difficulty or expense of traveling to trial centers (Steensma D et al Cancer 2018). Methods: We analyzed a pooled patient database from institutions of the US MDS Clinical Research Consortium (MDS CRC) to compare characteristics of participants in interventional trials with those patients who never enrolled in a trial during their disease course. Demographics, ZIP code of patient residence (a surrogate measure for income), distance from home to the referral center, presenting blood counts, World Health Organization (WHO) 2008 MDS classification, and Revised International Prognostic Scoring System (IPSS-R) score were compared between trial participants and non-participants. Results: Clinical trial enrollment data were available on 2,138 patients with MDS who had been evaluated at sites in the MDS CRC, of whom 515 (24.1%) participated in an interventional clinical trial. The median age of patients was 67.0 years and 63.4% were male. Patients who participated in trials were on average 1.2 years younger than non-participants (66.1 vs 67.3 years, p=0.037) while men were more likely to participate in a trial (70% of trial participants were male compared to 30% female, compare to non-participants of whom 61% were male and 39% female; p<0.01.) Clinical trial participants tended to live a little closer to the trial center (median distance 134.5 miles for participants vs. 154.8 miles for non-participants, p=0.15). Race was not associated with likelihood of trial enrollment, but Hispanic ethnicity was associated with trial non-participation (p=0.045) and patients in more affluent ZIP codes had a higher participation rate (p<0.01). Patients with RAEB-2, RCMD and RARS were over-represented in trials compared to disease subtype prevalence, while del(5q) was underrepresented (p=0.06). IPSS-R did not influence participation. Conclusion: Even at large referral centers, only a minority of patients with MDS enroll in interventional trials. Younger, male, affluent non-Hispanic patients were more likely to enroll in studies. Understanding barriers to trial accrual may help investigators and study sponsors design trials that will accrue more rapidly and augment treatment options for patients with MDS. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Roboz:Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Sandoz: Consultancy; Jazz Pharmaceuticals: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Argenx: Consultancy; Novartis: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Aphivena Therapeutics: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; AbbVie: Consultancy. Brunner:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Novartis: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees