Children with leukemias and increasing mixed chimerism (increasing MC) after allogeneic stem cell transplantation have the highest risk to relapse. Early immunological intervention was found to be effective in these cases. To substantiate this on a defined group of pediatric acute myelogenous leukemia (AML) patients, we performed serial analysis of post transplant chimerism and pre-emptive immunotherapy in patients with increasing MC. In total, 81 children were monitored, 62 patients revealed complete chimerism (CC), low-level MC or decreasing MC. Increasing MC was detected in 19 cases. Despite early immunological intervention relapse was still significantly more frequent in patients with increasing MC (9/19) than in patients with CC, low-level or decreasing MC (8/62, P<0.005). The probability of 3-year event-free survival (EFS) was 52% for all patients (n=81), 59% for patients with CC, low-level MC, 60% for patients with decreasing MC (n=62), and 28% for patients with increasing MC (n=19, P<0.005). Patients with increasing MC who received early immunological intervention showed a significantly enhanced probability for event-free survival (pEFS 36%, n=15) compared to patients with increasing MC without intervention (pEFS 0%, n=4, P<0.05). These results prove that pediatric AML patients with increasing MC are at highest risk for relapse and that early immunological intervention can prevent relapse in these patients.
Allogeneic stem cell transplantation (allo-SCT) has evolved to a convincing treatment modality for children with a high-risk acute myelogenous leukemia (AML), but the success is still mainly threatened by relapses.1 In case of relapse, an additional allo-SCT may provide a small curative chance, but success is limited by the high lethality.2,3,4,5 Therefore, a wide range of procedures has been tried in patients with relapses, all following the same principle to control malignant cells by engendering a graft-versus-leukemia (GVL) effect.2,3,4,6,7,8,9,10, 11,12,13 These treatment regimens were based on (1) cessation of cyclosporine A (CSA) or other immunosuppressive drugs,14,15 (2) administration of lymphocyte activating cytokines6,11,16 and (3) additional infusion of donor lymphocyte (DLI) eventually supported by cytokines.17,18 These attempts are convincing in patients with chronic myelogenous leukemias (CML)13,19,20,21,22 but still questionable in patients with relapsed acute leukemias.9,11,18,23 A major risk of this approach is the induction of severe graft-versus-host disease (GVHD), caused by the high cell numbers given, which are necessary in the treatment of an open relapse.
Vice versa, pre-emptive treatment of an impending relapse might allow DLI with low cell numbers, which in turn might prevent the occurrence of GVHD.18,24,25,26 In previous studies we found evidence that patients with different types of high-risk leukemias and myelodysplastic syndromes (MDS) who developed a dynamic increase of autologous hematopoietic cells (increasing mixed chimerism, increasing MC) in peripheral blood relapse significantly more often (P<0.0001) than patients with a stable complete chimerism (CC).27,28
In a small series of such increasing MC patients, the relapse rate could be reduced by termination of CSA or application of low-dose DLI. These findings supported the hypothesis that patients with low leukemic cell numbers might be more effectively controlled by immune modulatory treatment modalities than those patients with acute leukemia who had developed an open relapse post transplant.
To prove this hypothesis especially in AML pediatric patients after allo-SCT, we performed a prospective multicenter trial to investigate two important questions: (1) does increasing MC significantly predict outcome and (2) can outcome be improved by early immunological intervention?
Patients and methods
Between January 1996 and December 2001, post transplant samples of 81 children who had received allo-SCT for AML were referred from 13 pediatric transplant centers in Germany to the study center in Tübingen. The study protocol was approved by the Clinical Ethics Committee of the University of Tübingen, and the study was performed according to the principles of the Declaration of Helsinki. Informed consent was obtained from the patients and parents according to the institutional guidelines. Data were obtained for analysis until May 2002. Table 1 summarizes the patient characteristics, the types of stem cell donors, the sources of stem cells, and the conditioning regimens.
