New Criteria for Evaluating Outcomes of Myelofibrosis Therapy

Background New therapies for myelofibrosis (MF) are being developed but how these compare with current therapies is limited to analyzing single outcome measures such as spleen volume reduction or quality-of-life (QoL). However, these outcome trajectories might diverge and some endpoints may not be clinically relevant. To remedy this an ELN (European LeukemiaNet) taskforce developed a composite endpoint using the Desirability-Of-Outcome-Ranking (DOOR) method which allows multiple outcomes to be simultaneously considered and therapies achieving diverging endpoints compared.

Methods An Expert Panel used DOOR to divide outcome relevancy into 8 dimensions: clinical meaningfulness, modifiability, reliability, feasibility, decisional value, acceptability, frequency, and cost. Next, a weight was assigned to each dimension using the mean Likert score assigned by the panelists. Next, the panel validated which dimensions were met by each of 30 outcomes most frequently listed by clinical trials. A weighted score (WS) for each outcome was calculated based on weights assigned to a dimension and accomplishment rates assigned to outcomes. Outcomes were then distributed into quartiles. Next, operational definitions of outcomes were tested in Delphi consensus method requiring > 75% agreement. Last, a literature review indicated correlations of the outcomes ranked in the 1st 2 quartiles with survival.

Results Three composite endpoints were developed and named DEMYOs (DEsirability-of-MYelofibrosis-Outcomes). DEMYO-1, the proportion of people alive and free of severe vascular events, blast transformation, severe anaemia and thrombocytopenia and very-severe symptom burden, encompassed outcomes in the 1st quartile (WS > 29.5) and is the proposed composite endpoint for trials of people with advanced JAK-inhibitor refractory MF. DEMYO-2, defined as the proportion of people alive and free of accelerated or blast phase, severe or worsening anaemia, severe and major vascular events, severe or symptomatic splenomegaly, severe or worsening symptoms and any emergent adverse genetic abnormality, included the outcomes ranked in the 1st 2 quartiles (WS > 26.5) and is proposed for trials of people with a sub-optimal response to JAK-inhibitors. DEMYO-3, defined as the proportion of people alive and free of blast transformation, vascular events, severe, symptomatic or worsening clinical features and of worsening prognostic co-variates, included outcomes in the 1st 3 quartiles (WS > 23.5) and is proposed for trials of people not yet receiving JAK-inhibitors.

Interpretation DEMYO composite endpoints capture relevant clinical features of MF and represent endpoints important to patients, physicians and other stakeholders. DEMYO validation is feasible by available trial data and, once validated, the composite endpoints can be endorsed by medicines regulatory agencies. DOOR proved feasible and robust in this 1st-in-haematology application and we encourage further use.

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Marchetti:GILEAD: Consultancy; MSD: Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Vannucchi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AOP: Honoraria, Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mascarenhas:MorphoSys: Consultancy; Karyopharm: Consultancy; Ajax: Research Funding; Geron: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Support , Research Funding, Speakers Bureau; GSK: Consultancy; Disc: Consultancy; Celgene: Consultancy, Other: Travel Support, Speakers Bureau; Keros: Consultancy; Pfizer: Research Funding; Blueprint Medicines: Consultancy; Roche: Consultancy; Bristol Myers Squibb: Research Funding; Kartos: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; PharmaEssentia: Consultancy, Research Funding; CTI BioPharma/SOBI: Consultancy, Research Funding; Merck: Consultancy; Icahn School of Medicine at Mount Sinai: Current Employment; Sumitomo: Consultancy; NS Pharma: Research Funding; Ariad: Speakers Bureau; Incyte Corporation: Consultancy, Speakers Bureau; Astellas: Research Funding. Alvarez-Larran:AOP: Consultancy. Bose:Karyopharm: Honoraria; Incyte: Honoraria, Research Funding; PharmaEssentia: Honoraria; Disc Medicine: Research Funding; GSK: Honoraria; Novartis: Honoraria; MorphSys: Honoraria, Research Funding; Telios: Research Funding; CTI Biopharma Corp: Honoraria, Research Funding; Cogent: Honoraria, Research Funding; Astellas: Research Funding; Kartos: Honoraria, Research Funding; Ionis Pharmaceuticals: Research Funding; BMS: Honoraria, Research Funding; Blueprint: Honoraria, Research Funding; AbbVie: Honoraria; Pfizer: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. 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