Multiparameter flow cytometry for assessment of minimal residual disease in patients with myelodysplastic syndromes treated with allogeneic stem cell transplantation
Abstract:AbstractBackgroundMyelodysplastic syndromes (MDSs) are a heterogeneous group of clonal myeloid neoplasms. Allogeneic stem cell transplantation (allo-SCT) remains the curative method for MDS treatment. Little is known about the monitoring of minimal residual disease (MRD) in patients with MDS after allo-SCT.AimWe aimed to evaluate the significance of leukemia-associated immunophenot… Show more
“…However, aberrant phenotypes were distinctly present in multiple (nontransplanted) high-risk MDS/AML BM samples included as controls ( Figure 5 A-D; supplemental Table 1 ), although not for all aberrant phenotypes investigated, in agreement with other studies. 11 , 41 , 42 , 43 Figure 5. FCM–based leukemic stem cell and aberrant antigen expression analysis.…”
Section: Resultsmentioning
confidence: 99%
“…Although confirming their usefulness in diagnostic assessment of high-risk MDS/AML, these panels lacked the specificity and sensitivity required for MRD analysis at CR, in agreement with previous studies failing to identify leukemia-associated immunophenotype for MRD assessment in MDS. 42 , 43 …”
Relapse following complete remission (CR) remains the main cause of mortality after allogeneic stem cell transplantation for hematological malignancies and therefore improved biomarkers for early prediction of relapse remains a critical goal towards development and assessment of preemptive relapse treatment. Since the significance of cancer stem cells as a source of relapses remains unclear, we investigated whether mutational screening for persistence of rare cancer stem cells would enhance measurable residual disease (MRD) and early relapse-prediction post-transplantation. In a retrospective study of relapse patients and continuous-CR patients with myelodysplastic syndromes and related myeloid malignancies, combined flow cytometric cell sorting and mutational screening for persistence of rare relapse-initiating stem cells was performed in bone marrow at multiple CR time points post-transplantation. In 25 CR samples from 15 patients that later relapsed, only 9 samples were MRD-positive in mononuclear cells (MNCs) whereas flowcytometric sorted hematopoietic stem and progenitor cells (HSPCs) were MRD-positive in all samples, and always with a higher variant allele frequency than in MNCs (mean 97-fold). MRD-positivity in HSPCs preceded MNCs in multiple sequential samples, in some cases preceding relapse by more than 2 years. In distinction, in 13 patients in long-term continuous-CR, HSPCs remained MRD-negative. Enhanced MRD-sensitivity was also observed in total CD34+ cells, but HSPCs were always more clonally involved (mean 8-fold).In conclusion, identification of relapse-initiating cancer stem cells and mutational MRD-screening for their persistence consistently enhances MRD-sensitivity and earlier prediction of relapse after allogeneic stem cell transplantation.
“…However, aberrant phenotypes were distinctly present in multiple (nontransplanted) high-risk MDS/AML BM samples included as controls ( Figure 5 A-D; supplemental Table 1 ), although not for all aberrant phenotypes investigated, in agreement with other studies. 11 , 41 , 42 , 43 Figure 5. FCM–based leukemic stem cell and aberrant antigen expression analysis.…”
Section: Resultsmentioning
confidence: 99%
“…Although confirming their usefulness in diagnostic assessment of high-risk MDS/AML, these panels lacked the specificity and sensitivity required for MRD analysis at CR, in agreement with previous studies failing to identify leukemia-associated immunophenotype for MRD assessment in MDS. 42 , 43 …”
Relapse following complete remission (CR) remains the main cause of mortality after allogeneic stem cell transplantation for hematological malignancies and therefore improved biomarkers for early prediction of relapse remains a critical goal towards development and assessment of preemptive relapse treatment. Since the significance of cancer stem cells as a source of relapses remains unclear, we investigated whether mutational screening for persistence of rare cancer stem cells would enhance measurable residual disease (MRD) and early relapse-prediction post-transplantation. In a retrospective study of relapse patients and continuous-CR patients with myelodysplastic syndromes and related myeloid malignancies, combined flow cytometric cell sorting and mutational screening for persistence of rare relapse-initiating stem cells was performed in bone marrow at multiple CR time points post-transplantation. In 25 CR samples from 15 patients that later relapsed, only 9 samples were MRD-positive in mononuclear cells (MNCs) whereas flowcytometric sorted hematopoietic stem and progenitor cells (HSPCs) were MRD-positive in all samples, and always with a higher variant allele frequency than in MNCs (mean 97-fold). MRD-positivity in HSPCs preceded MNCs in multiple sequential samples, in some cases preceding relapse by more than 2 years. In distinction, in 13 patients in long-term continuous-CR, HSPCs remained MRD-negative. Enhanced MRD-sensitivity was also observed in total CD34+ cells, but HSPCs were always more clonally involved (mean 8-fold).In conclusion, identification of relapse-initiating cancer stem cells and mutational MRD-screening for their persistence consistently enhances MRD-sensitivity and earlier prediction of relapse after allogeneic stem cell transplantation.
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