Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia

Abstract

A llogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapserisk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34 + and CD8 + cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34 + and CD8 + leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical.trials.gov with the number NC01423747.

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

“…This number increased slightly for STR-PCR in leukocyte subpopulations but was still lower than previously reported frequencies. 26,28 Likely, this low number is due to omission of samples closer than 30 days to diagnosis of relapse, as a detection of 5% recipient or more DNA in peripheral blood by STR-PCR is often detected in conjunction to diagnosis of morphological relapse in bone marrow, and This study has limitations, and results should be interpreted with caution. As it is a retrospective study, the frequency of samples was not controlled prospectively and is likely biased.…”

“…Two children had an episode of IMC using STR‐PCR in whole blood. This number increased slightly for STR‐PCR in leukocyte subpopulations but was still lower than previously reported frequencies . Likely, this low number is due to omission of samples closer than 30 days to diagnosis of relapse, as a detection of 5% recipient or more DNA in peripheral blood by STR‐PCR is often detected in conjunction to diagnosis of morphological relapse in bone marrow, and these samples are thus not included in this analysis.…”

“…Likely, this low number is due to omission of samples closer than 30 days to diagnosis of relapse, as a detection of 5% recipient or more DNA in peripheral blood by STR‐PCR is often detected in conjunction to diagnosis of morphological relapse in bone marrow, and these samples are thus not included in this analysis. Further, some publications apply a detection level of 1% for STR‐PCR chimerism which could further explain this discrepancy . The low number of positive samples by STR‐PCR means subsequent analysis is low in power and the lack of a significant association with relapse should be seen in this light.…”

“…STR-PCR is the gold standard and has a sensitivity of 1%-5%. [22][23][24] Increasing recipient chimerism has repeatedly been associated with increased risk of relapse in pediatric ALL and AML, 6,10,25,26 although some studies have failed to reproduce these results. 27,28 Moreover, therapeutic interventions based on changes in chimerism have been associated with increased OS and EFS.…”

State of Chimerism as a Promising Tool for Follow up of Hematopoietic Stem Cell Transplantation in Egyptian Patients

“…And they confirm that the reappearance of recipient cells preceded hematological relapse in patients with acute leukemia may strengthen the hypothesis that these re-emerging host cells weaken the GVL effect of donor effector cell, possibly as the result of the induction of tolerance towards host antigens. Preuner et al (35) and Bader et al, (33) Patients with ALL who were not completely chimeric on day 28 after transplantation had increased risk of relapse, they concluded that within a median observation time of 4.5 years of ALL patients, the appearance of recipientcells after a period of pure donor chimerism in the CD34+ and CD8+ leukocyte subsets revealed adynamic indicative of significantly elevated riskof relapse or imminent disease recurrence. Depending on previous studies, which revealed that Lineage restricted chimerism is a very useful tool as to follow up post-transplant results (16) .…”