Peripheral blood late mixed chimerism in leucocyte subpopulations following allogeneic stem cell transplantation for childhood malignancies: does it matter?

Abstract

The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse.

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.…”

“…STR‐PCR is the gold standard and has a sensitivity of 1%‐5% . Increasing recipient chimerism has repeatedly been associated with increased risk of relapse in pediatric ALL and AML, although some studies have failed to reproduce these results . Moreover, therapeutic interventions based on changes in chimerism have been associated with increased OS and EFS .…”

“…[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. 3,9,10,14,29 However, the use of chimerism analysis by STR-PCR is limited by the relatively low sensitivity, since the presence of 1%-5% recipient DNA in peripheral blood will often translate into overt relapse, thus limiting the window of opportunity for effective intervention.…”

Longitudinal assessment of peripheral blood BRAFV600E levels in patients with Langerhans cell histiocytosis

“…The number of cells isolated for subsequent FISH analysis ranged from 1000 to 10,000. Chimerism analyses from gender-mismatched donor were analyzed using Dual-color FISH performed according to the standard procedures 15 with commercially available probes specific for the centromeric and heterochromatic regions of the X and Y chromosomes, respectively. Depending on the number of cells available, up to 500 cells were analyzed within each sorted cell fraction.…”