Chimerism assays and immunotherapy
Hematopoietic chimerism of each patient was assayed in the peripheral blood at weekly intervals during the first 100 days and monthly thereafter. A previously described semiquantitative PCR approach based on the amplification of STR markers was used.29,30 Patients who showed increasing MC post transplant, as defined in detail below, were offered immunotherapy according to the study protocol.31 We decided against performing a randomized trial, which would have given the greatest evidence as we have discussed in detail elsewhere.32 This was because (i) we observed almost solely fatal outcome in children with increasing MC and (ii) we had experienced that relapse could be prevented by pre-emptive immunotherapy in some of these patients without serious side effects.28,31
Immunotherapy for patients receiving CSA consisted of immediate discontinuation of the immunosuppressive agent. Chimerism was further assayed weekly until CC status was restored. If MC showed an additional increase of more than 5% after cessation of CSA, a DLI was given.
Immunotherapy for patients not receiving CSA consisted of DLI as frontline treatment. The cell dose administered was based on the number and potential severity of HLA mismatches between the donor and recipient. The study design prescribed to administer 1 × 105 CD3-positive cells per kilogram of body weight in case of an MFD, 5 × 104 in case of a MUD and 2.5 × 104 in case of MMUD or MMFD. After DLI, chimerism status was assayed weekly until CC status was restored. Patients who would have shown a further increase in MC were scheduled to receive an additional DLI after at least 3 weeks had elapsed. However, this was not necessary in any of these patients, because they had either relapsed within this time span or responded.
Definition of chimerism status and response
The patients were differentiated exclusively on the basis of serial analysis by STR-PCR, within the limits of sensitivity (approximately 1%). Patients who showed no evidence of autologous cells at any time post transplant were considered to have CC. Patients who manifested weak autologous signals not exceeding 1% were defined as having low-level MC. Patients who showed autologous signals immediately post transplant that decreased spontaneously during follow-up were classified as having decreasing MC. Patients who showed a significant increase (5% or more) in the proportion of autologous cells between sequential assessments were defined as having increasing MC. Response was defined as a return to CC. GVHD was graded according to clinical criteria as previously described.33,34
The probability of survival and of event- (EFS) and relapse-free survival was estimated by the Kaplan–Meier method.35 Univariate analyses of prognostic factors were performed by using the log-rank test and Fisher's exact test. Multivariate analyses have been performed using the Cox proportional hazards model to analyze different risk factors simultaneously.
In total, 81 patients were included in the analysis. These patients showed either CC (n=35), low-level MC (n=22), decreasing MC (n=5) or increasing MC (n=19). Early immunological intervention was recommended to all patients with increasing MC but was performed in only 15 of those cases. Although the study protocol assigned all patients with increasing MC to be treated as described above, each transplant center made its own final decision on whether to start immunotherapy. In four patients physicians decided against treatment for different reasons. In 3/4 patients a DLI from the donor was not available on time, and 1/4 patients suffered from severe infection and toxicity.
Relapses occurred significantly more often in the group of patients with increasing MC (7/19) than in patients with CC, low-level MC or decreasing MC (8/62, P<0.01). Further analysis of the increasing MC group revealed a striking difference between treated and untreated patients. In total, 6/15 patients with increasing MC who received early immunological intervention remained in complete remission, 2/15 died from transplant-related causes, and 7/15 relapsed. A total of 4/4 patients with increasing MC who did not receive prophylactic treatment either rejected their graft (n=2) or relapsed (n=2) and none of these patients survived. Survival rate in treated compared to untreated patients turned out to differ significantly (log rank: P<0.05; Table 2).
Patients who responded to cessation of CSA as frontline therapy generally showed a decrease of autologous DNA in the peripheral blood approximately 1 week after cessation of CSA. Patients who responded to DLI did not show a decrease of autologous DNA until 2 to 3 weeks after treatment.
