Impact-AML: A European Master Framework for Cohort Studies and Pragmatic Clinical Trials in Relapse or Refractory Acute Myeloid Leukemia
Authors: Marconi Giovanni , Kountouris Petros , Mayer Jiri , Bullinger Lars , Reinhardt Dirk , Montesinos Pau , Merli Pietro , Vignetti Marco , Dumortier Jos , Hernández-Rivas Jesús María , Heuser Michael , Gerbutavicius Rolandas , Maturo Antonio Francesco , D'Errico Gianni , Nier Samantha , Zingaretti Chiara , Azzali Irene , Campacci Federica , Mañú-Pereira Maria Del Mar , Locatelli Franco , Hehlmann Rüdiger , Niederwieser Dietger W. , Martinelli Giovanni 
Published: December 2023

Background and Significance:
The treatment outcomes for acute myeloid leukemia (AML) have improved in recent decades, particularly for patients who can tolerate intensified treatment approaches. However, current therapies only cure a small portion of patients, with therapy resistance and relapse being the main causes of death. Relapsed or refractory (R/R) AML has a poor prognosis, and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option. However, there is no common therapeutic strategy for R/R AML, and most of the clinical trials have primarily focused on first-line treatments. The lack of standardized approaches leads to a wide range of variations in treatment choices across centers.
Study Design and Methods:
Founded by the European Union (EU) through Mission Cancer in the Horizon Europe research and innovation program, we will create STREAM, an inclusive, prospective, master framework for the design and conduction of pragmatic trials in R/R AML. In STREAM, we will enroll patients across Europe, proficiently acquiring an unselected population for clinical trials and monitoring outcomes of neglected cohorts. STREAM will involve more than 200 institutions and will represent a first of a kind large accrual network; online registration of patients will made available at participating sites through a user-friendly form designed in cooperation with the European Rare Blood Disorders Platform (ENROL), an EuroBloodNet initiative of ERN-EuroBloodNet.
Within STREAM, we will conduct a proof-of-concept prospective randomized pragmatic clinical trial (RPCT) that will compare the classical “high intensity” rescue chemotherapy with biology-driven, “low intensity” rescue to obtain real world data on the benefit of one of the two different strategies in term of survival. In the RPCT we will also consider and gather patients and caregivers' preferences also through patient-reported outcomes, assess accessibility barriers and social cost of the disease. The RPCT will aim to evaluate the effectiveness of real-world clinical alternatives in routine care; in addition to retaining the high internal validity of traditional randomized trials, it will maximize external validity, i.e. generalizability of results to many settings. In this context, the inclusion of an RPCT in the master framework will allow dynamic inclusion and the collection of the excluded population as an instrument to predict the real-life applicability of clinical trial results. Risk-oriented monitoring and technical developments will pave the way for academy driven clinical trials in the setting. Standard operative procedures for decentralized mesurable residual disease assessment and samples biobanking will be provided.
With the aim to generate evidences also in rare subsets, we will run single arm cohort studies that will allow the inclusion of rare patients and will be available for molecular-oriented cohort studies, studies in elderly or fragile patients, and studies in minorities. Single cohort studies external validity will be maximized compared with the STREAM general registered population.
The project will receive the support of patients themselves in the creation of both STREAM and clinical trials through patient-directed living labs and patient advocates advice.
Conclusion: Maximizing outcomes in R/R AML involves aiming for deep complete remission while minimizing adverse events. Unfortunately, it is not feasible in most patients, and - in treatment-eligible patients -the best path to reach this objective is unclear. IMPACT-AML represents an innovative platform to foster prospective generation of evidence in R/R AML, with a special focus on personalized medicine and innovative treatments for neglected cohorts.
IMPACT-AML is funded by the European Union with the grant agreement n. 101104421 in the Mission Cancer cluster of projects on “Diagnosis and treatment”.