Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia

Abstract

Analysis of chimerism in blood post‐HCT using STR‐PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. RQ‐PCR chimerism is 10‐ to 100‐fold more sensitive, but clinical studies in children are sparse. We analyzed IMC in blood samples following transplantation for acute lymphoblastic or myeloid leukemia in 56 children. IMC was defined as a minimum increase of (a) 0.1% or (b) 0.05% recipient DNA between two samples. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (HR 12.8 [95% CI: 3.9‐41.4; P < .0001] and 7.6 [95% CI: 2.2‐26.9; P < .01], respectively). The first IMC was detected at a median of 208 days prior to relapse. The 5‐year cumulative incidence of relapse for children with a single IMC was 45.5% (CI 12.3‐74.4) and 41.0% (14.2‐66.6) for IMC above 0.1% and 0.05%, respectively. However, in 47 and 38 children never attaining IMC > 0.1% and >0.05%, 10 and 8 children relapsed, respectively. In a landmark analysis, no association was found between IMC prior to 90 days post‐HCT and subsequent relapse by either classification of IMC and AUC for RQ‐PCR chimerism was 54.2% (95 CI 27.7‐ 84.8). Although limited by a retrospective design, these results indicate that monitoring of RQ‐PCR chimerism in peripheral blood may have a role in early detection of relapse in acute childhood leukemia.

Short Tandem Repeats (STRs) as Biomarkers for the Quantitative Follow-Up of Chimerism after Stem Cell Transplantation: Methodological Considerations and Clinical Application

“…Another aspect that has raised interest with the use of qPCR is the detection of low levels of recipient DNA in patients that do not subsequently develop relapse. Like other authors [24,30,38], we think that this finding may correlate with the presence of residual healthy recipient hematopoietic cells or cells from non-hematopoietic origin, which would not be replaced by donor-derived cells after HSCT. This is especially relevant in BM samples, for which STR-PCR is known to provide higher sensitivity [39][40][41], but have also shown higher sensitivity when using qPCR [42].…”

Peripheral blood molecular measurable residual disease is sufficient to identify patients with acute myeloid leukaemia with imminent clinical relapse

“…Analysis of chimerism after SCT is applicable across all leukaemia subtypes but sensitivity is limited to only 1-5%, albeit may be improved with the use of more sensitive qPCR techniques including microchimerism. 61 However, although increasing recipient chimerism is associated with disease recurrence not all cases lead to relapse in contrast to increasing qPCR MRD in PB. While mounting evidence suggest a strong prognostic impact of pre-transplant NPM1 MRD, [62][63][64][65] the predictive value of longitudinal surveillance of NPM1 MRD after SCT is also becoming increasingly apparent.…”

Performance Assessment of the Devyser High-Throughput Sequencing–Based Assay for Chimerism Monitoring in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

“…Depending on the report, the definition of increasing HC (eg, one or two increases), and the size of increase (eg, 0.05%, 0.10% increase compared with the previous sample), the negative and positive predictive values varied. 4,32 Timing of follow-up samples in these studies was lacking. Taken together, the small case series presented here and evidence from qPCR assays that exhibit a similar detection limit as the HTS assay indicate that the HTS assay may allow for prediction of early relapse compared with PCR-CE assays.…”