Chimerism analysis has become an important tool for the peri-transplant surveillance of engraftment. It offers the possibility to realize impending graft rejection and can serve as an indicator for the recurrence of the underlying malignant or nonmalignant disease. Most recently, these investigations have become the basis for treatment intervention, for example, to avoid graft rejection, to maintain engraftment and to treat imminent relapse by pre-emptive immunotherapy. This invited review focuses on the clinical implications of characterization of hematopoietic chimerism in stem cell transplantation.
During the past three decades, bone marrow transplantation and transplantation of peripheral blood stem cells have become a well-established treatment procedure for many malignant and nonmalignant disorders in children and in adult patients.1,2,3,4,5,6,7,8 After transplantation, it has been of central interest whether the newly developed hematopoietic system is of recipient or donor origin. The investigations of the genotypic origin of post-transplant hematopoiesis are called chimerism analysis. ‘Chimera’ refers to Greek mythology where Homer described a fire-spitting monster with the head of a lion, the body of a goat and the tail of a serpent terrorizing Lycia, a region in Asia Minor, and which was finally sacrificed by the ancient hero Bellerophon.9 The term chimerism was first introduced into medicine by Anderson et al10 in 1951, when they wrote that ‘a chimera is an organism whose cells derive from two or more distinct zygote lineages’, and it was first used in the field of transplantation by Ford in 1956.11
Originally, it was believed that complete donor hematopoiesis is essential to maintain engraftment after allogeneic stem cell transplantation (allo-SCT) in humans.12 In the last few decades, however, it became evident that donor and recipient hematopoiesis could coexist after allo-SCT in the recipient. This state of coexistence of hematopoietic cells is called mixed chimerism, which might end in an ‘autologous recovery’. If all hematopoietic cells post transplant are of donor origin, the patient is called a ‘complete chimera’ and shows a ‘complete chimerism’. It has been demonstrated, however, that the evolution of post-transplant chimerism most often is a dynamic process.13,14,15 Therefore, patients with complete chimerism at a certain time point post transplant can later develop a state of ‘mixed chimerism’ and vice versa. In patients with mixed chimerism, the degree of autologous cells can increase or decrease. These patients are then referred to have an ‘increasing’ or an ‘decreasing mixed chimerism’.14,16,17 Peripheral blood or bone marrow is most often used for chimerism analysis with or without further manipulation of different cell subpopulations. It is important to realize that patients could show complete chimerism in one compartment, for example, NK cells, whereas others could be totally or in part recipient derived. This is called ‘split chimerism’.18,19 Finally, the sensitivity of the applied method has also an impact on the degree of chimerism. A patient could be complete chimera with a method detecting about 1% autologous cells, whereas recipient cells could have been detected with a more sensitive technique. A summary of these definitions is given in Table 1.
Methods for chimerism analysis
Since chimerism analyses were first performed, many different methods have been developed and implemented, all following the same basic principle using differences in polymorphic genetic markers and their products. These methods include, for example, cytogenetics,20,21 red cell phenotyping,22,23 restriction fragment length polymorphism analysis (RFLP)24,25,26,27 and fluorescence in situ hybridization of sex chromosomes.28,29,30,31,32,33 A major limitation of these different techniques was that they were time consuming and did not offer the possibility to study all patients (for reviews, see Thiede et al17 and Thomas et al34). Different techniques and their characteristics are summarized in Table 2.
The breakthrough for the clinical applicability came when polymerase chain reaction (PCR) technique was developed35 and also utilized for investigation of chimerism.36,37,38,39,40,41,42 During the 1990s, these analyses were mainly performed by amplification of variable number of tandem repeats (VNTR) or by the characterization of short tandem repeat (STR) markers (for a review, see Khan et al43). Fluorescent labeling of the primers and resolution of PCR products with capillary electrophoresis allowed accurate quantification of the degree of mixed chimerism. Semi-automated PCR analyses using the appropriate hardware allowed moreover a high sample throughput.41,44,45,46,47 This made it possible to study chimerism in all patients and in short time intervals (already early) after transplantation. In this way, accurate monitoring of engraftment as well as surveillance of impending graft rejection in patients transplanted for nonmalignant disease has become possible. Whether STR-based analyses of post-transplant chimerism with a sensitivity of 1–5% are also suitable to identify patients with malignant disease and imminent relapse will be discussed below.
