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Impact of pretransplant measurable residual disease on the outcome of allogeneic hematopoietic cell transplantation in adult monosomal karyotype AML.

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is often unsuccessful for monosomal karyotype (MK) acute myeloid leukemia (AML). To what degree failures are associated with pretransplant measurable residual disease (MRD)-a dominant adverse-risk factor-is unknown. We therefore studied 606 adults with intermediate- or adverse-risk AML in morphologic remission who underwent allogeneic HCT between 4/2006 and 1/2019. Sixty-eight (11%) patients had MK AML, the majority of whom with complex cytogenetics. Before HCT, MK AML patients more often tested MRDpos by multiparameter flow cytometry (49 vs. 18%; P?

SUBMITTER: Morsink LM

PROVIDER: S-EPMC7272254 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Impact of pretransplant measurable residual disease on the outcome of allogeneic hematopoietic cell transplantation in adult monosomal karyotype AML.

Morsink Linde M LM Othus Megan M Bezerra Evandro D ED Wood Brent L BL Fang Min M Sandmaier Brenda M BM Mielcarek Marco M Schoch Gary G Storb Rainer R Deeg H Joachim HJ Appelbaum Frederick R FR Walter Roland B RB

Leukemia 20200123 6

Allogeneic hematopoietic cell transplantation (HCT) is often unsuccessful for monosomal karyotype (MK) acute myeloid leukemia (AML). To what degree failures are associated with pretransplant measurable residual disease (MRD)-a dominant adverse-risk factor-is unknown. We therefore studied 606 adults with intermediate- or adverse-risk AML in morphologic remission who underwent allogeneic HCT between 4/2006 and 1/2019. Sixty-eight (11%) patients had MK AML, the majority of whom with complex cytogen ...[more]

PMID: 31974434

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Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML.

Project description:Molecular measurable residual disease (MRD) assessment is not established in approximately 60% of acute myeloid leukemia (AML) patients because of the lack of suitable markers for quantitative real-time polymerase chain reaction. To overcome this limitation, we established an error-corrected next-generation sequencing (NGS) MRD approach that can be applied to any somatic gene mutation. The clinical significance of this approach was evaluated in 116 AML patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) in complete morphologic remission (CR). Targeted resequencing at the time of diagnosis identified a suitable mutation in 93% of the patients, covering 24 different genes. MRD was measured in CR samples from peripheral blood or bone marrow before alloHCT and identified 12 patients with persistence of an ancestral clone (variant allele frequency [VAF] >5%). The remaining 96 patients formed the final cohort of which 45% were MRD+ (median VAF, 0.33%; range, 0.016%-4.91%). In competing risk analysis, cumulative incidence of relapse (CIR) was higher in MRD+ than in MRD- patients (hazard ratio [HR], 5.58; P < .001; 5-year CIR, 66% vs 17%), whereas nonrelapse mortality was not significantly different (HR, 0.60; P = .47). In multivariate analysis, MRD positivity was an independent negative predictor of CIR (HR, 5.68; P < .001), in addition to FLT3-ITD and NPM1 mutation status at the time of diagnosis, and of overall survival (HR, 3.0; P = .004), in addition to conditioning regimen and TP53 and KRAS mutation status. In conclusion, NGS-based MRD is widely applicable to AML patients, is highly predictive of relapse and survival, and may help refine transplantation and posttransplantation management in AML patients.

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Monitoring of Measurable Residual Disease Using Circulating DNA after Allogeneic Hematopoietic Cell Transplantation.

Project description:Relapse of the underlying disease is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we describe the clinical utility of measurable residual disease (MRD) and mixed chimerism (MC) assessment in circulating cell-free DNA (cfDNA) analysis to detect earlier relapse in patients with hematological malignancies after allo-HSCT. A total of 326 plasma and peripheral blood mononuclear cell (PBMCs) samples obtained from 62 patients with myeloid malignancies were analyzed by droplet-digital PCR (median follow-up: 827 days). Comparison of MC in patients at relapse and in complete remission identified an optimal discriminating threshold of 18% of recipient-derived cfDNA. After performing a targeted next-generation sequencing (NGS) panel, 136 mutations in 58 patients were detected. In a total of 119 paired samples, the putative mutations were detected in both cfDNA and PBMCs in 73 samples (61.3%). In 45 samples (37.8%) they were detected only in cfDNA, and in only one patient (0.9%) were they detected solely in DNA from PBMCs. Hence, in 6 out of 23 patients (26%) with relapse after allo-HSCT, MRD positivity was detected earlier in cfDNA (mean 397 days) than in DNA derived from PBMCs (mean 451 days). In summary, monitoring of MRD and MC in cfDNA might be useful for earlier relapse detection in patients with myeloid malignancies after allo-HSCT.

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Genotype-outcome correlations in pediatric AML: the impact of a monosomal karyotype in trial AML-BFM 2004.

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