In seven patients, the hematological relapse could not be anticipated by the serial analysis of hematopoietic chimerism. In 2/7 patients, the relapse occurred beyond day +100 (day 208 and 543). In these patients, the monthly intervals between the respective analyses beyond day +100 might have been too long. Five out of seven patients developed relapse before day +100 post transplant. Serial analysis of chimerism in weekly intervals was not able to identify these high-risk patients. They all developed a fulminate relapse and died.
The probability of estimated 3-year EFS was 52% for all patients (n=81, Figure 1). Patients who showed CC, low-level MC (n=57) or decreasing MC (n=5) showed significantly higher 3-year EFS estimates (59 and 60%, resp.) than patients with increasing MC (n=19, 28%, Figure 2).
Patients with increasing MC who received additional immunotherapy (n=15) had an estimated 3-year EFS of 36% and patients with increasing MC who did not receive additional treatment (n=4) had an estimated 3-year EFS of 0% (P<0.05; Figure 3).
Univariate analyses revealed that outcome was also affected by the type of donor and state of remission. The 3-year EFS estimates were 73% for MFD (n=28), 51% for MUD (n=32), 15% for MMFD (n=13), 50% for MMUD (n=8) (Log rank: P<0.05), 69% for CR1 (n=34), 48% for CR2 (n=29), 40% for>CR2 (n=5), and 20% for patients where a remission could not be achieved prior to transplantation (n=13) (Log rank: P<0.05). Patients who received a busulfan containing regimen (n=71) had an estimated 3-year EFS of 56% compared to 27% in patients who were treated with total body irradiation (n=10). This difference was barely not significant (Log rank: P=0.07).
Toxicity and GVHD
After immunotherapy, 10 of the 15 patients developed acute GVHD with different severity. Of the 10 patients who developed GVHD, four survived in complete remission, five died of relapsed disease, one died of transplant-related causes and one developed chronic GVHD (Tables 3 and 4). Of the five children who did not develop acute GVHD after immunological intervention, two survived in complete remission, two died after relapse, and one died of transplant-related causes (Table 5).
We found a relatively high TRM with respect to all patients included in this study (Table 2). Although there is a trend to a higher TRM rate in patients with CC and low level MC (14/57 patients; 25%), compared to 1/5 patients with decreasing MC (20%), or to 2/19 patients with increasing MC (11%) this difference was not significant (P=0.388). In a proportional hazards analysis, the five patients with MMUD were disregarded to avoid spurious results; neither the donor, nor the remission status, nor the conditioning regimen (TBI vs BUS) had influence on the TRM rate. However, no T-cell depletion decreased the risk for TRM by a factor 0.169 (95 CI: 0.05–0.579; P<0.005) compared to T-cell depletion of the graft.
The efficacy of immunotherapy after allo-SCT for acute leukemia is still a matter of debate.11,12,13,18,36 Compared to patients with chronic myelogenous leukemia (CML) where DLI has been demonstrated to be effective,13,20,21,22 experience with immunotherapy in patients with acute leukemias has shown that DLI initiated in a stage of frank hematological relapse only rarely induces complete remission (8% of patients with acute lymphoblastic leukemia (ALL) and 22% of patients with AML).14,37,38,39 If tumor burden is effectively reduced by chemotherapy prior to DLI, the rate of complete response can be significantly improved (33% in ALL and 37% in AML).40,41 This gives evidence that immunotherapy is more effective when the amount of malignant cells is still very small so that the limited number of lymphocytes to which clinicians are restricted to avoid severe GVHD efficiently overcomes relapse.18,25,26 Hence, it is desirable to identify those patients who represent the high-risk group for relapse at the very early stage of its development, so that additional immunotherapy might be more effective even with low doses of DLI. Patients with increasing MC represent such high-risk patients and can be identified with short-term monitoring of hematopoietic chimerism. These investigations can serve as a basis for additional immunotherapy.
