title: Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations.
abstract: A high proportion of patients with lower-risk del(5q) myelodysplastic syndromes will respond to treatment with lenalidomide. The median duration of transfusion-independence is 2 years with some long-lasting responses, but almost 40% of patients progress to acute leukemia by 5 years after starting treatment. The mechanisms underlying disease progression other than the well-established finding of smallTP53-mutated subclones at diagnosis remain unclear. We studied a longitudinal cohort of 35 low- and intermediate-1-risk del(5q) patients treated with lenalidomide (n=22) or not (n=13) by flow cytometric surveillance of hematopoietic stem and progenitor cell subsets, targeted sequencing of mutational patterns, and changes in the bone marrow microenvironment. All 13 patients with disease progression were identified by a limited number of mutations inTP53,RUNX1, andTET2, respectively, withPTPN11andSF3B1occurring in one patient each.TP53mutations were found in seven of nine patients who developed acute leukemia, and were documented to be present in the earliest sample (n=1) and acquired during lenalidomide treatment (n=6). By contrast, analysis of the microenvironment, and of hematopoietic stem and progenitor cells by flow cytometry was of limited prognostic value. Based on our data, we advocate conducting a prospective study aimed at investigating, in a larger number of cases of del(5q) myelodysplastic syndromes, whether the detection of such mutations before and after lenalidomide treatment can guide clinical decision-making.
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.|Department of Medicine, Division of Hematology, Skaraborgs Hospital, Skövde, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Scharenberg
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Valentina
authors.initials: V
authors.lastname: Giai
authors.affiliation: Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and NIHR Biomedical Research Centre, Oxford, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.affiliation: Department of Pathology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonie
authors.initials: L
authors.lastname: Saft
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marios
authors.initials: M
authors.lastname: Dimitriou
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Jansson
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Jädersten
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alf
authors.initials: A
authors.lastname: Grandien
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Iyadh
authors.initials: I
authors.lastname: Douagi
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: LeBlanc
authors.affiliation: Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and NIHR Biomedical Research Centre, Oxford, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Petter S
authors.initials: PS
authors.lastname: Woll
authors.affiliation: Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden eva.hellstrom-lindberg@ki.se.
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D019295:Computational Biology / Q000379:methods; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D011379:Prognosis; D055153:Stem Cell Niche; D013792:Thalidomide / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D013792:Thalidomide; D000077269:Lenalidomide