Core outcome set measurement for future clinical trials in acute myeloid leukemia: the HARMONY study protocol using a multi-stakeholder consensus-based Delphi process and a final consensus meeting

Abstract

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults and has an unacceptably low cure rate. In recent years, a number of new treatment strategies and compounds were developed for the treatment of AML. There were several randomized controlled clinical trials with the objective to improve patients' management and patients' outcome in AML. Unfortunately, these trials are not always directly comparable since they do not measure the same outcomes, and currently there are no core outcome sets that can be used to guide outcome selection and harmonization in this disease area. The HARMONY (Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms in Hematology) Alliance is a public-private European network established in 2017 and currently includes 53 partners and 32 associated members from 22 countries. Amongst many other goals of the HARMONY Alliance, Work Package 2 focuses on defining outcomes that are relevant to each hematological malignancy. Accordingly, this pilot study will be performed to define a core outcome set in AML. Methods: The pilot study will use a three-round Delphi survey and a final consensus meeting to define a core outcome set. Participants will be recruited from different stakeholder groups, including patients, clinicians, regulators and members of the European Federation of Pharmaceutical Industries and Associations. At the pre-Delphi stage, a literature research was conducted followed by several semi-structured interviews of clinical public and private key opinion leaders. Subsequently, the preliminary outcome list was discussed in several multistakeholder face-to-face meetings. The Delphi survey will reduce the preliminary outcome list to essential core outcomes. After completion of the last Delphi round, a final face-to-face meeting is planned to achieve consensus about the core outcome set in AML.

Differential impact of IDH1/2 mutational subclasses on outcome in adult AML: results from a large multicenter study

“…Second, this highlights the need for coordinated multicenter 'big data' efforts like the HARMONY consortium 41 to illuminate the clinical and biological importance of rare mutations in myeloid neoplasms.…”

“…First, this provides further evidence for improved outcomes in patients with AML with IDH2 -R172K mutations without other class-defining lesions, thereby yielding potential implications for future patient care and treatment selection. Second, this highlights the need for coordinated multicenter big data efforts like the HARMONY Consortium 41 to illuminate the clinical and biological importance of rare mutations in myeloid neoplasms.…”

“…The median variant allele fractionequency (VAF) for IDH mutations was 38% (IQR: [30][31][32][33][34][35][36][37][38][39][40][41][42][43] with no difference in VAF between mutational subgroups (Supplement Tbl.1).…”

Unsupervised meta-clustering identifies risk clusters in acute myeloid leukemia based on clinical and genetic profiles

“…unmutated NPM1 + FLT3 -ITD high ) or higher dimensional mapping to be included without sacrificing model stability while potentially increasing the information gain. With the availability of a much larger patient cohort, e. g. through collaborative data collection efforts in hematology such as HARMONY 54 , clustering could be extended to methods such as deep learning 55 , potentially unveiling more nuanced differences between patient groups. Additionally, all patients in our cohort received intensive chemotherapy, and – with the exception of patients from the SORAML trial 17 which showed no impact on long-term overall survival for the addition of sorafenib 56 —did not receive molecular targeted therapy.…”