Recently, a real-time PCR assay for the analysis of the SRY gene on the Y chromosome has been established, which allows the identification of male DNA in the background of female DNA at very low levels.48 A similar method was reported by Fehse et al49 for the evaluation of post-transplant chimerism. Thiede reported to detect one male cell in the background of 100 000 female cells using a quantitative real-time PCR for the SRY gene on the Y chromosome.50 These techniques increased the sensitivity enormously. However, increasing the sensitivity allowed the detection of recipient hematopoietic cells in virtually all patients post transplant. Using endpoint PCR to assess a single gene did not offer the possibility of measuring chimerism quantitatively and thus made it impossible to assess its dynamics. For this reason, earlier studies could not rule out the impact of mixed chimerism on the clinical outcome.51,52 As modern real-time PCR now allows one to follow the dynamics of mixed chimerism already at very low levels in the individual patient, this problem might be overcome in future studies.50 However, this technique is only suitable for male patients being transplanted from a female donor, which occurs in less than 50%.
Most recently, new real-time PCR techniques aiming at the amplification of ‘single-nucleotide polymorphisms’ (SNPs) were established. SNPs are biallelic variants that differ from each other only at a single nucleotide and occur on average every 1.3 kb in the human genome.53 Alizadeh et al54 were the first who reported a set of 11 biallelic SNPs using real-time PCR amplification for chimerism analysis. The limit of detection for the minor cell population was higher than in STR-PCR and was reported to be 0.1%. This study was followed by others demonstrating the possibility of accurate characterization of chimerism by SNP real-time PCR.55,56 In contrast to STR-PCR, where virtually all donor/recipients pairs could be characterized, with this assay only 90% of donor/recipients could currently be discriminated. This real-time PCR has a less quantitative accuracy with a variation coefficient of only 30–50%54,55 compared to 5% of the STR systems.44,46,57,58,59 This does not hamper the analysis when only very low levels of mixed chimerism are needed to be quantified. However, in the range above 5% autologous cells, a variation coefficient of approximately 50% does not yet permit accurate quantitative investigations of the dynamic of mixed chimerism post transplant. Large prospective trials using these new real-time PCR methods are now needed to reveal whether clinical impact of chimerism analysis can be improved. For the time being, fluorescence-based PCR amplification of STR seems to be the gold standard method for post-transplant chimerism surveillance and the great majority of the major studies published have used this technique for the evaluation of post-transplant chimerism.
