Patient-Specific Measurable Residual Disease Markers Predict Outcome in Patients With Myelodysplastic Syndrome and Related Diseases After Hematopoietic Stem-Cell Transplantation.
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Tobiasson Magnus, Pandzic Tatjana, Illman Johanna, Nilsson Lars, Weström Simone, Ejerblad Elisabeth, Olesen Gitte, Björklund Andreas, Olsnes Kittang Astrid, Werlenius Olle, Lorentz Fryderyk, Rasmussen Bengt, Cammenga Jörg, Weber Duruta, Lindholm Carolin, Wiggh Joel, Dimitriou Marios, Moen Ann Elin, Yip Lundström Laimei, von Bahr Lena, Baltzer-Sollander Karin, Jädersten Martin, Kytölä Soili, Walldin Gunilla, Ljungman Per, Groenbaek Kirsten, Mielke Stephan, Jacobsen Sten Eirik W, Ebeling Freja, Cavelier Lucia, Smidstrup Friis Lone, Dybedal Ingunn, Hellström-Lindberg Eva
Аннотация
METHODS: Patients with MDS planned for HSCT were enrolled in a prospective, observational study evaluating the association between MRD and clinical outcome. We collected bone marrow (BM) and peripheral blood samples until relapse, death, or end of study 24 months after HSCT. Patient-specific mutations were identified with targeted next-generation sequencing (NGS) panel and traced using droplet digital polymerase chain reaction (ddPCR).
RESULTS: Of 266 included patients, estimated relapse-free survival (RFS) and overall survival (OS) rates 3 years after HSCT were 59% and 64%, respectively. MRD results were available for 221 patients. Relapse was preceded by positive BM MRD in 42/44 relapses with complete MRD data, by a median of 71 (23-283) days. Of 137 patients in continuous complete remission, 93 were consistently MRD-negative, 39 reverted from MRD+ to MRD-, and five were MRD+ at last sampling. Estimated 1 year-RFS after first positive MRD was 49%, 39%, and 30%, using cutoff levels of 0.1%, 0.3%, and 0.5%, respectively. In a multivariate Cox model, MRD (hazard ratio [HR], 7.99), WHO subgroup AML (HR, 4.87), TP53 multi-hit (HR, 2.38), NRAS (HR, 3.55), and acute GVHD grade III-IV (HR, 4.13) were associated with shorter RFS. MRD+ was also independently associated with shorter OS (HR, 2.65). In a subgroup analysis of 100 MRD+ patients, presence of chronic GVHD was associated with longer RFS (HR, 0.32).
CONCLUSION: Assessment of individualized MRD using NGS + ddPCR is feasible and can be used for early detection of relapse. Positive MRD is associated with shorter RFS and OS (ClinicalTrials.gov identifier: NCT02872662).