Our prospective study on children who received allo-SCT for high-risk AML is based on 81 evaluable patients and therefore represents a relative large cohort for this rare entity in children. Seven out of 26 patients could not be identified in advance as high-risk patients for impending relapse. Two of them relapsed, beyond day +200 (days 208 and 543) when chimerism was monitored only at monthly intervals. Thus, the time span between last analysis of chimerism and relapse might have been too long in these cases, but 5/7 patients developed a relapse before day +100. Even weekly analysis of chimerism was not able to identify these patients in advance. We hypothesize whether the pre-transplant leukemia burden was so overwhelmingly high that the transplanted immune system was not able to control the residual disease. It must be accepted that some children with aggressive AML developed a fulminate relapse, which could neither be identified in advance nor influenced by a pre-emptive immunotherapy with any method presently available.
We also acknowledge that this study was not randomized for early immunological intervention due to the fact that prior results on patients after allo-SCT with heterogeneous entities of severe hematological malignancies already showed significant results.31 Early immunotherapy was recommended for all patients with increasing MC as has been argued in detail elsewhere.32 Therefore, comparison can only be made between treated patients and patients who were not treated for different reasons. Consequently, a selection bias as a factor in our results cannot be ruled out. Nonetheless, the data were gained in a prospective study and substantiate recent findings.
Furthermore, our previous study revealed that MC first developed within various subgroups of peripheral hematopoietic cells. Within the first year of observation, the reappearance of leukemia relapse is regularly preceded by a dynamic increase of recipient cells of different hematopoietic cell subpopulations.
We recently showed that the type of normal autologous hematopoietic cells that initially dominate in increase greatly differ individually and more often represent just normal autologous granulocytes or monocytes.42 However, this increase of normal autologous cells very reliably predicts relapse and can therefore be taken as a decisive signal that development of relapse has commenced without a chance for self-limitation.
These results are in line with reports from solid organ transplants where mixed hematopoietic chimerism seems to be associated with the development of graft tolerance.43 We therefore hypothesize that this immune tolerance might be accompanied with a loss of the GVL effect, thus giving low numbers of residual leukemia cells a novel chance to expand. An immunological intervention just enough to overcome this fatal immune tolerance might then be effective in suppressing an imminent relapse at this very early stage. These findings and the underlying hypothesis can be supported by recent experimental findings in animals. Mice sublethally irradiated and coinjected with allogeneic bone marrow and leukemic blast cells develop MC followed by leukemia. In contrast, mice supra-lethally irradiated and subsequently treated identically maintain a CC and remain free from leukemic blasts.44 These interesting results substantiate a model that the phenotype of increasing MC is based on an increase of autologous cells and suggests that immune tolerance is a crucial factor for the expansion of leukemic blasts.
In conclusion, this study confirms that semiquantitative and serial analysis of hematopoietic chimerism in peripheral blood can detect at a high rate the critical increasing MC phenotype, which indicates AML patients after allo-SCT with highest risk for relapse. Furthermore, early immunological intervention might improve their outcome. However, future trials are necessary to optimize treatment modalities.
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We thank all participating centers and all colleagues who included less than four patients in the study: Prof Dr W Holter, University Children's Hospital Erlangen; Prof Dr S Müller-Weihrich, University Children's Hospital München-Schwabing; Dr I Schmidt, München v Haunersches Kinderspital; Prof Dr C Bender-Götze, München-Poliklinik. This work was supported by the ‘Deutsche Krebshilfe’ (70-2178-Kl I)’, Bonn, Germany, the ‘Fortüne-Programm’ of the University of Tuebingen (925-0-0) and by the ‘Förderverein für Krebskranke Kinder Tübingen e.V.’, Tübingen, Germany. We are indebted to Nicole Ata for the critical reading of the manuscript and helpful suggestions.
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Bader, P., Kreyenberg, H., Hoelle, W. et al. Increasing mixed chimerism defines a high-risk group of childhood acute myelogenous leukemia patients after allogeneic stem cell transplantation where pre-emptive immunotherapy may be effective. Bone Marrow Transplant 33, 815–821 (2004). https://doi.org/10.1038/sj.bmt.1704444
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