Chimerism in nonmalignant diseases
Allogeneic stem cell transplantation is the only curative treatment option for many patients with inherited or acquired nonmalignant diseases as thalassemia, sickle cell disease, immunodeficiency diseases, osteopetrosis, storage diseases, severe aplastic anemia, bone marrow failure syndromes and others (for a review, see Section IV in Thomas et al34). The aim of the procedure in these diseases is to achieve sustained engraftment to (i) improve the hematopoietic function, to (ii) correct the immune competence and/or to (iii) increase or normalize the respective enzyme shortage. Therefore a priori, it is not necessary to replace the recipient hematopoietic system completely. The implementation of a state of mixed chimerism is mostly sufficient to substantially improve the patient's well being. Thus, to reduce toxic side effects, most conditioning regimens are less myeloablative and thereby mixed chimerism is more likely.60,61,62,63 As a consequence, graft rejection or nonengraftment remained the major causes of treatment failures in this diseases. Sensitization to minor histocompatibility antigens by prior blood product transfusion might increase this danger. The rapid development of complete chimerism in NK and T cells seems to play an important role in achieving sustained engraftment especially in patients who were treated with a dose reduced conditioning regimen.64,65,66,67
Hereditary anemias caused by β-thalassemia and sickle cell disease are the most common genetic diseases. Large studies evaluating the impact of mixed chimerism on graft rejection in patients with thalassemia were published, mostly performed by the Pesaro group in Italy. The first analysis was published in 1992 by Nesci et al, reporting 74 patients who underwent allogeneic bone marrow transplantation from HLA-identical sibling donors. Chimerism was investigated at 2, 6 and 12 months. It was found that all patients who developed more than 30% mixed chimerism at any time finally rejected the graft.68 Amrolia et al69 found in their study on 35 children with thalassemia that patients who showed more than 15% autologous cells at 3 months post transplant were more likely to reject the graft. These results could not be confirmed by smaller series of other investigators.70 Again, the Pesaro group could show in their most recent update of 335 patients with a minimum follow-up of 2 years, that the incidence of mixed chimerism was 32.2% at 2 months. None of the 227 patients with complete chimerism rejected the graft, whereas 35 out of 108 patients with mixed chimerism at the same time lost the graft.71 Rejection was related to the amount of residual host cells at 2 months. Nearly all patients whose host cells exceeded more than 25% rejected their graft with consecutive autologous marrow reconstitution and transfusion dependency. Out of 335 patients, 34 developed persistent mixed chimerism beyond 2 years post transplant. Interestingly, in 15 of these patients residual host cells increased over 25% in the course of follow-up beyond 2 years, although the patients remained transfusion independent.72 Thus, after tolerance has been established between residual host and donor immune system, graft rejection has become unlikely.
Although allogeneic transplantation in patients with sickle cell disease (SCD) is the only curative treatment option,73,74,75 there are far less transplantations performed than in patients with thalassemia. In a multicenter study including 50 patients who were transplanted for sickle cell disease in 24 centers in Europe and the United States, the probabilities of disease-free survival and overall survival were 84 and 94%, respectively.76 The cumulative incidence of graft rejection was 10%. This rejection rate was confirmed by Vermylen et al.77 In an elaborate evaluation of the updated multicentre trial from Walters et al,78 the authors concluded that 10% of donor cell engraftment seemed to be necessary for effective treatment of sickle cell disease in patients who were transplanted with a HbAA donor, whereas levels of mixed chimerism as high as 30–40% may be required in patients who were grafted with a heterozygous HbAS donor. Taken together, patients with hereditary anemia who developed increasing mixed chimerism were more likely to reject their grafts. An example how impending graft rejection could be elucidated by STR-based chimerism analysis is given in Figure 1. Recently, a first report was published, showing that impending graft rejection in sickle cell disease can be avoided by donor lymphocyte infusion based on the serial detection of chimerism.79
Transplantation for severe aplastic anemia (SAA) is usually performed using a nonmyeloablative conditioning regimen. Therefore, mixed chimerism is a common finding. Several retrospective studies have been performed during the last 20 years, reporting in general that mixed chimerism is more associated with graft rejection.63,80,81,82 There are no reports about the threshold of donor cells needed to overcome the disease as is reported for thalassemia and sickle cell disease. We have performed a prospective trial in 32 children transplanted for SAA. Chimerism was assessed by fluorescence-based STR PCR weekly during the first 100 days and thereafter once a month. After the first two children who developed increasing mixed chimerism finally rejected their graft, we decided to start immunotherapy by low-dose donor lymphocyte infusion (DLI) when the amount of autologous cells exceeded more than 30%. In the following patients who again developed increasing mixed chimerism, graft rejection could be prevented by this approach.83 The same strategy was reported by Woodard and co-workers who also implemented pre-emptive DLI on the basis of increasing mixed chimerism to improve and stabilize engraftment after haploidentical transplantation in children with SAA.84 In summary, monitoring of chimerism after transplantation for SAA is feasible and offers the possibility for pre-emptive immunotherapy when graft rejection is impending by low-dose DLI with a calculable risk to induce GVHD.
