Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning
Pediatric blood & cancer. 2020;:e28523
BACKGROUND Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. PROCEDURE Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. RESULTS Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3). CONCLUSION The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.
Is microchimerism a sign of imminent disease recurrence after allogeneic hematopoietic stem cell transplantation? A systematic review of the literature
Blood reviews. 2020;:100673
Chimerism analysis following hematopoietic stem cell transplantation (HSCT) for leukemia is routinely applied in parallel with quantification of minimal residual disease (MRD) to identify imminent relapse. In the past decades, new methods with a lower limit of detection compared to standard methods have been developed, so-called microchimerism analysis. Microchimerism analysis is fast, simple, applicable across pre-HSCT disease-type and can be applied on peripheral blood allowing frequent testing during follow-up. Monitoring of microchimerism in blood could replace repeated bone marrow analysis for MRD and allow earlier detection of imminent relapse or graft failure. Clinical studies in single center cohorts have shown conflicting but promising results. There is currently no consensus on the interpretation of microchimerism analysis and heterogeneity of studies remains a major obstacle for inter-study comparisons and meta-analysis in this field. We have conducted a systematic review of studies investigating associations between microchimerism and relapse of leukemia post-HSCT. We summarize current evidence and provide suggestions for future research.
[Development and Application of Automatic Analysis and Surveillance Platform for Chrimerism in Donors and Recipients after Allo-HSCT]
Zhongguo shi yan xue ye xue za zhi. 2020;28(3):1012-1018
OBJECTIVE To develop an automated chimeric analysis and reporting platform based on short tandem repeat (STR) and capillary electrophoresis methods for allogeneic hematopoietic stem cell transplantation (allo-HSCT) so as to improve work efficiency. METHODS Apache, MySQL, PHP and HTML5 were used to build the database and interface. The STR locus geno typing and chimeric analysis logic and flow were set up on the basis of STR rules and capillary electrophoresis. STR genotyping and 194 times of chimeric testing data of 100 patients after allo-HSCT were used to test the platform for automatic STR locus genotyping, chimeric calculation and report generation. RESULTS The established platform could realize the functions of STR locus customization, STR genotype determination, automatic chimeric analysis, and detection information database management, which can automatically generate an integrated report including multiple sequential chimeric results and trend graphs for the same patient and can be accessed and used simultaneously by different users through different browser interfaces. The results of automated analysis by the platform are completely consistent with that of manual analysis by experienced technicians, and the possibility of manual analysis error is reduced through automation. The time required for automatic analysis using this platform is approximately 1/6-1/5 of manual analysis. CONCLUSION The automatic analysis platform built in this study is operation stable and reliable in analysis results, which can improve work efficiency and report connotation, thus worthing popularized and applicable.
A SNP panel for early detection of artificial chimerism in HSCT patients using TaqMan technology
International journal of legal medicine. 2020
The monitoring of chimerism status in a hematopoietic stem cell transplantation patient is a crucial process and is performed periodically in a short time interval. A short tandem repeat marker is widely used for chimerism analysis due to its high discrimination power. However, the sensitivity of this approach was limited to 5% of a minor contributor and the interpretation is usually interrupted with PCR stochastic phenomena. Here, we developed an SNP panel for chimerism analysis using TaqMan technology. A set of SNPs was selected from Thai ancestry informative markers and open-access databases with proper criteria. We examined the 30 recipient-donor pairs that underwent HSCT and showed that the panel can provide an informative marker from 90% of all pairs. An early detection of artificial chimerism in post-HSCT samples was observed when compared with STR analysis. In addition, the detail of cases was discussed.
Use of chimerism analysis after allogeneic stem cell transplantation: Belgian guidelines and review of the current literature
Acta clinica Belgica. 2020;:1-9
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option in both adult and pediatric patients with malignant and non-malignant hematological diseases. Chimerism analysis, which determines the donor or recipient origin of hematopoietic cells in HSCT recipients, is an essential aspect of post-HSCT follow-up.Objectives: To review the current literature and develop Belgian consensus guidelines for the use of chimerism analysis in the standard of care after allogeneic HSCT.Methods: Non-systematic review of the literature in consultancy with the members of the BHS transplantation committee.Results: Clinical application with regards to prediction of graft failure or relapse as well as cell source are reviewed. A consensus guideline on the use of chimerism analysis after HSCT is presented.Conclusion: Monitoring of the dynamics or kinetics of a patient's chimerism status by serial analysis at fixed time points, as well as on suspicion of relapse or graft failure, is needed to monitor engraftment levels, as well as disease control and possible relapse.
Assessment of chimerism and immunomodulation to prevent post-transplantation relapse in childhood acute myeloblastic leukemia: is it the right approach?
Pediatric hematology and oncology. 2020;:1-10
Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.
Early Mixed Lymphoid Donor/Host Chimerism is Associated with Improved Transplant Outcome in Patients with Primary or Secondary Myelofibrosis
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
We investigated risk factors for the development of mixed chimerism in 131 patients transplanted for myelofibrosis and determined the impact of lymphoid (CD3+) and myeloid (CD33+) chimerism on transplant outcome. Disease risk included DIPSS plus categories low to high. The median patient age was 58 years. Patients were conditioned with high intensity (myeloablative) or low/reduced intensity (non-myeloablative) regimens and transplanted from related or unrelated donors. Mixed CD3+ chimerism was observed earlier after HCT, while CD33+ chimerism occurred later. Mixed chimerism was more frequent with low intensity than with high intensity regimens. Mixed CD3+ chimerism did not lead to graft failure and was associated with a reduced incidence of acute GVHD, and improved survival overall and relapse-free, while mixed CD33+ chimerism was associated with an increased relapse incidence and reduced overall and relapse-free survival, independent from the CD34+ cell dose transplanted. Thus, mixed CD3+ chimerism in patients with myelofibrosis had a favorable impact on transplant outcome and does not require therapeutic interventions.
Donor-derived DNA variability in fingernails of acute myeloid leukemia patients after allogeneic hematopoietic stem cell transplantation detected by direct PCR
Bone marrow transplantation. 2020
Short Tandem Repeats (STRs) as Biomarkers for the Quantitative Follow-Up of Chimerism after Stem Cell Transplantation: Methodological Considerations and Clinical Application
Chimerism refers to the relative proportion of donor and recipient DNA after hematopoietic stem cell transplantation (HSCT) and its quantitative follow-up is of great clinical utility in this setting. PCR of short tandem repeats (STR-PCR) constitutes the gold standard method for chimerism quantification, although more sensitive PCR techniques (such as qPCR) have recently arisen. We compared the sensitivity and the quantification capacity of both techniques in patient samples and artificial mixtures and demonstrated adequate performance of both methods, with higher sensitivity of qPCR and better quantification skills of STR-PCR. By qPCR, we then prospectively followed up 57 patients that were in complete chimerism (CC) by STR-PCR. Twenty-seven patients (59%) showed 0.1-1% recipient DNA in the bone marrow. Only 4 patients presented 0.1-1% recipient DNA in peripheral blood (PB), and one of them relapsed. Finally, by qPCR, we retrospectively studied the last sample that showed CC by STR-PCR prior to relapse in 8 relapsed patients. At a median of 59 days prior to relapse, six patients presented mixed chimerism by qPCR in PB. Since both approaches have complementary characteristics, we conclude that different techniques should be applied in different clinical settings and therefore propose a methodological algorithm for chimerism follow-up after HSCT.
Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia
Pediatric transplantation. 2019;:e13549
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.