Prospective evaluation of residual disease in intensively treated patients with acute myeloid leukemia (AML) as surrogate endpoint for survival
Final Report Abstract
Acute myeloid leukemia is a genetically and phenotypically heterogeneous disorder with an incidence of 3 to 4 per 100,000 men and women per year and a median age at diagnosis of about 70 years. Prognosis, especially in older patients, has remained poor with intensive chemotherapy but improved significantly by the approval of the non-intensive combination therapy with azacytidine s.c. and venetoclax p.o. (VEN-AZA) in the European Union 2021. The very convincing results published in 2020 in the New England Journal of Medicine in older patients not fit for intensive chemotherapy (DiNardo CD, et al. N Engl J Med. 2020 Aug 13;383(7):617-629.) and the approval of VEN-AZA in the United States of America already in 2018 prompted also a rapidly increasing proportion of patients fit for intensive chemotherapy being treated with VEN-AZA instead of intensive chemotherapy also in Germany. Thus, recruitment of investigator initiated clinical trials evaluating intensive chemotherapy plus targeted therapy such as GnG was heavily affected with early termination after recruitment of 28 of planned 252 patients and even planned studies such as Q-SOC with sample size of 156 patients were no longer pursued. Furthermore, the approval of the FLT3 inhibitor gilteritinib as single agent therapy for relapsed/refractory FLT3 mutated AML did directly negatively impact on the recruitment of the Q-HAM study evaluating the FLT3 inhibitor quizartinib with intensive chemotherapy leading to early termination after recruitment of n=11 of planned n=80 patients. Likewise, the recruitment of the BLAST study evaluating the high affinity CXCR4 Inhibitor BL-8040 as addition to consolidation therapy was terminated preterm after recruitment of 134 of planned 202 patients due to slow recruitment and futility. Although measurable residual disease (MRD) during treatment and follow up emerges as an important prognostic factor in first CR as well as a tool for a read-out of therapeutic efficacy, still methodological difficulties arise from the enormous genetic and phenotypic heterogeneity of AML in the context of a one-size fits all approach to measure MRD using multiparameter flow cytometry across all AML subtypes. Thus, the PERDAM study (ClinicalTrials.gov Identifier: NCT03549351) initially planned in 2015 to measure MRD with multiparameter flow cytometry in 1000 patients across several randomized studies faced several problems, which we were not able to completely overcome during the project lifetime. However, project funding enabled us to further develop and refine methodology of multiparameter flow cytometry, allowing both a less subjective and less biased evaluation, a high grade of standardization and also a significant reduction in turn-around time. These results have been disseminated at international hematology meetings and published in Leukemia, one of the leading peer-reviewed hematological journals.
Publications
- Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML. Trials; 22: 765.
Jaramillo S.
(See online at https://doi.org/10.1186/s13063-021-05703-w) - Reproducible measurable residual disease detection by multiparametric flow cytometry in acute myeloid leukemia. Leukemia; 36(9): 2208–2217.
Röhnert MA et al.
(See online at https://doi.org/10.1038/s41375-022-01647-5)