There are many more other inherited and acquired diseases of early childhood, for example, Wiskott Aldrich syndrome, Hurler's syndrome, X-linked adreno leukodystrophia, metachromatic leukodystrophia, malignant osteopetrosis, bone marrow failure syndromes, lymphophagocytic lymphohistiocytosis and other rare diseases, which can be cured by allogeneic stem cell transplantation. There are no prospective trials published revealing the impact of mixed chimerism in these diseases. It is reported that mixed chimerism is observed in up to 50% of the cases and it is known that mixed chimerism even in the range of only 10–20% donor cells is sufficient to significantly improve the clinical performance and well being of these patients. Mixed chimerism can increase and decrease during the time of follow-up without specific intervention;85 however, late graft rejection is observed even after (more than) 2 years from transplant in patients with increasing mixed chimerism (P Bader, unpublished observation).
Our Tübingen strategy therefore is to monitor these patients every week until engraftment, thereafter every second week until day 100. Patients who became complete chimeras during the first 100 days were followed every 2 months during the first 2 years. If patients develop increasing mixed chimerism that exceeds more than 30%, pre-emptive DLI will be offered. Thus far, we have followed the post-transplant course of 54 children transplanted for a variety of nonmalignant diseases by this approach. In all, 28/54 were complete chimeras at all time points investigated, 2/54 failed to engraft and recovered autologous and 20 patients developed increasing mixed chimerism. Altogether, 15/20 received additional low-dose DLI; 11 responded with their chimerism and decreased below 30% and remained in remission, three developed a partial remission and one patient did not respond and rejected the graft. Most importantly, GVHD did not occur in any of the treated patients.86 We therefore recommend timely monitoring of post-transplant chimerism and adjuvant immunotherapy to reliably avoid graft rejection in children transplanted for these rare entities of nonmalignant diseases.
Chimerism in malignant diseases
Molecular evidence of persisting or reappearing recipient cells may be a reflection of either survival of leukemic cells or of survival of normal host hematopoietic cells or a combination of both. Surviving host hematopoietic cells may in turn facilitate the re-emergence of a malignant cell clone by inhibiting immunocompetent donor effector cells. For patients with CML, it could be clearly demonstrated that reappearance of host hematopoietic cells in the mononuclear cell fraction preceded hematological relapse87,88,89,90 Therefore, mixed chimerism has been considered to reduce the graft-versus-leukemia effect (GVL) in this particular group of patients.87,88,91
In patients with acute leukemias and MDS, several early studies have left the question unanswered whether patients with mixed chimerism do have an increased risk of relapse.37,39,92,93,94,95 In the middle of the 90s, it was realized that evolution of chimerism is a dynamic process and chimerism analysis should be carried out serially in short time intervals. Using STR–PCR-based serial analysis of microsatellite regions in short time intervals, it could be shown that patients with rapidly increasing mixed chimerism have the highest risk of relapse.13,14,15 These reports could be confirmed by others,96,97,98,99 whereas some studies did not find a correlation between chimerism and relapse.22,38,100,101 These discrepancies may partly be explained with sampling protocols used in the studies. Investigations of subpopulations in patients with acute leukemias showed that there might also be a difference between adult and pediatric patients. Guimond et al could demonstrate that mixed chimerism in T- and NK-cell subpopulations can frequently be found in pediatric patients with leukemia relapse, but not in children in remission. In contrast, mixed chimerism in these subsets was not found in adult patients with relapse.102 In our own study, we could show that persistent mixed chimerism in the early post-transplant period is caused predominantly by normal recipient hematopoietic cells.103 Its increase precedes the reappearance of the underlying disease. These findings therefore support the hypothesis that a state of mixed hematopoietic chimerism may reduce the clinical GVL effect of alloreactive donor-derived effector cells also in patients with acute leukemias and MDS, and thus facilitate the proliferation of residual malignant cells that may have survived the preparative regimen. Barrios et al104 could prove in 133 patients with acute leukemias that patients with increasing mixed chimerism have a significantly elevated risk to develop relapse. Based on these studies, several consecutive trials were initiated, evaluating the possibility to prevent relapse by pre-emptive immunotherapy on the basis of chimerism analysis in patients with acute leukemias.96,99,105,106,107,108 Most recently, our group could show in 163 children with ALL that STR-based chimerism analysis in short time interval is able to define a great cohort of children with impending relapse and also that overt relapse, in principle, could be prevented by pre-emptive immunotherapy on the basis of increasing mixed chimerism.109 However, these analysis showed also that (i) it was not possible to realize impending relapse in all patients and (ii) the time interval between the conversion of chimerism and relapse can be very short.
