Quantification of mixed chimerism allows early therapeutic interventions

Abstract

Hematopoietic stem cell transplantation is the curative option for patients with myelodysplastic syndrome; however, it requires a long post-transplantation follow-up. A 53-year-old woman with a diagnosis of myelodysplastic syndrome underwent related donor allogeneic hematopoietic stem cell transplantation in July 2006. Three months after transplantation, a comparative short tandem repeat analysis between donor and recipient revealed full chimerism, indicating complete, healthy bone marrow reconstitution. Three years and ten months after hematopoietic stem cell transplantation, the patient developed leukopenia and thrombocytopenia. Another short tandem repeat analysis was carried out which showed mixed chimerism (52.62%), indicating relapsed disease. A donor lymphocyte infusion was administered. The purpose of donor lymphocyte infusion is to induce a graft-versus-leukemia effect; in fact, this donor's lymphocyte infusion induced full chimerism. Successive short tandem repeat analyses were performed as part of post-transplantation follow-up, and in July 2010, one such analysis again showed mixed chimerism (64.25%). Based on this finding, a second donor lymphocyte infusion was administered, but failed to eradicate the disease. In September 2011, the patient presented with relapsed disease, and a second related donor allogeneic hematopoietic stem cell transplantation was performed. Subsequent short tandem repeat analyses revealed full chimerism, indicating complete bone marrow reconstitution. We conclude that quantitative detection of mixed chimerism is an important diagnostic tool that can guide early therapeutic intervention.

Chimerism Monitoring Techniques after Hematopoietic Stem Cell Transplantation: An Overview of the Last 15 Years of Innovations

“…Despite all of this, doubts exist that a higher sensitivity should necessarily have a clinical significance in terms of therapeutic strategies or prognostic value [ 49 , 50 ]. In addition, with more sensitive techniques, we have to consider that false positive MC can be due to skin, epithelium, or stromal recipient cells collected together with PB and BM samples [ 26 , 34 ], which deserve attention and further studies to explore whether qPCR, dPCR, and NGS can enable an earlier therapeutic intervention [ 30 , 38 , 49 , 60 ].…”

“…Furthermore, dPCR does not need to use replicates because its partitioning of the DNA sample generates “mini-reactors” which can be considered independent units [ 26 , 31 , 38 , 58 ]. NGS is characterized by the exceptional capacity to distinguish between two different genomes, even in the absence of pre-transplantation donor DNA or in the presence of chromosomal abnormalities [ 30 , 60 ].…”

“…Overall, a major limitation of MC analysis, as with chimerism analysis in general, is the consistent report of patients with relapse without prior detection of MC as well as patients with MC that maintain the complete remission. Nevertheless, it is commonly agreed that a continuous chimerism monitoring should be performed in order to favor a timely intervention to expand the window for intervention, thus reducing the negative outcome [ 22 , 27 , 28 , 29 , 30 ].…”

Predicting Outcomes of Rat Vascularized Composite Allotransplants through Quantitative Measurement of Chimerism with PCR-Amplified Short Tandem Repeat

“…STR (also called microsatellites) are repetitive sequences of two to seven base pairs in genomic DNA. They have high degrees of heterozygosity and polymorphism and are shown to be good indicators of individuality [10]. Herein, we demonstrate that a PCR-based method would help to achieve precise measuring chimerism of a common rat allotransplantation combination, i.e., Brown Norway (BN) donor to Lewis (LEW) recipient.…”

“…In clinical settings, changes of chimerism based on accurate assessment by STR-PCR have been shown with diagnostic potential to track disease relapse following HSCT. Therapeutic intervention can thus be applied early [10].…”