Chimerism analysis does provide information about the alloreactivity and/or tolerance induction of the graft, and thereby serves more likely as a ‘prognostic factor’ than as an indirect marker for minimal residual disease (MRD). It is moreover, important to stress that, due to its low sensitivity of about 1%, chimerism analysis is not a reliable procedure for the detection of MRD.
It could be shown in children transplanted for ALL that the level of MRD prior to transplant has a significant impact on post-transplant outcome.110,111,112 Patients with high level MRD at the time of transplant (>10−3 malignant cells in the background of nonmalignant cells) could be rarely cured. Most likely, neither the conditioning nor the alloreactive potential of the graft could clear the disease. In this group, relapse is also occurring although patients are complete chimeras throughout the follow-up. On the other hand, in patients who have a low MRD burden (<10−3 malignant cells in the background of nonmalignant cells), residual disease can be controlled by a conversion of mixed chimerism to complete chimerism, for example, by pre-emptive immunotherapy. This is illustrated in Figures 2 and 3.
MRD should be monitored using disease-specific PCR techniques as, for example, TCR- or IG- gene rearrangements for ALL and BCR/ABL fusion mRNA transcripts for CML (for reviews, see van Dongen et al113, Gabert et al114 and van der Velden et al115). When a disease-specific marker is not available, for example, regularly in patients with AML, chimerism analysis in cell subpopulations may serve as a surrogate marker for MRD. A very elegant approach was presented by Thiede et al,116,117 who could show that mixed chimerism in CD34-positive cells is predictive for relapse in patients with AML and ALL in peripheral blood. They could show that increasing autologous cells within this subset precedes relapse with a median interval of 52 days (range 12–97).118 To enrich this rare subpopulation in the periphery, however, 50 ml of blood is needed, which limits the applicability of this procedure to adult patients only. Mattsson and coworkers performed a prospective analysis in 30 patients with AML and MDS. They have investigated chimerism in CD33-, CD7- or CD45-positive cells and found significantly more relapses in patients whose subpopulation was mixed, compared to patients with complete chimerism.119 In ALL patients, several studies have been performed evaluating the impact of mixed chimerism after enrichment of the cell population carrying the leukemic phenotype (possible targets could be: CD10, CD19, CD34 for precursor B-ALL, CD3, CD4, CD5 and CD8 for T-lineage ALL).28,120,121,122,123 These studies showed a remarkable correlation between minimal residual disease and mixed chimerism in the respective subset. However, large studies in ALL patients, indicating the predictive value of mixed chimerism in different subsets for the individual patient with regard to disease recurrence, are yet missing.
Taken together, serial and quantitative analysis of chimerism in the whole peripheral blood by STR–PCR allows the identification of patients at the highest risk for relapse. However, not all patients can be highlighted and the time interval between onset of mixed chimerism and relapse can be very short. Therefore, it is essential to perform these analyses weekly during the first 100, better during the first 200, days since the majority of relapses occurs during this time. Performing chimerism analysis in subpopulations increases the sensitivity of the approach enormously. In this setting, chimerism analysis can be considered as a surrogate marker for minimal residual disease. Combining chimerism and MRD analysis does allow accurate documentation of engraftment and surveillance of post-transplant remission status, thus providing a rational basis for individual pre-emptive immunotherapy strategies to prevent recurrence of the underlying disease.
Chimerism in nonmyeloablative transplant regimens for malignant diseases
In contrast to conventional stem cell transplant procedures that use high doses of radiation and/or chemotherapy to eradicate recipient immune system as well as the underlying disease, this approach is based on graft-versus-host-effects for disease eradication. Since 1997 different regimens have been established, all resulting in initial mixed chimerism in the majority of patients.124,125,126,127
Complete chimerism is likely necessary to control the malignant disease.124 To convert mixed chimerism into complete chimerism, repetitive DLIs are performed.128,129,130,131 While patients rapidly achieved high donor chimerism, the majority remained mixed chimeras during the first 6 months.132,133 Pediatric patients with mixed chimerism in T-cell and NK-cell fraction at day +28 post transplant seemed to be more likely to reject the graft.134 Bornhäuser et al135 could show that patients with NK-cell donor chimerism below 75% on days 10–30 after SCT more often rejected their grafts than those with more than 75%. Most recently, Baron et al could show that NK- and T-cell chimerism levels below 50% were significantly associated with higher risk for graft rejection.132 The impact of sustained mixed chimerism is not yet cleared. Keil et al66 demonstrated a significantly higher risk of relapse with mixed T-cell chimerism after nonmyeloablative conditioning and Girgis et al136 found a trend towards increased relapse risk in mixed chimeras on day +30. To finally elucidate the impact of chimerism evolution for the prediction of relapse, more and larger studies are needed in patients with uniform diseases and conditioning regimens.
Taken together, chimerism analysis should be performed in cell subpopulations allowing the investigation of at least the myeloid compartment, T cells and NK cells. These analyses should be frequently performed until predominantly donor chimerism is achieved. Bornhäuser et al135 were performing these investigations twice a week, the Seattle group every second week until day 84. After stable conditions were achieved, the intervals were lengthened.132 In the report of the National Marrow Donor Program (NMDP) and the International Bone Marrow Transplant Registry (IBMTR), the importance of T-cell chimerism was emphasized. Analysis of chimerism in subsets was recommended in 2–4 weeks interval until stable and sustained engraftment is achieved.85
Chimerism analyses are now routinely performed for the surveillance of engraftment. These analyses are frequently used as indicators for the recurrence of the underlying nonmalignant or malignant disease. In most recent years, these investigations have become the basis for treatment intervention, for example, to avoid graft rejection, to maintain engraftment and to treat imminent relapse by pre-emptive immunotherapy (see Table 3). We are performing these analyses using a quantitative fluorescence-based STR–PCR with capillary electrophoresis for PCR product resolution. The investigations are performed weekly during engraftment in malignant and nonmalignant diseases in whole peripheral blood. When graft failure or graft rejection is clinically suspicious, analysis of subsets is performed.
If chimerism analysis based on STR amplification is used for remission surveillance in malignant diseases, it is most important that the intervals are kept short. We recommend weekly intervals until day 200 post transplant. Thereafter, the intervals are lengthened to monthly investigations during the first 18 months post transplant. After 100 days, in nonmalignant diseases the investigations are performed every second month until 24 months post transplant. In patients with increasing mixed chimerism, additional immunotherapy is performed to augment the alloreactive potential of the graft (see Figure 4). Besides chimerism investigations, MRD analyses are performed in bone marrow and peripheral blood samples according to the underlying disease with leukemia clone-specific PCR systems.
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This work was supported by the ‘Deutsche Krebshilfe’ (grants 70-2178 and 50-2737), Bonn, Germany.
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Bader, P., Niethammer, D., Willasch, A. et al. How and when should we monitor chimerism after allogeneic stem cell transplantation?. Bone Marrow Transplant 35, 107–119 (2005). https://doi.org/10.1038/sj.bmt.1704715
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